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1、Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures Renee W. Y. Chan,a,bMichael C. W. Chan,aSudhakar Agnihothram,cLouisa L. Y. Chan,aDenise I. T. Kuok,aJoanne H. M. Fong,a Y. Guan,a,dLeo L. M. Poon,a,dRalph S. Baric,cJ
2、ohn M. Nicholls,bJ. S. Malik Peirisa,d Centre of Infl uenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, Chinaa; Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, Chinab; Departm
3、ents of Epidemiology and Microbiology and Immunology, Gillings School of Global Public Health, and School of Medicine, The University of North Carolina, Chapel Hill, North Carolina, USAc; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Ko
4、ng, Hong Kong SAR, Chinad SinceApril2012,therehavebeen17laboratory-confi rmedhumancasesofrespiratorydiseaseassociatedwithnewlyrecognized humanbetacoronaviruslineageCvirusEMC(HCoV-EMC),and7ofthemwerefatal.Thetransmissibilityandpathogenesisof HCoV-EMCremainpoorlyunderstood,andelucidatingitscellulartro
5、pisminhumanrespiratorytissueswillprovidemechanis- tic insights into the key cellular targets for virus propagation and spread. We utilized ex vivo cultures of human bronchial and lungtissuespecimenstoinvestigatethetissuetropismandvirusreplicationkineticsfollowingexperimentalinfectionwith HCoV-EMCcom
6、paredwiththosefollowinginfectionwithhumancoronavirus229E(HCoV-229E)andsevereacuterespiratory syndromecoronavirus(SARS-CoV).TheinnateimmuneresponseselicitedbyHCoV-EMCwerealsoinvestigated.HCoV-EMC productively replicated in human bronchial and lung ex vivo organ cultures. While SARS-CoV productively r
7、eplicated in lung tissue,replicationinhumanbronchialtissuewaslimited.ImmunohistochemistryrevealedthatHCoV-EMCinfectednonciliated bronchialepithelium,bronchiolarepithelialcells,alveolarepithelialcells,andendothelialcells.Transmissionelectronmicros- copyshowedvirionswithinthecytoplasmofbronchialepithe
8、lialcellsandbuddingvirionsfromalveolarepithelialcells(typeII). Incontrast,therewasminimalHCoV-229Einfectioninthesetissues.HCoV-EMCfailedtoelicitstrongtypeIorIIIinterferon (IFN) or proinfl ammatory innate immune responses in ex vivo respiratory tissue cultures. Treatment of human lung tissue ex vivoo
9、rgancultureswithtypeIIFNs(alphaandbetaIFNs)at1hpostinfectionreducedthereplicationofHCoV-EMC,suggesting apotentialtherapeuticuseofIFNsfortreatmentofhumaninfection. C oronavirus (CoV) infections in humans are generally mild andself-limited.Untiltheoutbreakofsevereacuterespiratory syndrome (SARS) cause
10、d by severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, there was limited research on the tissue tropism and host response following human infection with coronaviruses. In comparison to human betacoronavirus 229E (HCoV-229E), SARS-CoV was found to be defi cient at elic- iting beta int
11、erferon (IFN-?) innate immune responses in pri- mary human macrophages and dendritic cells (1, 2) since SARS- CoV encodes several antagonists of innate immune-sensing and signaling pathways (3, 4). The tropism of SARS-CoV in the respi- ratory tract was primarily restricted to differentiated human ai
12、r- way epithelium (5) and alveolar type II pneumocytes (68), with limited tropism for alveolar type I pneumocytes (9). In2012,anovelcoronaviruswasdetectedintwopatientsfrom Saudi Arabia and Qatar (10, 11). Thereafter, more cases were identifi ed both prospectively and retrospectively in Saudi Arabia,
13、 Qatar,Jordan,andtheUnitedKingdom,andasofFebruary2013, a total of 13 laboratory-confi rmed cases and seven deaths have been reported (12). The apparent severity of this novel coronavi- rus contrasts with those seen for other human coronaviruses (HCoVs), with the exception of SARS-CoV (10, 13). The f
14、i rst reportedcase,whichwasfatal,occurredinJune2012ina60-year- old man in Saudi Arabia (11); the second reported case occurred ina49-year-oldQatarimanwhowastreatedanddischargedinthe United Kingdom. From early case descriptions, it appeared that pneumonia leading to acute respiratory distress syndrom
15、e is the primary manifestation of the disease, but renal dysfunction was also observed in some cases. The WHO has provided a working case defi nition of the disease (12). The disease appears to have an incubation period of up to 10 days and is not easily transmitted between humans. The retrospective
16、 investigation of an outbreak of severe respiratory illness in Zarqa, Jordan, in April 2012 (14) confi rmed that at least some of these cases were also caused by human betacoronavirus lineage C virus EMC (HCoV-EMC). Of the 13 cases confi rmed to date, some have given a history of con- tact with animals (e.g., camels and sheep) (13), and a zoonotic originoftheinfectionisconsideredlikely.Morerecently,anindex case who acquired infection in the Middle East transmitted infec- tiontotwofamilycontactsi
