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• W4285604310 abstract "Human respiratory viruses induce a wide breadth of disease phenotypes and outcomes of varying severity. Innovative models that recapitulate the human respiratory tract are needed to study such viruses, understand the virus-host interactions underlying replication and pathogenesis, and to develop effective countermeasures for prevention and treatment. Human organoid models provide a platform to study virus-host interactions in the proximal to distal lung in the absence of a human in vivo model. These cultures fill the niche of a suitable ex vivo model that represents the in vivo lung environment and encapsulates the structure and function of the native human lung. Human respiratory viruses induce a wide breadth of disease phenotypes and outcomes of varying severity. Innovative models that recapitulate the human respiratory tract are needed to study such viruses, understand the virus-host interactions underlying replication and pathogenesis, and to develop effective countermeasures for prevention and treatment. Human organoid models provide a platform to study virus-host interactions in the proximal to distal lung in the absence of a human in vivo model. These cultures fill the niche of a suitable ex vivo model that represents the in vivo lung environment and encapsulates the structure and function of the native human lung. Human respiratory virus infections cause a wide spectrum of asymptomatic to severe disease phenotypes each year, resulting in high morbidity and mortality outcomes globally. Common respiratory viruses, such as human influenza, respiratory syncytial virus (RSV), parainfluenza (HPIV), rhinoviruses and common cold coronaviruses (CoV), represent diverse families of viruses characterized by different genome organizations, unique transmission patterns and pathogenic outcomes in the upper and lower respiratory tract of human populations. Contemporary human respiratory viruses oftentimes cause seasonal epidemics, such as influenza, RSV, and HPIV, or have widespread endemic transmission across the calendar year, such as the common cold CoV and rhinovirus strains. While infections usually cause mild upper respiratory tract disease, patients may progress to more serious lower respiratory tract infections like bronchiolitis and croup, or to life threatening pneumonias that can progress to acute lung injury and/or organizing chronic pneumonias with fibrosis. Moreover, due to waning immune responses in upper respiratory mucosal compartments, coupled with antigenic changes in response to host immune memory responses, many contemporary respiratory viruses have the potential to cause dramatic spikes in disease prevalence, hospitalization, and mortality, associated with epidemic or pandemic spread.1Bleier BS Ramanathan M Lane AP. COVID-19 vaccines may not prevent nasal SARS-CoV-2 infection and asymptomatic transmission.Otolaryngol Head Neck Surg. 2021; 164: 305-307https://doi.org/10.1177/0194599820982633Crossref PubMed Scopus (71) Google Scholar,2Kissling E Valenciano M Larrauri A et al.Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.Euro Surv. 2013; 18https://doi.org/10.2807/ese.18.05.20390-enCrossref Scopus (145) Google Scholar Alarmingly, extensive zoonotic virus reservoirs exist for many of these virus families, providing unparalleled opportunities for the sudden emergence and spread of “new” strains which have not circulated previously in human populations. Typified by avian influenza viruses like H5N1 and H7N9 and the emerging bat coronaviruses from the Sarbecovirus (Severe Acute Respiratory Coronavirus: SARS-CoV, SARS-CoV-2) and Merbecovirus (Middle East Respiratory Coronavirus: MERS-CoV) lineages, these pathogens have caused repeat outbreaks of disease some of which have progressed to large epidemics or global pandemics in the 21st century. Seasonal influenza epidemics are caused by two main antigenic types, designated A and B strains, and strain variation is further driven by progressive evolution in the hemagglutinin (HA) gene in the dominant strain of influenza A each year. Influenza virus evolves by yearly antigenic variation (mutation) and periodic antigenic shift (RNA reassortment), where human strains encoding the HA and neuraminidase (NA) can reassort with highly heterologous strains circulating in zoonotic reservoirs and introduce avian or other mammalian HA or NA genes into the human population. Influenza A strains encoding HA1, HA2 and HA3 have predominated over the past 75 years, supported by antigenic drift caused by adaptative mutations in influenza A HA that arise in response to and that ultimately dimmish human herd immunity.3Background and epidemiology. Available at: https://www.cdc.gov/flu/professionals/acip/background-epidemiology.htm Accessed April 1, 2022.Google Scholar Evolution in the neuraminidase (NA) glycoproteins of influenza A also support the emergence and propagation of new viral variants that serve as the basis of both annual seasonal epidemics and the emergence of pandemic strains, such as those in 1918, 1956, 1968 and 20093. Prior to the COVID-19 pandemic, and despite effective public health measures and vaccine campaigns that have substantially curbed the frequency of severe influenza, 35 million flu related illnesses, 380K hospitalizations, and 20K flu related deaths were reported in 2019.4Estimated flu-related illnesses, medical visits, hospitalizations, and deaths in the United States — 2019–2020 Flu Season. CDC. Available at: https://www.cdc.gov/flu/about/burden/2019-2020.html Accessed March 29, 2022.Google Scholar While an influenza vaccine exists, the vaccine must be adjusted each year to include the predicted annual strain, sometimes resulting in a mismatch and poor protection against the true circulating strain.5Krammer F Smith GJD Fouchier RAM et al.Influenza.Nat Rev Dis Primers. 2018; 4: 3https://doi.org/10.1038/s41572-018-0002-yCrossref PubMed Scopus (485) Google Scholar In the study of a universal influenza vaccine, models to study vaccine candidates in ex vivo human respiratory tissues, such as human lung organoids, are critical and have revealed novel differences in the tropism and pathogenesis of contemporary and avian influenza strain infections.6Martins de Camargo M Caetano AR Ferreira de Miranda Santos IK. Evolutionary pressures rendered by animal husbandry practices for avian influenza viruses to adapt to humans.iScience. 2022; 25104005https://doi.org/10.1016/J.ISCI.2022.104005Abstract Full Text Full Text PDF PubMed Google Scholar Paramyxovirus infections, typified by RSV, metapneumoviruses and HPIV, cause seasonal outbreaks but are most commonly diagnosed in infants, with nearly all children affected by the time they reach age 2.7RSV trends and surveillance.CDC. 2022; (Available at:) (Accessed March 29, 2022.)https://www.cdc.gov/rsv/research/us-surveillance.htmlGoogle Scholar, 8Clinical overview of human parainfluenza viruses (HPIVs).CDC. 2022; (Available at:) (Accessed March 29, 2022)https://www.cdc.gov/parainfluenza/hcp/clinical.htmlGoogle Scholar, 9Schuster JE Williams JV Human metapneumovirus.Microbiol Spectr. 2014; 2https://doi.org/10.1128/microbiolspec.AID-0020-2014Crossref PubMed Scopus (10) Google Scholar Seniors are also vulnerable to severe RSV infection.10Pierangeli A Scagnolari C Antonelli G. Respiratory syncytial virus.Minerva Pediatr. 2018; 70: 553-565https://doi.org/10.23736/S0026-4946.18.05312-4Crossref PubMed Scopus (16) Google Scholar While influenza is typically associated with fever, cough, sore throat, a runny or stuffy nose, as well as frequent lower respiratory tract infections, RSV and HPIV typically cause upper or lower respiratory infection that more frequently progress into bronchiolitis or pneumonia.7RSV trends and surveillance.CDC. 2022; (Available at:) (Accessed March 29, 2022.)https://www.cdc.gov/rsv/research/us-surveillance.htmlGoogle Scholar,8Clinical overview of human parainfluenza viruses (HPIVs).CDC. 2022; (Available at:) (Accessed March 29, 2022)https://www.cdc.gov/parainfluenza/hcp/clinical.htmlGoogle Scholar Each year, RSV alone causes 2.1 million outpatient visits and 58K hospitalizations in children <5 years of age.7RSV trends and surveillance.CDC. 2022; (Available at:) (Accessed March 29, 2022.)https://www.cdc.gov/rsv/research/us-surveillance.htmlGoogle Scholar Currently, no vaccine exists for either RSV or HPIV, although critical new developments in RSV vaccine design and the development of therapeutic antibodies offer hope.11Simões EAF Center KJ Tita ATN et al.Prefusion F protein-based respiratory syncytial virus immunization in pregnancy.N Engl J Med. 2022; 386: 1615-1626https://doi.org/10.1056/NEJMoa2106062Crossref PubMed Scopus (8) Google Scholar,12Hammitt LL Dagan R Yuan Y et al.Nirsevimab for prevention of RSV in healthy late-preterm and term infants.N Engl J Med. 2022; 386: 837-846https://doi.org/10.1056/NEJMoa2110275Crossref PubMed Scopus (40) Google Scholar Endemic human coronaviruses (HCoV) make up a family of “common cold” viruses with similar symptoms, resulting in, on average, 1 billion annual infections in the US alone.13Islam A Ferdous J Islam S et al.Evolutionary dynamics and epidemiology of endemic and emerging coronaviruses in humans, domestic animals, and wildlife.Viruses. 2021; 13https://doi.org/10.3390/V13101908Crossref Google Scholar While rhinoviruses also cause common cold symptoms, endemic coronaviruses are often associated with more a more severe symptomatic response, especially in young and aged populations. Four endemic coronaviruses are commonly associated with upper respiratory tract infections, including HCoV 229E, HCoV OC43, HCoV NL63, and HCoV HKU1. All contemporary human coronaviruses have origins in wildlife, including bats, cattle, and mice over the past few hundred years.14Mulabbi EN Tweyongyere R Byarugaba DK. The history of the emergence and transmission of human coronaviruses.Onderstepoort J Vet Res. 2021; 88: 1-8https://doi.org/10.4102/OJVR.V88I1.1872Crossref Google Scholar,15Huynh J Li S Yount B et al.Evidence supporting a zoonotic origin of human coronavirus strain NL63.J Virol. 2012; 86: 12816-12825https://doi.org/10.1128/JVI.00906-12Crossref PubMed Scopus (175) Google Scholar The more historic of these viruses, 229E and OC43, were identified in the late 1960s and are highly prevalent in children.13Islam A Ferdous J Islam S et al.Evolutionary dynamics and epidemiology of endemic and emerging coronaviruses in humans, domestic animals, and wildlife.Viruses. 2021; 13https://doi.org/10.3390/V13101908Crossref Google Scholar HCoV infection typically elicits the common cold, but the very young and old or persons with co-morbidities can develop more severe conditions such as pneumonia and bronchiolitis. Additional studies are needed to determine if some HCoV strains cause more severe disease than others as lethal outbreaks of HCoV OC43 have been reported in retirement communities and other HCoV infections have been associated with life threatening infections in infants and the elderly.16Patrick DM Petric M Skowronski DM et al.An outbreak of human coronavirus OC43 infection and serological cross-reactivity with SARS coronavirus.Canad J Infect Dis Med Microbiol. 2006; 17: 330-336https://doi.org/10.1155/2006/152612Crossref PubMed Scopus (98) Google Scholar Importantly, NL63 and HKU1 were first identified in the early 2000s and are associated with widespread, mild, self-limiting upper respiratory infections.13Islam A Ferdous J Islam S et al.Evolutionary dynamics and epidemiology of endemic and emerging coronaviruses in humans, domestic animals, and wildlife.Viruses. 2021; 13https://doi.org/10.3390/V13101908Crossref Google Scholar However, HKU1 has also been known to cause a high incidence of febrile seizures in children in addition to cold-like symptoms and was initially isolated from a life-threatening infection in a patient during the SARS-CoV epidemic. As seen with RSV and HPIV, all four endemic coronaviruses lack an effective vaccine or treatment, dictating a need for adequate models and investment to efficiently develop countermeasures using human lung tissue models. While endemic coronaviruses make up a large proportion of human respiratory infections each year, numerous highly pathogenic epidemic coronaviruses have emerged in the last two decades, exacerbating the need for human respiratory models to study prophylactic and therapeutic treatments, such as vaccines and antivirals. In 2002, the emergence of SARS-CoV caused over 8K cases, 800 deaths, and approximately 11% mortality in the Asian-Pacific region and Canada.17Abdelrahman Z Li M Wang X. Comparative review of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A respiratory viruses.Front Immunol. 2020; 11https://doi.org/10.3389/fimmu.2020.552909Crossref PubMed Scopus (172) Google Scholar,18Kirtipal N Bharadwaj S Kang SG. From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses.Infect Genet Evol. 2020; 85https://doi.org/10.1016/J.MEEGID.2020.104502Crossref PubMed Google Scholar In 2012, MERS-CoV was discovered in Saudi Arabia and quickly spread to multiple countries in the Middle East outside the Arabian Peninsula, resulting in over 2,500 cases, 800 deaths, and ∼35% mortality from 27 countries.17Abdelrahman Z Li M Wang X. Comparative review of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A respiratory viruses.Front Immunol. 2020; 11https://doi.org/10.3389/fimmu.2020.552909Crossref PubMed Scopus (172) Google Scholar Finally, in 2019, the emergence of SARS-CoV-2, the virus responsible for COVID-19, rapidly evolved into an on-going global pandemic that has caused over 500 million cases and over 6 million deaths thus far.19COVID-19 Map - Johns Hopkins Coronavirus Resource Center. Available at: https://coronavirus.jhu.edu/map.html. Accessed April 19, 2022Google Scholar Symptomatically, these three emerging epidemic coronaviruses share common clinical features such as sore throat, cough, fever, headaches, myalgia, and possible progression to acute respiratory distress syndrome (ARDS) in severe cases.17Abdelrahman Z Li M Wang X. Comparative review of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A respiratory viruses.Front Immunol. 2020; 11https://doi.org/10.3389/fimmu.2020.552909Crossref PubMed Scopus (172) Google Scholar,20Pustake M Tambolkar I Giri P Gandhi C. SARS, MERS and CoVID-19: An overview and comparison of clinical, laboratory and radiological features.J Family Med Prim Care. 2022; 11: 10https://doi.org/10.4103/JFMPC.JFMPC_839_21Crossref PubMed Google Scholar However, these viruses vary in other prominent symptoms, such as malaise and loss of taste and smell following SARS-CoV-2 infection, a large proportion of patients experiencing diarrhea following SARS-CoV infection, and possible renal injury and failure following MERS-CoV and SARS-CoV-2 infection.20Pustake M Tambolkar I Giri P Gandhi C. SARS, MERS and CoVID-19: An overview and comparison of clinical, laboratory and radiological features.J Family Med Prim Care. 2022; 11: 10https://doi.org/10.4103/JFMPC.JFMPC_839_21Crossref PubMed Google Scholar,21Legrand M Bell S Forni L et al.Pathophysiology of COVID-19-associated acute kidney injury.Nat Rev Nephrol 2021 17:11. 2021; 17: 751-764https://doi.org/10.1038/s41581-021-00452-0Crossref Scopus (115) Google Scholar Given the highly plastic nature of coronavirus genomes, it is not surprising that these viruses have evolved and emerged well adapted to human hosts. However, the recent SARS-CoV-2 virus has continued to adapt throughout the pandemic, resulting in a number of recent variants, including 9 variants of interest and 5 variants of concern.22Tracking SARS-CoV-2 variants Available at: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/. Accessed March 31, 2022.Google Scholar,23Koelle K Martin MA Antia R Lopman B Dean NE. The changing epidemiology of SARS-CoV-2.Science (1979). 2022; 375: 1116-1121https://doi.org/10.1126/SCIENCE.ABM4915Crossref PubMed Scopus (0) Google Scholar The variability of this virus presents a challenge to developing universal vaccines and therapeutics that remain effective against current and future variants or viruses.24DeGrace MM Ghedin E Frieman MB et al.Defining the risk of SARS-CoV-2 variants on immune protection.Nature. 2022; 31 (Published online March)https://doi.org/10.1038/s41586-022-04690-5Crossref Scopus (15) Google Scholar In the human lung, SARS-CoV and SARS-CoV-2 primarily target airway epithelial cells reflecting high levels of hACE2 receptors and TMPRSS2 protease entry components.25Muus C Luecken MD Eraslan G et al.Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.Nat Med. 2021; 27: 546-559https://doi.org/10.1038/s41591-020-01227-zCrossref PubMed Scopus (117) Google Scholar, 26Deprez M Zaragosi LE Truchi M et al.A single-cell atlas of the human healthy airways.Am J Respir Crit Care Med. 2020; 202: 1636-1645https://doi.org/10.1164/RCCM.201911-2199OCCrossref PubMed Scopus (0) Google Scholar, 27Sungnak W Huang N Bécavin C et al.SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.Na Med. 2020; 26: 681-687https://doi.org/10.1038/s41591-020-0868-6Crossref PubMed Scopus (1463) Google Scholar In addition, low levels of virus replication are oftentimes seen in secretory goblet cells and club cells lining the smaller airways. In the gas exchange region of the lung, these Sarbecoviruses primarily target alveolar epithelial type 2 (AT2) cells, and to a lesser extent alveolar epithelial type 1 (AT1) cells.28Hou YJ Okuda K Edwards CE et al.SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract.Cell. 2020; 182: 429https://doi.org/10.1016/J.CELL.2020.05.042Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,29Xu J Xu X Jiang L Dua K Hansbro PM Liu G. SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis.Respir Res. 2020; 21: 1-12https://doi.org/10.1186/S12931-020-01445-6/FIGURES/7Crossref PubMed Google Scholar In contrast, MERS-CoV targets non-ciliated airway epithelial cells in the conducting airways and AT2 and AT1 cells in the alveoli. MERS-CoV also replicates efficiently in lung fibroblasts and lung endothelial cells, reflecting the wider distribution of the dipeptidyl peptidase receptor and TMPRSS2 protease distributions in the human lung.30Scobey T Yount BL Sims AC et al.Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus.Proc Natl Acad Sci U S A. 2013; 110: 16157-16162https://doi.org/10.1073/PNAS.1311542110/SUPPL_FILE/PNAS.201311542SI.PDFCrossref PubMed Scopus (0) Google Scholar,31Sims AC Mitchell HD Gralinski LE et al.Unfolded protein response inhibition reduces middle east respiratory syndrome coronavirus-induced acute lung injury.mBio. 2021; 12https://doi.org/10.1128/MBIO.01572-21Crossref PubMed Google Scholar Organoid models that allow for emerging coronavirus replication in the presence of multiple tissues and inflammatory cells of the human lung have the potential to offer exciting new insights into virus-host interactions and pathogenesis. Recent advances in technologies, like single-cell RNA sequencing, GeoMx, and CODEX Multiplexed Tissue Staining and Image Acquisition and related technologies allow for detailed characterization of human host innate and acquired immunologic responses at single cell resolution. Although biopsies and bronchial alveolar lavage fluids provide for infrequent but targeted longitudinal sampling opportunities, however, most of these genomic analyses focus on samples derived from end stage lung samples associated with lethal outcomes, thereby missing many of the critical time-ordered events associated with infection, clearance, disease progression and/or repair of the lung. Consequently, the virologic, host and immunologic factors that contribute to altered disease outcomes in humans remains a critical question in viral pathogenesis, the development of treatments and vaccines. Moreover, direct acting antivirals have limited opportunities for reversing disease progression in human patients unless given early in infection. Especially evident after influenza, RSV, and emerging coronavirus infections, disease severity is associated with complex immune pathologic and host response patterns, which can progress to end stage lung diseases. Therefore, later stage pathologic features require treatment modalities that focus on mitigating disease enhancing host response networks and/or immunopathologic signatures, dictating the need for host and immune based interventions that do not directly target live virus replication. Variation in disease severity can be attributed to microvariation in virus strain and sequence variants, changes in virus antigenicity, cell tropism, mutations that enhance virus replication/gene expression and the presence of viral genes that antagonize host innate immune responses. Moreover, natural genetic variation in outbred human populations, which present either as strong monogenic or polygenic traits, can regulate virus disease severity across individuals and promote pathogenic or protective immune/host responses that promote lethal disease.32Niemi MEK Karjalainen J Liao RG et al.Mapping the human genetic architecture of COVID-19.Nature. 2021; 600: 472-477https://doi.org/10.1038/s41586-021-03767-xCrossref PubMed Scopus (227) Google Scholar While many immune responses occur within the airway epithelium, multiple subtypes of lymphoid cells and myeloid cells play critical roles in lung development, homeostasis, immunity and disease, including acute lung injury, lung fibrosis, and chronic obstructive pulmonary disease (COPD).33Ji JJ Fan J. Discovering myeloid cell heterogeneity in the lung by means of next generation sequencing.Mil Med Res. 2019; 6: 1-10https://doi.org/10.1186/S40779-019-0222-9/FIGURES/1Crossref PubMed Google Scholar As human studies provide discovery and correlative insights into the virologic, immunologic and host responses that associate with disease severity, more definitive model platforms are needed to validate host and immunologic response patterns associated with severe in vivo disease. Recent developments in long term expansion of primary human cells and complex organoid models derived from the proximal to distal lung provide a suitable strategy to study cell and tissue specific host response patterns after infection, the role of host genetics on virus replication efficiency and a platform to perturbate key host responses predicted to regulate disease severity. This review focuses on new discoveries in lung organoid biology and biochemistry related to viral pathogenesis associated with contemporary and newly emerging viral diseases of humans. Human organoid models provide a reliable platform to study virus-host interactions in the proximal to distal lung in the absence of a human in vivo model. Alternatively, these cultures provide an ex vivo model that presents the in vivo environment and recapitulates the structure and function of the native human lung. While commonly used 2D human airway epithelial cultures provide a resource for understanding viral fitness and potential efficacy of clinical interventions, they fail to represent the 3D lung structure and interactions between cells that is conferred by organoid models. Additionally, such ex vivo models can be adapted to represent differing compartments of the respiratory tract, providing novel opportunities to study virus tropism, virus tissue specific host response patterns, lung function, disease pathology, and provide a suitable platform to target therapeutics of various viruses by focusing on distinct cell types or areas of the lung. Historically, human primary cells have been used to reveal mechanisms essential to virus-host interactions and as a platform to evaluate drug performance in key cell types within the human respiratory tract that are targeted by virulent viruses.34Schäfer A Martinez DR Won JJ et al.Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice.Sci Transl Med. 2022; 22 (Published online March)https://doi.org/10.1126/SCITRANSLMED.ABM3410Crossref Google Scholar, 35Sheahan TP Sims AC Leist SR et al.Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV.Nat Commun. 2020; 11https://doi.org/10.1038/S41467-019-13940-6Crossref PubMed Google Scholar, 36Sheahan TP Sims AC Graham RL et al.Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.Sci Transl Med. 2017; 9https://doi.org/10.1126/SCITRANSLMED.AAL3653Crossref PubMed Google Scholar However, these models fail to fully replicate the native environment of the human lung, including complex cellular interactions between virus and host epithelium and the host immune response. These models do, however, provide a strong foundation for understanding viral pathogenesis and potential targets for clinical interventions in vitro. These cells can be harvested and cultured to represent the nasal cavity, the large airway consisting of the bronchi, and the small airway consisting of the bronchioles and alveoli (Fig 1).37Sheahan TP Sims AC Zhou S et al.An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.Sci Transl Med. 2020; 12https://doi.org/10.1126/SCITRANSLMED.ABB5883Crossref PubMed Scopus (539) Google Scholar Human airway cultures are ground on porous membranes at an air-liquid interface (ALI) that mimics that air-liquid barrier of the epithelium lining to respiratory tract.38Fulcher ML Randell SH. Human nasal and tracheo-bronchial respiratory epithelial cell culture.Methods Mol Biol. 2013; 945: 109-121https://doi.org/10.1007/978-1-62703-125-7_8Crossref PubMed Scopus (169) Google Scholar,39Fulcher ML Gabriel S Burns KA Yankaskas JR Randell SH Well-differentiated human airway epithelial cell cultures.Methods Mol Med. 2005; 107: 183-206https://doi.org/10.1385/1-59259-861-7:183Crossref PubMed Google Scholar Once differentiated and matured, these cells as a whole can provide clues about viral pathogenesis and the innate immune response from the proximal to distal airway. Additional human primary cell types that do not require an air-liquid interface, such as fibroblasts and microvascular endothelial cells, can be cultured in order to further tease apart cellular tropism and phenotype following viral infection. 3D models, such as human organoids, involve arranged complex structures of multiple cells that can self-organize to replicate in vivo tissue structure and morphology while mimicking cellular interactions and the dynamic regulation of signaling pathways in an ex vivo culture. Organoids derived from human pluripotent stem cells (hPSC) are the most common and well-known type of human organoids that can be derived from peripheral blood and differentiated towards airway and alveolar epithelial cells.40Konishi S Gotoh S Tateishi K et al.Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells.Stem Cell Reports. 2016; 6: 18-25https://doi.org/10.1016/J.STEMCR.2015.11.010Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,41Gotoh S Ito I Nagasaki T et al.Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells.Stem Cell Reports. 2014; 3: 394-403https://doi.org/10.1016/J.STEMCR.2014.07.005Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar hPSC derived organoids have a broad use as they can be induced to differentiate into specific cell lineages and form tissue-specific organoids using biochemical signaling and cellular markers that orchestrate the process during embryonic development in which a zygote matures into a self-organized unit of cells as an organ.42Tian L Gao J Garcia IM Chen HJ Castaldi A Chen Y. Human pluripotent stem cell-derived lung organoids: potential applications in development and disease modeling.WIREs Devel Biol. 2021; 10https://doi.org/10.1002/wdev.399Crossref Scopus (18) Google Scholar,43Porotto M Ferren M Chen YW et al.Authentic modeling of human respiratory virus infection in human pluripotent stem cell-derived lung organoids.mBio. 2019; 10https://doi.org/10.1128/mBio.00723-19Crossref Scopus (77) Google Scholar These cells are then co-cultured with mesenchymal and endothelial cells to stimulate the generation and maturation of a 3D organoid structure that represents a section of the human lung. Once matured, hPSC derived organoids can possess both upper and lower respiratory-like epithelium containing basal cells, ciliated cells or alveolar-like structures, respectively. However, hPSC-derived organoids may not completely recapitulate the functionality and gene expression profiles compare to mature cells of adult human lungs. Despite this limitation, hPSC remain a reliable tool for studying both viral-host interactions, pathogenesis, and clinical interventions as they better replicate the human airway than previously developed models of the human respiratory tract.44Hsia GSP Esposito J da Rocha LA Ramos SLG Okamoto OK. Clinical application of human induced pluripotent stem cell-derived organoids as an alternative to organ transplantation.Stem Cells Int. 2021; : 2021https://doi.org/10.1155/2021/6632160Crossref Scopus (8) Google Scholar,45Li Y Wu Q Sun X Shen J Chen H. Organoids as a powerful model for respiratory diseases.Stem Cells Int. 2020; 2020: 1-8https://doi.org/10.1155/2020/5847876Crossref Scopus (35) Google Scholar While hPSC derived lung organo" @default.
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• W4285604310 title "Human lung organoids as a model for respiratory virus replication and countermeasure performance in human hosts" @default.
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