Nicolas Bertho
email: nicolas.bertho@inrae.fr

François Meurens

The pig as a medical model for acquired respiratory diseases and dysfunction: an immunological perspective

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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Porcine Respiratory System Structure

The size and the weight of the pig is age-, sex-and breed-dependent. Some minipig breeds like the Yucatan or the Göttingen present adult pigs with size and weight similar to human adults making the breeds attractive in biomedical research [START_REF] Meurens | The pig: A model for human infectious diseases[END_REF][START_REF] Swindle | Swine as Models in Biomedical Research and Toxicology Testing[END_REF]. Overall, the porcine anatomy and physiology are quite similar to human anatomy and physiology, both species are all-eating for instance [START_REF] Käser | Contribution of the swine model in the study of human sexually transmitted infections[END_REF][START_REF] Meurens | The pig: A model for human infectious diseases[END_REF][START_REF] Swindle | Swine as Models in Biomedical Research and Toxicology Testing[END_REF]. Moreover, pigs are widely available with usually manageable size allowing for smooth handling and easy experimental interventions.

Regarding specifically the porcine respiratory tract, the pig has been extensively characterized and compared with the human one [START_REF] Judge | Anatomy and bronchoscopy of the porcine lung: A model for translational respiratory medicine[END_REF][START_REF] Krejci | The respiratory tract in pigs and its immune system: A review[END_REF] as well as in exhaustive reviews that were assessing its potential as a model for cystic fibrosis [START_REF] Rogers | The porcine lung as a potential model for cystic fibrosis[END_REF] and asthma [START_REF] Kirschvink | Use of Alternative Animals as Asthma Models[END_REF]. The respiratory tract can be divided into the upper and lower respiratory tracts. The upper respiratory tract is including the nasal cavities, the sinuses, the nasopharynx, the larynx and the trachea while the lower respiratory tract includes overall the lung with the bronchi, the bronchioles, the terminal and respiratory bronchioles, and alveoli. Air enters the porcine respiratory tract through round nostrils and a pair of nasal cavities situated in the snout (rostrum). In the nasal cavities, the epithelium is typically pseudostratified with ciliated columnar cells. The epithelium contains loose lymphocytes, lympho-reticular tissue aggregates and tuboalveolar glands. Regarding submucosal glands in nasal turbinates and trachea, some differences have been shown between pigs and humans using the porcine cystic fibrosis model [START_REF] Cho | Defective fluid secretion from submucosal glands of nasal turbinates from CFTR -/-and CFTRΔ ΔF508/ΔF508 pigs[END_REF]. Similarly, to humans, pigs have ethmoid and maxillary sinuses at birth and develop frontal and sphenoid sinuses [START_REF] Sisson | Porcine osteology: skull[END_REF]. Then, after its circulation in the nasal cavities, the air moves through the nasopharyngeal tube into the pharynx with the possibility to gain access to the esophagus. The respiratory part of the pharynx, called nasopharynx, also presents a pseudostratified ciliated columnar epithelium with goblet cells. In the upper respiratory tract, its nasal-associated lymphoid tissue (NALT) resembles the human's Waldeyer ring and pigs, like humans, possess several tonsils (veli palatine, pharyngea, tubaria, paraepiglotica and lingualis) [START_REF] Horter | A review of porcine tonsils in immunity and disease[END_REF][START_REF] Liebler-Tenorio | MALT structure and function in farm animals[END_REF][START_REF] Swindle | Swine as Models in Biomedical Research and Toxicology Testing[END_REF]. This lymphoid tissue is comprised of the Lamina propria mucosae as well as fine glandules. Then, the larynx links the nasopharynx and the lower respiratory tract, including epiglotis and vocal cords. In the larynx the mucosa showed again a pseudostratified columnar epithelium with isolated goblet cells. In the submucosa of epiglottis, plicae aryepiglotticae and vestibulum larynges, an accumulation of lymphoid tissue is observed. The trachea consists of 32-36 C-shaped rings of hyaline cartilage with strong fibro-elastic membranes observed between the rings. The trachea shows a ciliated pseudostratified columnar epithelium and isolated goblet cells. Below, in the mucosa, small islets of lympho-reticular tissue and combined tubo-alveolar glands are observed. Regarding the gross anatomy of the porcine lung, two lobes on the left sides and four on the right have been described [START_REF] Rogers | The porcine lung as a potential model for cystic fibrosis[END_REF][START_REF] Swindle | Swine as Models in Biomedical Research and Toxicology Testing[END_REF]. On the left side, the lobes are designated as left cranial and caudal and on the right as right cranial, right middle, right caudal and right accessory. Interestingly, the right cranial lobe is directly linked to the trachea. Looking at subgross anatomy, pig like human lung, and in contrast to murine lung shows extensive intralobular and interlobular connective tissue. This tissue joins the bronchi and the main blood vessels to the pleural surface [START_REF] Tyler | Small Airways and Terminal Units Comparative Subgross Anatomy of Lungs[END_REF]. However, the interlobular collagenous network is incomplete in humans whereas in the pig the interlobular septa are "complete" blocking the collateral ventilation [START_REF] Rogers | The porcine lung as a potential model for cystic fibrosis[END_REF][START_REF] Woolcock | Mechanical factors influencing collateral ventilation in human, dog, and pig lungs[END_REF]. The porcine pleura like its human counterpart is relatively thick and collagenous and has a vascular supply originating from the bronchial arteries [START_REF] Mclaughlin | A study of the subgross pulmonary anatomy in various mammals[END_REF][START_REF] Tyler | Small Airways and Terminal Units Comparative Subgross Anatomy of Lungs[END_REF]. Regarding the lymph nodes (LN) in the thoracic cavity, they are concentrated into four lymphoid centres, two parietal (thoracicum dorsal and ventral) and two visceral (mediastional and bronchale). Moreover, there are the LN adjacent to the bronchi (tracheobronchales dextri, sinistri and medii). While the vascular circulation of the pig follows a common pattern of organization and development with human vascular circulation there is an inverted structure of swine LN compared to their human and murine counterparts. Indeed, in most of the mammalians, including mouse and man, afferent lymph percolates in a centripetal manner from the periphery to the center (hilum) of the node. In swine, the afferent lymph diffuses from the center to the periphery in a centrifugal manner [START_REF] Mcfarlin | Lymph node function and lymphocyte circulation in the pig[END_REF]. In addition, in pig, lymphocytes exit the LN through the high-endothelial venules whereas in mouse and man they exit through the efferent lymphatics [START_REF] Sasaki | The unique ultrastructure of high-endothelial venules in inguinal lymph nodes of the pig[END_REF]. The functional implications of these oddities have not been explored yet. Overall, even if similar to human airways, the porcine airways show small differences [START_REF] Haworth | Adaptation of the pulmonary circulation to extra-uterine life in the pig and its relevance to the human infant[END_REF][START_REF] Mclaughlin | A study of the subgross pulmonary anatomy in various mammals[END_REF][START_REF] Rendas | Growth of pulmonary circulation in normal pig: Structural analysis and cardiopulmonary function[END_REF]: i) the cartilage around porcine airways is more developed than in humans; ii) a lower number of bronchi generations, after the last cartilage plate, has been reported in pigs compared to what is reported in humans; and iii) longer terminal bronchioles and overall less-defined respiratory bronchioles are described. At the microscopic level, porcine lungs show similar cell lineages to human lungs [START_REF] Haworth | Adaptation of the pulmonary circulation to extra-uterine life in the pig and its relevance to the human infant[END_REF][START_REF] Jones | Histochemical Identification Of Glycoproteins In Pig Bronchial Epithelium: (a) Normal And (b) Hypertrophied From Enzootic[END_REF][START_REF] Mills | Development of the airway epithelium and submucosal glands in the pig lung: Changes in epithelial glycoprotein profiles[END_REF][START_REF] Rogers | The porcine lung as a potential model for cystic fibrosis[END_REF][START_REF] Winkler | The neonatal porcine lung: Ultrastructural morphology and postnatal development of the terminal airways and alveolar region[END_REF].

General systemic immunology

Before addressing specifically the porcine lung immunology, a brief overview of the systemic porcine immune system is needed. Comparably to the whole genome comparisons, the immunome analysis demonstrated a greater similarity between human and pig than between human and mouse. However, a peculiarity of swine immune system that can be highlighted is the expansion of the type I IFN gene families, especially the IFNδ and the IFNω [START_REF] Dawson | Structural and functional annotation of the porcine immunome[END_REF]. IFNδ clearly distinguishes pig from human and mouse since pig has 11 functional IFNδ genes and mouse and man have none. IFNδ bind to the same type 1 receptor as IFNα, it has high antiviral and anti-proliferative activities on porcine cells, but not on human cells [START_REF] Lefèvre | Interferon-delta: The first member of a novel type I interferon family[END_REF]. Conversely IFNω separates mouse from the two other species since mouse has no functional IFNω gene, man 1, and pig 7. IFNω presented highly cross-species antiviral (but little anti-proliferative) activity [START_REF] Jennings | Porcine interferon complex and co-evolution with increasing viral pressure after domestication[END_REF][START_REF] Shields | Cross-species genome-wide analysis reveals molecular and functional diversity of the unconventional interferon-ω subtype[END_REF]. A recent review summarized the different porcine cytokines, chemokines and growth factors, and described the tools available to study them [START_REF] Dawson | Porcine cytokines, chemokines and growth factors: 2019 update[END_REF].

Looking more precisely at the different immune cell types, three relatively recent reviews have been published on the porcine innate immune response [START_REF] Mair | The porcine innate immune system: An update[END_REF], mononuclear phagocytes [START_REF] Fairbairn | The mononuclear phagocyte system of the pig as a model for understanding human innate immunity and disease[END_REF] and the B and T lymphocytes development [START_REF] Sinkora | Progress in the use of swine in developmental immunology of B and T lymphocytes[END_REF]. However, we would like here to recall some important swine specific features: Myeloid cells: Neutrophil serine proteases (NSP) have critical roles in neutrophil-associated tissuedestructive diseases. Human and mouse NSP present different peptide substrate specificities [START_REF] Kalupov | Structural characterization of mouse neutrophil serine proteases and identification of their substrate specificities: Relevance to mouse models of human inflammatory diseases[END_REF] whereas porcine NSP, present on the surface of triggered neutrophils and neutrophil extracellular traps (NETs) are efficiently inhibited by human NSP inhibitors [START_REF] Bréa | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases[END_REF]. In addition to neutrophils, porcine basophils and eosinophils can be identified by flow cytometry [START_REF] Blanc | The Composition of Circulating Leukocytes Varies With Age and Melanoma Onset in the MeLiM Pig Biomedical Model[END_REF][START_REF] Haverson | Characterization of monoclonal antibodies specific for monocytes, macrophages and granulocytes from porcine peripheral blood and mucosal tissues[END_REF]. Peripheral blood monocytes present in pig a similar division in CCR2+/CX3CR1-/CD14+/CD163-/MHC-II-and CX3CR1+ CCR2-/CD14-/CD163+/MHC-II+ monocytes [START_REF] Moreno | Porcine monocyte subsets differ in the expression of CCR2 and in their responsiveness to CCL2[END_REF]. When human, mouse and porcine monocytes were compared by a transcriptomic study, porcine CD14+ and CD14-blood monocytes resembled more to their human counterparts than mouse monocytes [START_REF] Fairbairn | Comparative Analysis of Monocyte Subsets in the Pig[END_REF].

Dendritic cells (DC) subpopulations corresponding to cDC1, cDC2, pDC and moDC [START_REF] Guilliams | Dendritic cells, monocytes and macrophages: A unified nomenclature based on ontogeny[END_REF] can be readily identified in blood [START_REF] Auray | Characterization and Transcriptomic Analysis of Porcine Blood Conventional and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific Differences[END_REF], skin [START_REF] Marquet | Pig Skin Includes Dendritic Cell Subsets Transcriptomically Related to Human CD1a and CD14 Dendritic Cells Presenting Different Migrating Behaviors and T Cell Activation Capacities[END_REF], spleen (Soledevila, personal communication), tonsils [START_REF] Soldevila | Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil[END_REF], tracheal epithelium and lung [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF], with minimal species-specific features. The main swine DC peculiarity is the differential expression of TLR3, which is almost exclusively expressed on pDC in swine [START_REF] Auray | Characterization and Transcriptomic Analysis of Porcine Blood Conventional and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific Differences[END_REF][START_REF] Soldevila | Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil[END_REF] but on cDC1 in human [START_REF] Poulin | Characterization of human DNGR-1 + BDCA3 + leukocytes as putative equivalents of mouse CD8α + dendritic cells[END_REF] and mouse [START_REF] Desch | CD103 + pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen[END_REF]. Despite this difference, the calculation of a similarity score between swine, human and mouse cDC1, cDC2 and pDC transcriptomic signatures highlighted that the three human's blood DC populations resembled more to their porcine than to their murine counterparts, especially cDC2, which appears to be the most similar between pig and man [START_REF] Auray | Characterization and Transcriptomic Analysis of Porcine Blood Conventional and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific Differences[END_REF]. Lymphoid cells: It has long been thought that porcine B cells were generated in ileal Peyer's patches, however it is now clear that porcine B lymphopoïesis is located in the bone marrow as for other mammals [START_REF] Sinkora | B Cell Lymphogenesis in Swine Is Located in the Bone Marrow[END_REF]. To note, the porcine B cell development studies are still impaired because of the absence of antibodies recognizing pan-B cells markers such as CD19 and CD20 [START_REF] Dawson | Porcine cluster of differentiation (CD) markers 2018 update[END_REF] and the absence of antibodies discriminating porcine IgG isotypes. Despite these difficulties, the porcine peripheral B lymphocyte differentiation steps have been described: IgM+CD2+CD21+ B cells are composed of naive B cells, IgM+CD2-CD21+ are activated or primed B cells and CD79α+CD2+CD21-or CD2-CD21-represent antibody producing B cells (Sinkora et al., 2013), memory and effector antibody-forming B cells remaining CD79α+CD2+CD21-while CD79α+CD2-CD21-B cells are probably composed of resting plasma cells. In a recent paper [START_REF] Bordet | Macrophage-B Cell Interactions in the Inverted Porcine Lymph Node and Their Response to Porcine Reproductive and Respiratory Syndrome Virus[END_REF], we investigated the structure of the trachea-bronchial inverted porcine LN and, thanks to the conservation of the B cell affinity maturation master-genes expressions (BCL6, Pax5, IRF4, XBP1 and Blimp1), we were able to distinguish the centroblasts, centrocytes, plasmablasts and plasma cells in their respective follicular and extrafollicular LN sublocalisations, as observed in mouse and human (for review see [START_REF] Klein | Germinal centres: Role in B-cell physiology and malignancy[END_REF]). Interestingly, we also identified a specific feature of swine inverted LN which is a centroblasts-like B cell type decorated with surface CD169 proteins [START_REF] Bordet | Macrophage-B Cell Interactions in the Inverted Porcine Lymph Node and Their Response to Porcine Reproductive and Respiratory Syndrome Virus[END_REF], that interact probably with perifollicular macrophages in order to capture antigens and transport them to follicular DC (fDC). This feature might be a consequence of LN inversion in pig. In the regular murine LN, naïve B cells have been shown to play this antigentransporting role [START_REF] Phan | Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation[END_REF]. Follicular DC have not been described so far in pig, however they have been identified in an evolutionary close species, the sheep, and their phenotype appeared similar to murine and human fDC [START_REF] Melzi | Follicular dendritic cell disruption as a novel mechanism of virus-induced immunosuppression[END_REF].

Development of thymic αβT cells follows mice and humans T-cell maturation model [START_REF] Sinkora | Different anti-CD21 antibodies can be used to discriminate developmentally and functionally different subsets of B lymphocytes in circulation of pigs[END_REF]. However, it is important to note that swine possess extrathymic CD4+/CD8α+ T cells, that appear to be regular memory/activated peripheral CD4 T cells [START_REF] Gerner | Porcine T lymphocytes and NK cells -An update[END_REF]. The peripheral blood re-expression of CD8α has been endowed with no specific role. Indeed, so far the same CD4 T cell subtypes have been described in pig, namely Th1, Th2, Th17, Treg expressing the same transcription factors (respectively T-bet, GATA-3, RORγT and FoxP3) than human and murine CD4 T cells (for review see [START_REF] Gerner | Phenotypic and functional differentiation of porcine αβ T cells: Current knowledge and available tools[END_REF]). To note, in swine some clues are in agreement with a B cell activation/Th2 pathways relying more on IL13 than on IL4 [START_REF] Murtaugh | Species specialization in cytokine biology: Is interleukin-4 central to the TH1-TH2 paradigm in swine?[END_REF]. Finally peripheral CD8 T cells expressing Eomesodermin (Eomes), a transcription factor involved in the differentiation and long-term survival of CD8 memory T cells have been described in pig like in mouse and human blood, although these cells are less numerous in swine than in human [START_REF] Rodríguez-Gómez | Expression of T-bet, Eomesodermin and GATA-3 in porcine αβ T cells[END_REF]. Finally, by using CD27 staining, Talker et al were able to distinguish bona fide effector memory cells (CD27 neg ) from naïve and early activated lymphocytes [START_REF] Reutner | CD27 expression discriminates porcine T helper cells with functionally distinct properties[END_REF].

As in other Laurasiatheria, pigs present a high proportion of γδ T cells [START_REF] Binns | Subsets of null and gamma delta T-cell receptor+ T lymphocytes in the blood of young pigs identified by specific monoclonal antibodies[END_REF], paralleled with more D-segments in the TCR delta gene than in human and mouse [START_REF] Dawson | Structural and functional annotation of the porcine immunome[END_REF]. Thus porcine γδ TCR have a strong diversity potential, with no tissue-specificity [START_REF] Holtmeier | Prenatal development of the porcine TCR δ repertoire: Dominant expression of an invariant T cell receptor Vδ3-Jδ3 chain[END_REF] or subset restrictions [START_REF] Stepanova | Porcine T Lymphocytes Can Be Categorized into Two Functionally and Developmentally Distinct Subsets according to Expression of CD2 and Level of TCR[END_REF] unlike in humans and mice. Moreover, conversely to murine and human ones, a consistent proportion of porcine γδ T cells retained a strong expression of GATA3 [START_REF] Rodríguez-Gómez | Expression of T-bet, eomesodermin, and GATA-3 correlates with distinct phenotypes and functional properties in porcine γδ T cells[END_REF]. Invariant NK T cells expressed a semi-invariant TCR which recognizes glycolipids presented on the non-polymorphic CD1d molecules and corresponding either to stress-related self-ligand or to microorganism surface-antigens. Interestingly, iNKT cells frequency [START_REF] Artiaga | Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell-diverse pigs[END_REF] as well as specific CD1d/TCR molecular interactions [START_REF] Yang | Next Generation Sequencing of the Pig αβ TCR Repertoire Identifies the Porcine Invariant NKT Cell Receptor[END_REF] are closer between swine and human than with mouse.

Conversely to the majority of mammals, swine possess an NK cell subset that does not express NKp46 [START_REF] Mair | NKp46 expression discriminates porcine NK cells with different functional properties[END_REF]. This might be relevant here since NKp46 recognizes hemagglutinins (HA) of influenza, parainfluenza, and Sendai virus and that its ligation leads to lysis of infected cells [START_REF] Arnon | The mechanisms controlling the recognition of tumor-and virus-infected cells by NKp46[END_REF]. In swine, NKP46 expression has also been observed on CD3+ cells expressing αβ or γδ TCR but presenting the main functions of NK cells [START_REF] Mair | Porcine CD3+NKp46+lymphocytes have NK-cell characteristics and are present in increased frequencies in the lungs of influenza-infected animals[END_REF]. Cells with a similar phenotype have been described in mice [START_REF] Arnon | The mechanisms controlling the recognition of tumor-and virus-infected cells by NKp46[END_REF] humans [START_REF] Arnon | The mechanisms controlling the recognition of tumor-and virus-infected cells by NKp46[END_REF] and cattle [START_REF] Connelley | NKp46 + CD3 + Cells: A Novel Nonconventional T Cell Subset in Cattle Exhibiting Both NK Cell and T Cell Features[END_REF].

Specific Lung immunology

Macrophages

In all mammalian species, lung macrophages are prominently composed of alveolar macrophages (AM). AM main roles are the phagocytosis of inhaled particles and the clearance of surfactant (for review see [START_REF] Hussell | Alveolar macrophages: Plasticity in a tissue-specific context[END_REF]). AM have been shown in mouse to originate from embryonic monocytes that settled before birth in the alveoli and self-renew independently of peripheral blood adult monocytes [START_REF] Guilliams | Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF[END_REF]. This scheme can be modified upon events that trigger both strong inflammation and partial or complete AM depletion. In this case, as documented in mice, recruited inflammatory monocytes will differentiate in pro-inflammatory monocyte-derived macrophages (moMθ) before entering AM 'niche' (for review see [START_REF] Guilliams | Does niche competition determine the origin of tissue-resident macrophages?[END_REF]) and differentiating finally in 'true' AM, undistinguishable from the original AM population (Aegerter et al., 2020).

Although not yet formally demonstrated, the belonging of human AM to the local-self-renewable macrophage type is also postulated. By analyzing AM from lung grafted patients, several teams tried to clarify the importance of AM self-renewal versus blood monocytes replacement in human, leading to contradictory conclusions [START_REF] Bittmann | Cellular chimerism of the lung after transplantation: An interphase cytogenetic study[END_REF][START_REF] Eguíluz-Gracia | Long-Term persistence of human donor alveolar macrophages in lung transplant recipients[END_REF][START_REF] Nayak | Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses[END_REF]. However a recent work using up to date single cell technology [START_REF] Byrne | Dynamics of human monocytes and airway macrophages during healthy aging and after transplant[END_REF] arbitrated toward a strong contribution of blood monocytes for long term AM maintenance, the authors arguing that human beings, conversely to lab's mice, are constantly challenged by inflammatory stimuli, in a much longer time frame, and that in human everyday life, the AM pool might be replaced by moMθ within a year. In porcine lung, we observed that AM did not express blood-related genes such as cKit, CSF1R CCR2 or CX3CR1 but did expressed HDAC10, PU.1 [START_REF] Bordet | Porcine alveolar macrophage-like cells are pro-inflammatory pulmonary intravascular macrophages that produce large titers of porcine reproductive and respiratory syndrome virus[END_REF][START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF] whose expressions are related to embryonically-derived macrophage precursors in mouse [START_REF] Guilliams | Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF[END_REF][START_REF] Schulz | A lineage of myeloid cells independent of myb and hematopoietic stem cells[END_REF], in agreement with a similar local-self-renewable capacity of porcine and mouse AM. However, according to the 'niche theory', these local-self-renewable AM could well be former moMθ that transdifferentiated in true AM upon AM-niche occupancy as postulated in human.

To note, similarly to mouse and man [START_REF] Keller | Regulation of immunoproteasome function in the lung[END_REF], porcine AM expressed the immunoproteasome subunits LMP2, LMP7, and MECL-1 upon respiratory viral infection [START_REF] Liu | Anti-viral immune response in the lung and thymus: Molecular characterization and expression analysis of immunoproteasome subunits LMP2, LMP7 and MECL-1 in pigs[END_REF][START_REF] Liu | Expression of immunoproteasome subunits in the porcine lung: Alterations during normal and inflammatory conditions[END_REF].

One intriguing feature of pulmonary macrophage network in swine, and the majority of the Laurasiatheria, is the presence of pulmonary intravascular macrophages (PIM, for review [START_REF] Schneberger | Pulmonary intravascular macrophages and lung health: What are we missing? AJP Lung Cell[END_REF]) that are not present, at least at steady state, in mouse, rat and human [START_REF] Brain | Pulmonary intravascular macrophages: their contribution to the mononuclear phagocyte system in 13 species[END_REF]. PIM are resident lung intravascular macrophages intimately tight with endothelial cells, what differentiates them from marginated blood monocytes (for review see [START_REF] Kuebler | The marginated pool[END_REF]). We recently isolated porcine PIM and demonstrated that they were very similar to AM [START_REF] Bordet | Porcine alveolar macrophage-like cells are pro-inflammatory pulmonary intravascular macrophages that produce large titers of porcine reproductive and respiratory syndrome virus[END_REF][START_REF] Crisci | Distinctive Cellular and Metabolic Reprogramming in Porcine Lung Mononuclear Phagocytes Infected With Type 1 PRRSV Strains[END_REF], indeed PIM and AM overexpressed genes such as PU.1 and HDAC10, leading us to suggest than PIM were, like AM, self-renewable embryonically derived macrophages, and/or that PIM may directly originate from AM [START_REF] Bordet | Porcine alveolar macrophage-like cells are pro-inflammatory pulmonary intravascular macrophages that produce large titers of porcine reproductive and respiratory syndrome virus[END_REF]. PIM have been involved in acute lung inflammation in Laurasiatheria species [START_REF] Cantu | Prolonged function of macrophage, von Willebrand factor-deficient porcine pulmonary xenografts[END_REF][START_REF] Singh | Depletion of pulmonary intravascular macrophages inhibits acute lung inflammation[END_REF]. Interestingly PIM can be induced in rat model of systemic induced inflammation triggered by biliary duct ligature [START_REF] Gill | Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model[END_REF] and some clues of PIM induction in humans suffering of liver dysfunctions [START_REF] Klingensmith | Lung uptake of Tc-99m sulfur colloid in liver and spleen imaging[END_REF][START_REF] Klingensmith | Factors Affecting the Uptake of 99mTc-Sulfur Colloid by the Lung and Kidney[END_REF]) have been reported. In a recent report using mice grafted with human bone-marrow ('humanized' mice), the authors detected PIM which were, in this model, monocyte-derived human macrophages in tight contact with murine endothelial cells [START_REF] Evren | Distinct developmental pathways from blood monocytes generate human lung macrophage diversity[END_REF].

Interstitial macrophages

Interstitial lung moMθ identities and functions have been recently revisited in mouse and man by the identification of two distinct populations [START_REF] Chakarov | Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches[END_REF], one Lyve1 low /MHC-II high /CD163 low , and the other Lyve1 high /MHC-II low /CD163 high respectively residing adjacent to nerve bundles and to blood vessels. The later Lyve1 high /MHC-II low moMθ secreted a high basal level of IL10, supported blood vessel integrity, and decreased inflammatory cells infiltrations upon pulmonary inflammation in mice. This degree of precision has not been reached in pig, although we identified an MHC-II high /CD163 low /CD169 high moMθ population [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF] as well as an MHC-II low /CD163 high /CD169 low (unpublished data), whose differential roles and locations remain to be explored.

Dendritic cells

Swine DC have been identified in tonsils [START_REF] Soldevila | Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil[END_REF], tracheal epithelium and pulmonary parenchyma [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF]. They can be divided in cDC1, cDC2 and moDC whose RNAseq signatures cluster with their mouse spleen and/or lung counterparts [START_REF] Crisci | Distinctive Cellular and Metabolic Reprogramming in Porcine Lung Mononuclear Phagocytes Infected With Type 1 PRRSV Strains[END_REF]. Plasmacytoid DC have also been identified in swine tonsil, they are E2.2 and IRF7 positive as observed in mouse and man. The porcine lung cDC and moDC populations present the functional characteristics of bona fide DC, migrating toward LN chemokine upon maturation, whereas only cDC, but not moDC significantly trigger naïve CD8 and CD4 T cells proliferation. Conventional DC2 are better in activating CD4 T cells than cDC1, and this in lung as well as in tonsil [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF][START_REF] Soldevila | Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil[END_REF], as previously described in mouse and human [START_REF] Schlitzer | Organization of the mouse and human DC network[END_REF]. Again consistent in tonsil and in lung, both porcine cDC1 and cDC2 activate CD8 T cells, conversely to what is observed in mouse [START_REF] Ng | Type 1 Conventional CD103+ Dendritic Cells Control Effector CD8+ T Cell Migration, Survival, and Memory Responses During Influenza Infection[END_REF]. Interestingly, in humanized mice, human cDC1 and cDC2 expend similarly influenza specific CD8 T cells, however only cDC2 induced mucosal effector CD8 T cells [START_REF] Yu | Human cd1c+dendritic cells drive the differentiation of cd103+cd8+mucosal effector t cells via the cytokine tgf-β[END_REF]. This property of cDC2 has not been explored yet in swine lung.

Another intriguing transpecies feature of DC is the expression of Langerin on cDC2 in pig [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF] and human [START_REF] Bigley | Langerin-expressing dendritic cells in human tissues are related to CD1c+ dendritic cells and distinct from Langerhans cells and CD141high XCR1+ dendritic cells[END_REF] but on cDC1 in mouse [START_REF] Sung | A Major Lung CD103 ( E)-7 Integrin-Positive Epithelial Dendritic Cell Population Expressing Langerin and Tight Junction Proteins[END_REF]. It has been shown in human that Langerin is rapidly induced in blood cDC2 upon TGFβ exposure [START_REF] Bigley | Langerin-expressing dendritic cells in human tissues are related to CD1c+ dendritic cells and distinct from Langerhans cells and CD141high XCR1+ dendritic cells[END_REF]. Interestingly, this might be interpreted in conjunction with the expression of CD103 (αEβ7 integrin) on lung porcine cDC2, as well as with the sub-epithelial location of cDC2 in man [START_REF] Yu | Human cd1c+dendritic cells drive the differentiation of cd103+cd8+mucosal effector t cells via the cytokine tgf-β[END_REF] and pig [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF]. Indeed, TGFβ is largely produced by respiratory epithelial cells and Langerin, like CD103, is induced upon TGFβ exposure [START_REF] Parker | A family of β7 integrins on human mucosal lymphocytes[END_REF][START_REF] Picarda | Functional Langerin high -Expressing Langerhans-like Cells Can Arise from CD14 high CD16 -Human Blood Monocytes in Serum-Free Condition[END_REF]. The sub-epithelial location of cDC2 in humans and pigs might explain both the Langerin and CD103 expression phenotype and the higher involvement of cDC2 in the activation of CD8 response compared with their mouse counterparts [START_REF] Yu | Human cd1c+dendritic cells drive the differentiation of cd103+cd8+mucosal effector t cells via the cytokine tgf-β[END_REF]. FcεRIα is expressed in pig [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF] and human [START_REF] Greer | Accumulation of BDCA1+ dendritic cells in interstitial fibrotic lung diseases and Th2-high asthma[END_REF] but not in mouse cDC2. Indeed in mouse inflammatory moDC expressed the FcεRIα (for review see [START_REF] Lambrecht | Lung Dendritic Cells in Respiratory Viral Infection and Asthma: From Protection to Immunopathology[END_REF]). This difference might be of great importance in the feedback of allergic response since IgE/FcεRIα signaling in human cDC2 trigger an inhibition of the inflammatory response [START_REF] Platzer | Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites[END_REF] whereas it is thought that FcεRIα expression on mouse moDC would allow an IgE-mediated allergen presentation in a positive amplification loop. Interestingly, a recent work in mice complicated the cDC1/cDC2/moDC picture by demonstrating that upon inflammation lung cDC2 can arbor cDC1 and moDC features such as IRF8, CD64 and FcεRIα expressions [START_REF] Bosteels | Inflammatory Type 2 cDCs Acquire Features of cDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection[END_REF]. It would be interesting to investigate if these modifications stand true for human and porcine cDC2. Finally, in pig, monocyte-derived DC have been identified upon influenza infection and their phenotype and functions are compatible with inflammatory DC, harboring low migratory capacities and strong production of IL1β and IL8 upon stimulation [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF]. Innate lymphocytes NK cells were shown to decrease in peripheral blood and to preferentially localize close to infected area in porcine influenza infected lung [START_REF] Forberg | Early responses of natural killer cells in pigs experimentally infected with 2009 pandemic H1N1 influenza a virus[END_REF], in agreement with an important role in the control of influenza infection as observed in mice [START_REF] Gazit | Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1[END_REF]. The CD3+NKp46+ lymphocyte population described by [START_REF] Mair | Porcine CD3+NKp46+lymphocytes have NK-cell characteristics and are present in increased frequencies in the lungs of influenza-infected animals[END_REF] was minimally detected in spleen, blood and mediastinal LN (< 2%) but presented a higher frequency, associated to a large variability according to the animal, in lung (1% to 10%), what may suggest a role of this population in lung immune surveillance in swine. Invariant NKT (iNKT) cells binding human CD1d tetramers loaded with an α-GalCer analog have been described in the porcine lung. They are CD3 and CD44 positive but do not express Nkp46 and CD11b, and can be subdivided in three main populations expressing no, low or high levels of CD8α (Yang et al., 2017a). Interestingly, it has been shown recently that porcine iNKT cells were able to respond to influenza-exposed myeloid cells in vitro [START_REF] Schäfer | Porcine Invariant Natural Killer T Cells : Functional Profiling and Dynamics in Steady State and Viral[END_REF].

To our knowledge, an interesting observation has been done only in pig lung, which is the demonstration that γδ T cells were the main alveolar population able to migrate to bronchial LN [START_REF] Pabst | Lymphocytes migrate from the bronchoalveolar space to regional bronchial lymph nodes[END_REF].

T Lymphocytes

As expected from mouse and man data, it has been observed in pig that parasitic Ascaris suum infection bias the lung immune response toward a Th2 response (GATA3, IL4, IL5 upregulation in the whole lung tissue) [START_REF] Steenhard | Ascaris suum infection negatively affects the response to a Mycoplasma hyopneumoniae vaccination and subsequent challenge infection in pigs[END_REF] and that Actinobacillus pleuropneumoniae bacterial infection triggered a Th17 immune response, as validated by the presence of antigen-specific IL17A secreting CD4 T cells [START_REF] Sassu | Frequency of Th17 cells correlates with the presence of lung lesions in pigs chronically infected with Actinobacillus pleuropneumoniae[END_REF]. Intranasal influenza vaccination triggered resident memory T cells [START_REF] Holzer | Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single-Cycle Influenza Vaccine[END_REF]. Moreover, proliferating poly-functional Th1 (IFNγ, TNFα and IL2secreting) and CD8 (IFNγ, TNFα-secreting) lymphocytes can be detected in the trachea-bronchial LN and the lung of influenza infected animals, from 6 to 44 days post-infection [START_REF] Talker | Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung[END_REF]. Interestingly flu-specific IFNγ-secreting CD8 T cells expressed perforine and were 30 times overrepresented in the lung than in the peripheral blood. Cytokine production was dominated by T cells with an early effector phenotype or central memory phenotype (CD27 pos ) as observed in mice [START_REF] Ballesteros-Tato | Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+T cell responses to influenza[END_REF] in agreement with the existence in porcine lung of tissue-resident memory T cells.

B lymphocytes

To our knowledge the B cell response in the porcine respiratory tract has only been addressed through nasal swabs and broncho-alveolar lavages antibody monitoring (among others [START_REF] Bernelin-Cottet | Electroporation of a nanoparticleassociated DNA vaccine induces higher inflammation and immunity compared to its delivery with microneedle patches in pigs[END_REF][START_REF] Heinen | Systemic and Mucosal Isotype-Specific Antibody[END_REF]).

In conclusion, considering the respiratory immune system, mice and swine present both similarities and differences compared with human beings (Table 1), which must be consciously considered before choosing one species as an animal model for the pathogen of interest.

Model

We will consider here the porcine models developed to tackle the main respiratory diseases identified by the WHO, at the exception of lung cancer. Id est, respiratory infections and vaccination, allergy and asthma, acute and chronic inflammations, to which we will add two short chapters on microbiota and lung graft (Table 2).

Respiratory infections

Swine has been frequently used to study human respiratory pathogens naturally infecting the pigs, including, amongst others , Mycobacterium sp [START_REF] Bolin | Infection of swine with Mycobacterium bovis as a model of human tuberculosis[END_REF][START_REF] Ramos | The minipig as an animal model to study Mycobacterium tuberculosis infection and natural transmission[END_REF], Pseudomonas aeruginosa [START_REF] Dehring | Comparison of live bacteria infusions in a porcine model of acute respiratory failure[END_REF][START_REF] Luna | Animal models of ventilator-associated pneumonia[END_REF], Staphylococcus aureus [START_REF] Martínez-Olondris | An experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated piglets[END_REF] and Alphainfluenzavirus [START_REF] Rajao | Swine as a model for influenza avirus infection and immunity[END_REF]. Alternatively, pigs can be susceptible to experimental infections of otherwise strictly human pathogens such as Bordetella pertussis [START_REF] Foreman-Wykert | A new animal model of Bordetella pertussis infection and immunity[END_REF]. One of the main gap of naturally occurring respiratory infections in swine is the absence of a porcine equivalent of the human respiratory syncytial virus (RSV), a very significant pathogen in human, although an orthopneumovirus close to RSV has been recently detected in pigs [START_REF] Hause | Feral swine virome is dominated by single-stranded DNA viruses and contains a novel Orthopneumovirus which circulates both in feral and domestic swine[END_REF] and might be present in France too (Richard et al., 2018). In this chapter we will expose the interest of the pig model for P. aeruginosa, influenza A and coronavirus infections.

-The bacterium P. aeruginosa rarely infects human lungs unless the host immune system has been impaired because of cystic fibrosis (CF), chronic obstructive disease (COPD) or ventilator-associated pneumonia. An infectious model has been developed in pig that recapitulates all the main features of this human infection, including bronchial contraction, transient increase in pro-inflammatory cytokines (IL8, IL6 and TNFα), neutrophilia, neutrophil extracellular trap (NET)osis, and the secretion of massive amounts of neutrophil serine proteases leading to lung damages [START_REF] Chevaleyre | The pig: A relevant model for evaluating the neutrophil serine protease activities during acute pseudomonas aeruginosa lung infection[END_REF].

-Orthomyxoviridae and more specifically Alphainfluenzavirus (IAV) are pathogens of major importance in animal and human medicines. As recently reviewed, pig is more and more considered as an alternative model to consider with ferret and mouse, for the study of human influenza infection [START_REF] Starbaek | Animal Models for Influenza A Virus Infection Incorporating the Involvement of Innate Host Defenses: Enhanced Translational Value of the Porcine Model[END_REF]. Pigs are natural hosts of different strains of IAV (Kuntz-Simon and Madec, 2009), presenting frequent interspecies transmissions from pig to man and the reverse (Chastagner et al., 2019a(Chastagner et al., , 2019b)), what underlines the proximity of swine and human IAV as well as the similarity of the respiratory systems in both species. The most frequently encountered subtypes in pigs, H1N1, H1N2 and H3N2, are the same than in humans. Besides that, the interest for the pig model is strengthened by the fact that pig is considered as a mixing vessel of human, porcine and avian influenza virus for the generation of new influenza virus reassortants [START_REF] Ma | The pig as a mixing vessel for influenza viruses: Human and veterinary implications[END_REF]. The susceptibility of pigs to infections with both avian and mammalian influenza virus was recently explained to some extent in a study showing that the porcine host factor ANP32A, contrary to porcine ANP32B and other mammalian ANP32, had stronger supporting activity to the avian viral RNA polymerase [START_REF] Zhang | A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs[END_REF]. In pigs, IAV are responsible of mild diseases (for review [START_REF] Crisci | Review: Influenza virus in pigs[END_REF]) with low fever (40.5°C versus 39.5°C for normal body temperature), low inflammatory signs of the upper respiratory tract (nasal/ ocular discharge and conjunctivitis), dyspnea and coughing [START_REF] Talker | Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung[END_REF] very similar to human common, mild influenza infections. In mice, which are not the natural hosts for IAV, adapted strains trigger whole lung infection and inflammation, leading to death, more similar to highly pathogenic avian influenza infections in human [START_REF] Gao | Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection[END_REF]. Ferrets are recognized among the best model for testing pathogenicity and transmission of human respiratory viruses including IAV [START_REF] Enkirch | Ferret models of viral pathogenesis[END_REF], although the evolutionary reasons for this convergence are still a mystery. Interestingly, a recent comparison of influenza heterosubtypic vaccination in pigs and ferrets, showed different outcome between species and underlined the interest of using different preclinical models to assess new vaccines against flu [START_REF] Holzer | Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single-Cycle Influenza Vaccine[END_REF]. Which animal model, the pig or the ferret, reflects best the situation in human remains however to be determined.

By keeping the immune response under control, AM are recognized as the 'peace-keepers' of the lung [START_REF] Schneider | Alveolar Macrophages Are Essential for Protection from Respiratory Failure and Associated Morbidity following Influenza Virus Infection[END_REF]. In mouse [START_REF] Schneider | Alveolar Macrophages Are Essential for Protection from Respiratory Failure and Associated Morbidity following Influenza Virus Infection[END_REF] like in pig [START_REF] Kim | Alveolar Macrophages Are Indispensable for Controlling Influenza Viruses in Lungs of Pigs[END_REF], AM depletion aggravate the IAV-mediated disease. In pigs, similarly to humans, disease severity has been associated with increased local pro-inflammatory cytokines [START_REF] Barbé | Cytokines and acute phase proteins associated with acute swine influenza infection in pigs[END_REF][START_REF] Khatri | Swine Influenza H1N1 Virus Induces Acute Inflammatory Immune Responses in Pig Lungs: a Potential Animal Model for Human H1N1 Influenza Virus[END_REF]. This cytokine storm has been associated in mice to the arrival of inflammatory moDC in the lung, indeed, pharmacological or genetic downregulation of moDC trafficking moderates the early inflammation, reduces morbidity and mortality without impacting the mounting of the adaptive immune response [START_REF] Aldridge | TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection[END_REF]. This model might also stand for IAV infection in swine, since we observed the arrival of similar pro-inflammatory moDC in the porcine lung as soon as 2 days post-IAV inoculation [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF]. As in mouse [START_REF] Westerhof | Multifunctional cytokine production reveals functional superiority of memory CD4 T cells[END_REF] and human [START_REF] Bonduelle | Characterization of pandemic influenza immune memory signature after vaccination or infection[END_REF], influenza virus infections in pigs trigger multifunctional blood [START_REF] Talker | Magnitude and kinetics of multifunctional CD4+ and CD8β+ T cells in pigs infected with swine influenza A virus[END_REF] and lung [START_REF] Talker | Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung[END_REF] antigen-specific CD8 and CD4 T cells. Interestingly a strain of inbred animals, the Babrahama pigs, allowed the use of swine major histocompatibility class I (MHC-I) tetramers to analyze the anti-NP CD8 T cells raised upon influenza intranasal vaccination [START_REF] Tungatt | Induction of influenza-specific local CD8 T-cells in the respiratory tract after aerosol delivery of vaccine antigen or virus in the Babraham inbred pig[END_REF], and influenza infection [START_REF] Edmans | Magnitude and Kinetics of T Cell and Antibody Responses During H1N1pdm09 Infection in Inbred Babraham Pigs and Outbred Pigs[END_REF]. This last study also detected a strong influx of γδ T cells in the alveolar space during influenza infection. Similarly, and in agreement with a role in respiratory immunity, the CD3+NKp46+ lymphocyte population described in swine by [START_REF] Mair | Porcine CD3+NKp46+lymphocytes have NK-cell characteristics and are present in increased frequencies in the lungs of influenza-infected animals[END_REF] presented a strong increase in the lung of influenza infected animal, most probably due to local proliferation. SCID human beings and pigs presenting an autologous deficiency in Artemis gene (DCLRE1C) [START_REF] Moshous | Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency[END_REF] do not develop adaptive immune T and B lymphocytes but harbor functional NK cells [START_REF] Powell | NK cells are intrinsically functional in pigs with Severe Combined Immunodeficiency (SCID) caused by spontaneous mutations in the Artemis gene[END_REF]. Human affected by this mutation present recurrent respiratory infections but not recorded influenza infections [START_REF] Volk | DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency[END_REF], and survived early childhood thanks to intravenous Ig therapy. Interestingly SCID/Artemis pigs presented higher virus excretion and delay in virus clearance, but milder lung lesions and clinical signs compared with their heterologous counterparts [START_REF] Rajao | Pigs with Severe Combined Immunodeficiency Are Impaired in Controlling Influenza A Virus Infection[END_REF], in agreement with a role of the adaptive immune response both in the control of the viremia and in the inflammatory pathology. In short, pigs can be an interesting model of human influenza infection using endemic porcine or human influenza viruses. The height of the influenza porcine model being to use pig-originated pdmH1N1 [START_REF] Mena | Origins of the 2009 H1N1 influenza pandemic in swine in Mexico[END_REF] human pandemic virus in porcine infectious assay as a model of the human infection [START_REF] Schwaiger | Experimental H1N1pdm09 infection in pigs mimics human seasonal influenza infections[END_REF].

-Coronavirus: With the recent COVID-19 crisis there is new need for the development of relevant animal models to study coronavirus infections. In pig, the only respiratory coronavirus (Porcine Respiratory Coronavirus, PrCoV) is an Alphacoronavirus which is a variant of the Transmissible Gastroenteritis Virus (TGEV) [START_REF] Wang | Emerging and re-emerging coronaviruses in pigs[END_REF]. Indeed, a large 5' deletion in the Spike gene of TGEV altered the tropism and the virulence of PrCoV. PrCoV receptor is the aminopeptidase N (APN also named CD13), mainly expressed on respiratory and intestinal epithelial cells, whereas human SARS-CoV and SARS-CoV-2 bind to ACE2, a protein similarly expressed on respiratory and intestinal epithelial cells but also on endothelial cells, which may have strong implication in virus pathogeny [START_REF] Saponaro | ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives[END_REF]. Indeed, engineering transgenic mice expressing the human ACE2 suffice to trigger the full clinical picture of SARS-CoV-2 in mice [START_REF] Bao | The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice[END_REF][START_REF] Israelow | Mouse model of SARS-CoV-2 reveals inflammatory role of type i interferon signaling[END_REF][START_REF] Sun | A Mouse Model of SARS-CoV-2 Infection and Pathogenesis[END_REF]. Regarding the first SARS-CoV, the pig has been demonstrated to be susceptible [START_REF] Chen | SARSassociated coronavirus transmitted from human to pig[END_REF]. With the SARS-CoV-2, the situation is less clear and contradictory results have been reported [START_REF] Meekins | Susceptibility of swine cells and domestic pigs to SARS-CoV-2[END_REF][START_REF] Pickering | Susceptibility of domestic swine to experimental infection with SARS-CoV-2 2. bioRxiv[END_REF][START_REF] Sclottau | SARS-CoV-2 in fruit bats, ferrets, pigs, and chickens: an experimental transmission study[END_REF][START_REF] Shi | Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2[END_REF]. In 3 out of 4 of these reports [START_REF] Meekins | Susceptibility of swine cells and domestic pigs to SARS-CoV-2[END_REF][START_REF] Sclottau | SARS-CoV-2 in fruit bats, ferrets, pigs, and chickens: an experimental transmission study[END_REF][START_REF] Shi | Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2[END_REF], pigs inoculated using nasal or oral routes did not develop any lesions nor clinical signs. Moreover, authors did not detect any viral excretion. However in one of these 3 studies [START_REF] Meekins | Susceptibility of swine cells and domestic pigs to SARS-CoV-2[END_REF]) SARS-CoV-2 replicated in porcine epithelial cell lines. In the fourth study [START_REF] Pickering | Susceptibility of domestic swine to experimental infection with SARS-CoV-2 2. bioRxiv[END_REF], mild clinical signs were observed in some inoculated pigs and viral RNA was detected in nasal lavage and oral fluid. Furthermore, infectious virus was isolated from submandibular LN in one pig 13 days postinoculation and a serological response was evidenced in two animals 11 days post-inoculation [START_REF] Meekins | Susceptibility of swine cells and domestic pigs to SARS-CoV-2[END_REF]. Thus, at this early stage, it is very difficult to definitely conclude about the relevance of the pig model for the study of SARS-CoV-2.

The SARS-Cov-2 emergence revealed the lack of knowledge on seasonal human coronavirus. The prototype viruses from the two main HCoV lineages are 229E (Alphacoronavirus, like the porcine PrCOV) and OC43 (Betacoronavirus). They cause 15-29% of all common colds, and are the best characterized HCoV, although 2 other human coronavirus are also considered as endemic (NL63 and HKU1) [START_REF] Su | Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses[END_REF]. In addition, HCOV-229E uses the same receptor as PrCOV. Thus swine might be a good model of seasonal coronavirus infections allowing, in addition, the investigation of coronavirus and IAV co-infections.

Regarding respiratory infections, it is worth to report here that pig lungs are suitable for the generation of precision cut lung slices (PCLS) permitting the analysis, using multiple in vitro conditions, of monoinfections [START_REF] Delgado-Ortega | Innate immune response to a H3N2 subtype swine influenza virus in newborn porcine trachea cells, alveolar macrophages, and precision-cut lung slices[END_REF] as well as of coinfecting viruses' complex interactions on primary tissue-samples [START_REF] Dobrescu | In vitro and ex vivo analyses of co-infections with swine influenza and porcine reproductive and respiratory syndrome viruses[END_REF][START_REF] Saade | Porcine reproductive and respiratory syndrome virus interferes with swine influenza a virus infection of epithelial cells[END_REF].

Vaccination

Reviews arguing for the use of large animal models, including swine, have been published in 2015 that inventoried pig usage for vaccination and challenge tests against Bordetella pertussis, Chlamydia trachomatis, human norovirus, rotavirus and IAV [START_REF] Gerdts | Large animal models for vaccine development and testing[END_REF][START_REF] Rajao | Swine as a model for influenza avirus infection and immunity[END_REF]. In addition to allow the evaluation of vaccines directly through protection against an infectious challenge, animal models can permit to evaluate vaccines indirectly through immune responses measurement without the final step of the infectious challenge. In this case, the animal model is not anymore needed to be susceptible to the pathogen. For instance, swine are commonly used to assess the potency of delivery devices and adjuvants.

-Delivery: The place and mode of delivery determine the localization of memory and effector cells upon challenge. For instance it has been shown in mice that epicutaneous (EP) vaccination allows mucosal immune response in mice [START_REF] Belyakov | Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells[END_REF]. Pig skin is recognized as a good model of human skin because of structure (hairiness, epidermis and dermis thickness, subcutaneous fat) and lipid composition [START_REF] Hammond | Transcutaneous immunization of domestic animals: Opportunities and challenges[END_REF] similarities, which makes pig skin permeability similar to the human one, as well as because of dendritic cells and macrophages resemblance [START_REF] Marquet | Pig Skin Includes Dendritic Cell Subsets Transcriptomically Related to Human CD1a and CD14 Dendritic Cells Presenting Different Migrating Behaviors and T Cell Activation Capacities[END_REF][START_REF] Summerfield | The immunology of the porcine skin and its value as a model for human skin[END_REF]. Thus pig is a model of choice to test EP, transcutaneous (TC) and intradermic (ID) vaccination protocols for the induction of respiratory immune protection. Direct intramuscular (IM) DNA vaccination presented early encouraging success in mouse [START_REF] Ulmer | Heterologous protection against influenza by injection of DNA encoding a viral protein[END_REF] that were not reproduced in large animals including humans and pigs. Although not further investigated, this discrepancy might rely on tissue stiffness differences according to the animal size. Vaccination against respiratory diseases can also favor a pulmonary localized immune response by directly exposing the target tissue to the antigens using aerosol (AS), intranasal (IN) or intratracheal (IT) deliveries. For that purpose, the size of swine upper respiratory tract, more similar to the human ones than small animals such as mouse or ferret, might guarantee a better compliance with clinical situations [START_REF] Kirschvink | Use of Alternative Animals as Asthma Models[END_REF][START_REF] Rogers | The porcine lung as a potential model for cystic fibrosis[END_REF]. As an illustration, herein some technics used in vaccination (mainly against influenza) in swine: prime-boost DNA/whole virus vaccine delivered ID/IM [START_REF] Hewitt | A prime-boost concept using a T-cell epitope-driven DNA vaccine followed by a whole virus vaccine effectively protected pigs in the pandemic H1N1 pig challenge model[END_REF], single ID Aujeszky's Disease Virus glycoproteins vaccine [START_REF] Le Luduec | Intradermal vaccination with un-adjuvanted sub-unit vaccines triggers skin innate immunity and confers protective respiratory immunity in domestic swine[END_REF], influenza-proteins, DC-targeted ID or IM vaccination [START_REF] Bernelin-Cottet | A universal influenza vaccine can lead to disease exacerbation or viral control depending on delivery strategies[END_REF], protein, epicutaneous anti-RSV vaccination [START_REF] Hervé | Non-invasive epicutaneous vaccine against Respiratory Syncytial Virus: Preclinical proof of concept[END_REF], single-cycle influenza virus delivered AS [START_REF] Holzer | Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single-Cycle Influenza Vaccine[END_REF], influenza virus-derived-replicon delivered IM [START_REF] Ricklin | Virus replicon particle vaccines expressing nucleoprotein of influenza A virus mediate enhanced inflammatory responses in pigs[END_REF], nanoparticules whole influenza virus encapsulation delivered IN [START_REF] Dhakal | Biodegradable nanoparticle delivery of inactivated swine influenza virus vaccine provides heterologous cell-mediated immune response in pigs[END_REF] and aerosol intranasal delivery [START_REF] Martini | Distribution of Droplets and Immune Responses After Aerosol and Intra-Nasal Delivery of Influenza Virus to the Respiratory Tract of Pigs[END_REF].

-Adjuvant: In addition to antigen and delivery, an essential part of a vaccine is the adjuvant used to increase the immunogenicity of dead vaccines. One of the main developing arm of adjuvant is the use of TLR-ligands, that trigger inflammation and antigen presenting cells activation. In that instance, swine present a restrictive expression of TLR3 on pDC [START_REF] Auray | Characterization and Transcriptomic Analysis of Porcine Blood Conventional and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific Differences[END_REF][START_REF] Soldevila | Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil[END_REF] compared to the TLR3 expression on cDC1 in human [START_REF] Poulin | Characterization of human DNGR-1 + BDCA3 + leukocytes as putative equivalents of mouse CD8α + dendritic cells[END_REF] and mouse [START_REF] Desch | CD103 + pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen[END_REF]. Conversely, pig and human, but not mouse, expressed an active TLR8 receptor that can detect RNA specifically from live bacteria [START_REF] Ugolini | Recognition of microbial viability via TLR8 drives TFHcell differentiation and vaccine responses[END_REF], leading to a better activation of follicular DC and the differentiation of high affinity antibodies. Finally, it has been proposed to use αGalSer as an adjuvant in human vaccination that would harness iNKT cells [START_REF] Speir | Engaging Natural Killer T Cells as 'Universal Helpers' for Vaccination[END_REF] and help for CD8 T cells activation. This strategy has been prospected in pig (for review (Yang et al., 2017b)). A first assay using αGalSer as immunostimulant before IAV infection did not allow protection [START_REF] Gu | Unaltered influenza disease outcomes in swine prophylactically treated with α-galactosylceramide[END_REF], although this result does not preclude the use of αGalSer as true vaccine adjuvant.

Microbiota

In the last years the importance of the microbiota and especially the gut microbiota in the preservation of homeostasis and health has been extensively studied. The gut microbiota can influence the lung health and the susceptibility of porcine host to respiratory infections [START_REF] Bassaganya-Riera | Conjugated linoleic acid ameliorates viral infectivity in a pig model of virally induced immunosuppression[END_REF][START_REF] Niederwerder | Role of the microbiome in swine respiratory disease[END_REF]. It is also known that all the mucosa in the body have some connections forming the common mucosal immune system in man [START_REF] Dang | Microbes, metabolites, and the gut-lung axis[END_REF] as in pig [START_REF] Wilson | Evidence for a common mucosal immune system in the pig[END_REF]. Because of the use of pigs in biomedical research, some comparisons between human and pig gut microbiota have been carried out. By deep metagenome sequencing of faecal DNA from 287 pigs, Xiao and collaborators showed that among functional pathways found in humans, 96% were present in pigs [START_REF] Xiao | A reference gene catalogue of the pig gut microbiome[END_REF]. However, in other studies comparing gut microbiota [START_REF] Xiao | A reference gene catalogue of the pig gut microbiome[END_REF] and fecal microbiota [START_REF] Kobayashi | Comparison of the fecal microbiota of two monogastric herbivorous and five omnivorous mammals[END_REF] in different species, it was shown that pig was less close to humans than marmosets and three shrews. Moreover the pig, even if omnivorous like humans, had fecal microbiota showing some common features with herbivores as the presence of Fibrobacter, a cellulolytic bacterium [START_REF] Kobayashi | Comparison of the fecal microbiota of two monogastric herbivorous and five omnivorous mammals[END_REF]. Recently a further demonstration of the gut lung axis has been demonstrated in swine with an impact of a porcine herpesvirus (Aujeszky's Disease Virus) on microbial community and immune status in the ileum and colon of piglets [START_REF] Zhang | Effects of intranasal pseudorabies virus AH02LA infection on microbial community and immune status in the ileum and colon of piglets[END_REF]. Finally, the last decade firmly established the existence and precisely described a symbiotic, stable respiratory microbiota in mouse and man (for review see [START_REF] Man | The microbiota of the respiratory tract: Gatekeeper to respiratory health[END_REF]. These investigations remain to be done in pig.

Respiratory Allergy and Asthma

Respiratory allergy corresponds to the improper activation of a Th2 response, leading to the establishment of an IgE mediated anamnestic immune response that will trigger eosinophils degranulation and asthma. Although food allergy is well-established in swine (for review see [START_REF] Rupa | Porcine allergy and IgE[END_REF]), allergic asthma does not occur spontaneously in the animal world, albeit guinea pigs, ferrets and pigs can be artificially sensitized. The establishment of a stable chronic porcine asthma model appears to be difficult because the sensitivity to the antigen declines after repeated allergen exposure [START_REF] Szelenyi | Animal models of bronchial asthma[END_REF]. However, upon Ascaris suum antigen sensitization consisting of an A. suum extract in Al(OH)3 followed by two booster doses and a challenge with nebulized allergen, pigs developed airway inflammation associated with eosinophils and neutrophils infiltration [START_REF] Fornhem | Granulocyte function in the airways of allergen-challenged pigs : effects of inhaled and systemic budesonide[END_REF]. On the induction side, cDC2 have been demonstrated to be the main trigger of the Th2 bias involved in the allergic response. As specified in the dendritic cells chapter above, porcine cDC2 resemble more to human than to mice cDC2 on several aspects in blood [START_REF] Auray | Characterization and Transcriptomic Analysis of Porcine Blood Conventional and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific Differences[END_REF] as well as in the respiratory tract [START_REF] Crisci | Distinctive Cellular and Metabolic Reprogramming in Porcine Lung Mononuclear Phagocytes Infected With Type 1 PRRSV Strains[END_REF]. For instance, the two main features important to recall here are the expression by cDC2 of the FcεRIα, a receptor of IgE, and the intra-epithelial and subepithelial cDC2 location in the trachea and the bronchia respectively [START_REF] Maisonnasse | The respiratory DC/macrophage network at steady-state and upon influenza infection in the swine biomedical model[END_REF][START_REF] Yu | Human cd1c+dendritic cells drive the differentiation of cd103+cd8+mucosal effector t cells via the cytokine tgf-β[END_REF]. Invariant NKT cells have been strongly involved in the Th2 bias of allergic responses (for review see [START_REF] Matangkasombut | Natural killer T cells and the regulation of asthma[END_REF]), interestingly Renukaradhya et al. demonstrated that intra-tracheal instillation of α-GalCer analog in pigs triggered iNKT cells activation and acute airway hyperactivity associated with a Th2 cytokine profile [START_REF] Renukaradhya | Functional invariant NKT cells in pig lungs regulate the airway hyperreactivity: A potential animal model[END_REF]. On the effector side, dendrograms indicate that porcine IgE is more similar to IgE of carnivores, horses and humans than to other artiodactyls IgE [START_REF] Butler | Immunoglobulins , antibody repertoire and[END_REF]. In swine as in human, mast cell tryptase inhibitor administrated prior to allergen challenge prevented acute bronchoconstrictive response and decreased histamine release [START_REF] Ploeg | The tryptase inhibitor APC-366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum[END_REF], while corticoid administration decreased airways inflammatory cells infiltration [START_REF] Fornhem | Granulocyte function in the airways of allergen-challenged pigs : effects of inhaled and systemic budesonide[END_REF]. Still on the clinical side, porcine lung smooth muscles reactions to inflammatory stimuli are a current model of asthma-muscle contraction [START_REF] Ram-Mohan | Tissue traction microscopy to quantify muscle contraction within precision-cut lung slices[END_REF][START_REF] Sieck | Mechanisms underlying TNF a -induced enhancement of force generation in airway smooth muscle[END_REF]. Interestingly, airway contractions upon in vivo acid treatment in piglets [START_REF] Reznikov | Sex-specific airway hyperreactivity and sex-specific transcriptome remodeling in neonatal piglets challenged with intra-airway acid[END_REF] recapitulated the airway hyper-responsiveness (AHR) gender bias observed in infants [START_REF] Van Merode | PEDIATRIC ALLERGY AND Gender-specific differences in the prevention of asthma-like symptoms in high-risk infants 196-200[END_REF].

Several intravenously administered compound such as nanomedicines, radiologic contrast agents and other pharmaceutical products may trigger in human rare events of pseudoallergic infusion reactions which are hypersensitivity reactions. Thanks to their high sensitivity, pigs have been used for decades to detect such reactions, using the "complement activation-related pseudoallergy" (CARPA) model (for review [START_REF] Szebeni | Human clinical relevance of the porcine model of pseudoallergic infusion reactions[END_REF]). Interestingly, pig high sensitivity seems strongly related to the presence of constitutive PIM [START_REF] Csukás | Pulmonary intravascular macrophages: Prime suspects as cellular mediators of porcine CARPA[END_REF], what might be a clue of the presence of induced PIM in humans susceptible to such reactions.

Acute and Chronic inflammations

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are responsible for more than 10% of intensive care unit admissions. ARDS conditions can be artificially reproduced in swine by using lung repeated lavages, and oleic acid or endotoxin instillations (for review see [START_REF] Ballard-Croft | Large-animal models of acute respiratory distress syndrome[END_REF]). Porcine models more related to human medical conditions have been developed recently such as hemorrhagic shock [START_REF] Morris | Early Identification of Acute Lung Injury in a Porcine Model of Hemorrhagic Shock[END_REF], hyperoxia [START_REF] Katalan | A novel swine model of ricin-induced acute respiratory distress syndrome[END_REF] or ricin induced-ARDS [START_REF] Katalan | A novel swine model of ricin-induced acute respiratory distress syndrome[END_REF]. To our knowledge, no porcine model of ARDS triggered upon infection-induced pneumonia has been reported. The early ARDS stage is characterized by an acute inflammatory response that includes release of IL1, TNF, IL8 and subsequent neutrophil recruitment (for review see [START_REF] Ware | Pathophysiology of acute lung injury and the acute respiratory distress syndrome[END_REF]), that can be mimicked in pig [START_REF] Morris | Early Identification of Acute Lung Injury in a Porcine Model of Hemorrhagic Shock[END_REF].

In developed countries, chronic obstructive disease (COPD) is mostly provoked by smoking and result in the remodeling and narrowing of small airway associated with pulmonary emphysema, likely due to chronic inflammation leading to increased numbers of neutrophils, macrophages, DC, T and B lymphocytes. Chronic inflammation is maintained by macrophages and neutrophils infiltration although autoimmunity related to autoantibodies and activated CD8 is suspected (for review see [START_REF] Caramori | COPD immunopathology[END_REF]). The emphysema appears to be linked to metalloproteinases (MMP) catalytic activity. A mutated-pig phenotype has been described presenting emphysema associated with MMP9 and 12 hyper-expression which might be the first step toward the development of a COPD porcine model [START_REF] Bruun | Functional characterization of a porcine emphysema model[END_REF]. To note, pigs are already used as model for cigarette smoke short [START_REF] Gilman | Vascular effects of cigarette smoke in isolated pig lungs[END_REF] and middle [START_REF] Gilman | Vascular effects of cigarette smoke in isolated pig lungs[END_REF] term effects. The development of pig as a COPD model would allow to explore an interesting hypothesis linking COPD and non-alcoholic fatty liver diseases [START_REF] Lonardo | Nonalcoholic fatty liver disease and COPD: is it time to cross the diaphragm?[END_REF] that we would like to bring together with the potential pro-inflammatory PIM induction in humans suffering of liver dysfunctions [START_REF] Klingensmith | Lung uptake of Tc-99m sulfur colloid in liver and spleen imaging[END_REF][START_REF] Klingensmith | Factors Affecting the Uptake of 99mTc-Sulfur Colloid by the Lung and Kidney[END_REF]. Whether the constitutional presence of PIM in swine might favor or impaired this model remains to be established.

Lung graft

Herein we will not tackle the field of xenotransplantation, that is beyond the scope of this review and has been reviewed recently elsewhere [START_REF] Burdorf | Progress and challenges in lung xenotransplantation: an update[END_REF]. Regular lung transplantation is the final treatment option for patients presenting end-stage lung diseases. The 1-year survival has greatly improved in the last 40 years, reaching now 84% [START_REF] Chambers | The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time[END_REF]. Pig is used as a model of lung transplantation [START_REF] Mariscal | Pig lung transplant survival model[END_REF] to study primary graft dysfunctions and test new preventive interventions to reduce or avoid these conditions [START_REF] Iskender | Human α1-antitrypsin improves early post-transplant lung function: Pre-clinical studies in a pig lung transplant model[END_REF][START_REF] Martins | Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model[END_REF]. Interestingly, pig lungs are currently used to improve and further develop the promising ex vivo lung perfusion (EVLP) method (for review [START_REF] Tane | Ex Vivo Lung Perfusion: A Key Tool for Translational Science in the Lungs[END_REF]) leading to the reconditioning of lung graft rejected in first instances because of not reaching the graft quality criteria. Porcine model allowed to validate methods that decreased the expression of acute lung injury related genes [START_REF] Dromparis | Ex vivo perfusion induces a timeand perfusate-dependent molecular repair response in explanted porcine lungs[END_REF] or that increased the extracorporeal surviving time [START_REF] Hozain | Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine[END_REF]. Moreover, EVLP development give accessibility and time for intervention on the lung graft before grafting. The pig model allows to test extracorporeal intervention such as IL10 gene-therapy in order to act specifically on the immune tolerability of the transplant [START_REF] Machuca | Safety and Efficacy of Ex Vivo Donor Lung Adenoviral IL-10 Gene Therapy in a Large Animal Lung Transplant Survival Model[END_REF].

Conclusions and perspectives:

In conclusion, we think that the development of pig as a respiratory model of medical conditions might be encouraged following three main research fields:

Because of the resemblances between porcine and human cutaneous, respiratory and intestinal systems, associated to the immunological similarities of these species, pig appears to be a model of choice to study the interactions between the different mucosae. In this perspective, a better knowledge of porcine skin, lung and intestinal microbiota will be needed.

The second important point would be to develop pig as a model of respiratory allergies according to the high similarity of cDC2 in pig and man, as well as to the good knowledge of porcine neutrophils and iNKT cells. The main immunological hurdle for this development remains the lack of reagents to follow the B cell response (B cells markers, such as CD19 and CD20 and tools to discriminate the different IgG isotypes).

Finally, according to the large knowledge accumulated on the pig blood monocytes and respiratory macrophages, as well as to the relative long life span of pigs, the long term consequences of immune system alterations triggered by immunostimulants or primary infections, leading to trained immunity [START_REF] Angulo | Oral administration of Debaryomyces hansenii CBS8339-β-glucan induces trained immunity in newborn goats[END_REF][START_REF] Guillon | Pneumonia recovery reprograms the alveolar macrophage pool[END_REF][START_REF] Stylianou | Mucosal delivery of tuberculosis vaccines: a review of current approaches and challenges[END_REF][START_REF] Yao | Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity[END_REF] or tolerance [START_REF] Bouras | Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia[END_REF][START_REF] Didierlaurent | Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection[END_REF]) might be advantageously studied in this model.

To summarize, thanks to the knowledge and tools developed during the last years, pig appears now as the third medical model after mice and non-human primates, and might be seriously considered when looking for a respiratory experimental model, especially in the fields of mucosal interactions, allergies and trained immunity. Bibliography Aegerter, H., Kulikauskaite, J., Crotta, S., Patel, H., Kelly, G., Hessel, E.M., Mack, M., Beinke, S., Wack, A., 2020. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat. Immunol. https://doi.org/10.1038/s41590-019-0568-x

Table I : Immune-related respiratory tract remarkable features of mouse, human and pig Mouse Human Pig Comments

 I

	Airways	-Muzzle	-Nose	-Snout	-hm ≠ pg ≠ ms
					≠ in higher respiratory
					tract size and structure
					-hm & pg ≠ ms
		-Small airways and	-Large airways and	-Large airways	≠ in lower respiratory
		lungs	lungs	and lungs	tract accessibility
	Lymph nodes	-Centripetal	-Centripetal	-Centrifugal	-hm & ms ≠ pg
		circulation	circulation	circulation	no known consequences
					-hm & ms ≠ pg
		-Lymphocytes exit	-Lymphocytes exit	-Lymphocytes	no known consequences
		through efferent	through efferent	exit through
		lymphatics	lymphatics	HEV
	Granulocytes	-Neutrophil serine	-Neutrophil serine	-Neutrophil	-hm & pg ≠ ms
		proteases not-	proteases sensitive	serine proteases	≠ in tissue inflammation
		sensitive to human	to human	sensitive to	handling
		inhibitors	inhibitors	human inhibitors
	AM	-Embryonic origin	-Probably of	-Probably of	-hm=ms=pg
			embryonic origin	embryonic origin
		-Self-renew	-No data	-No data
		-Inflammation,	-Large part of	-No data
		replacement by	moAM
		moAM
	PIM	-No information	-Induced PIM	-Constitutive	-hm & ms ≠ pg
			upon liver	inflammatory	high susceptibility of
			conditions?	PIM	pigs to infused particles
	moMθ/	-2 populations:	-2 populations:	-2 populations:	-hm=ms=pg
	interstitial Mθ	nerve-associated	nerve-associated	location not
		blood vessel	blood vessel	explored
		associated	associated
	DC	-TLR3 expressed	-TLR3 expressed	-TLR3 expressed	-hm & ms ≠ pg
		on cDC1	on cDC1	on pDC	≠ dsRNA response?
		-cDC1 mainly	-cDC1 and cDC2	-cDC1 and	-hm & pg ≠ ms
		involved in T CD8	involved in T CD8	cDC2 involved	≠ T CD8 induction?
		activation	activation	in T CD8
		-cDC2 FcεRIα-,	-cDC2 FcεRIα+,	activation	-hm & pg ≠ ms
		Lang-, CD103-,	Lang+, CD103+,	-cDC2 FcεRIα+,	≠ allergy induction?
		interstitial location	subepithelial	Lang+, CD103+,
			location	subepithelial
				location
	NK/NKT cells	-NKp46	-NKp46	-NK subset	-hm & ms ≠ pg
		specifically	specifically	NKP46-, T	no known consequences
		expressed on NK	expressed on NK	lymphocyte
		cells	cells	subset NKP46+
	T Lymphocytes	-CD4 T cells	-CD4 T cells	-CD8α on	-hm & ms ≠ pg
		devoid of CD8	devoid of CD8	memory CD4 T	no known consequences
		expression	expression	cells	-hm & ms ≠ pg
		-Low proportion of	-Low proportion of		≠ innate immune
		γδ T cells	γδ T cells	-High proportion	response?
				of γδ T cells
	B Lymphocytes	-Naïve B cells	-Not described	-Centroblasts	-hm & ms ≠ pg
		transporting		transporting	no known consequences
		antigens to fDC		antigens to fDC?

HEV: High-Endothelial Venules; AM: Alveolar Macrophage; PIM: Pulmonary Intravascular Macrophage; moAM: monocyte-derived AM; Mθ: Macrophages, moMθ: monocyte derived Macrophage; DC: Dendritic Cell; cDC: conventional Dendritic Cell; pDC: plasmacytoid Dendritic Cell; fDC: follicular Dendritic Cell; NK: Natural Killer; hm: human; ms: mouse; pg: pig. Bibliographic references are in the main text.

Table 2 : Non-transmissible respiratory diseases pro and con of the porcine model PROS CONS RESPIRATORY INFECTIONS

 2 Severe Acute Respiratory Syndrome; hRSV: human Respiratory Syncytial Virus; cDC: conventional Dendritic Cell; pDC: plasmacytoid Dendritic Cell; ARDS: Acute respiratory distress syndrome; PIM: Pulmonary Intravascular Lymphocyte. Bibliographic references are in the main text.

		B. pertussis	-naturally infected
		Mycobacterium sp -naturally infected
		S. aureus	-naturally infected
		P. aeroginosa	-naturally infected
		Influenzavirus	-natural sensitivity to	-no example of highly
			human and swine	pathogenic infections
			strains with mild
			clinical signs
		Coronavirus	-natural porcine	-disputed sensitivity to
			αCoronavirus (PrCoV)	SARS-CoV-2
			similar to the human
			seasonal HCoV-229E
		Orthopneumovirus -natural porcine	-not sensitive to hRSV
			Orthopneumovirus?
	VACCINATION	Delivery	-skin structure
			-upper respiratory tract
			structure
		Adjuvant	-functional TLR8	-TLR3 expression on
			-cDC1 interstitial and	pDC not on cDC1
			cDC2 intra-
			subepithelial locations
			-αGalSer response
	MICROBIOTA		-omnivorous species	-intestinal microbiota
				similar to herbivore
				-data paucity on
				porcine respiratory
				microbiota
	RESPIRATORY	Induction	-cDC2 location	-no stable chronic
	ALLERGY AND		-cDC2 expressing IgE	allergic asthma
	ASTHMA		receptor (FcεRIα)	porcine model
		Clinical signs	-IgE similar to human
			-lung smooth muscles
			porcine model
			-efficacy of tryptase
			inhibitors
	ACUTE AND		-model of early	-no infectious model
	CHRONIC		inflammatory ARDS	of ARDS induction
	INFLAMMATIONS		responses
			-constitutive PIM	-constitutive PIM
	LUNG GRAFT		-size allowing similar
			surgical intervention
			-primary graft
			dysfunction model
			-ex vivo lung perfusion
			model
	SARS: