病因学
病毒学
感染由新型 β 冠状病毒中东呼吸综合征冠状病毒 (Middle East respiratory syndrome coronavirus, MERS-CoV) 引起,这是一种有包膜的正义单链 RNA 病毒,其基因组大小约为 30,000 个核苷酸。[34]van Boheemen S, de Graaf M, Lauber C, et al. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio. 2012;3:e00473-12. http://mbio.asm.org/content/3/6/e00473-12.full http://www.ncbi.nlm.nih.gov/pubmed/23170002?tool=bestpractice.com
该病毒属于冠状病毒科(目:网巢病毒目;亚科:冠状病毒亚科;属:乙型冠状病毒属),谱系 C 组。[1]Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814-1820. http://www.nejm.org/doi/full/10.1056/NEJMoa1211721#t=article http://www.ncbi.nlm.nih.gov/pubmed/23075143?tool=bestpractice.com [2]Raj VS, Osterhaus AD, Fouchier RA, et al. MERS: emergence of a novel human coronavirus. Curr Opin Virol. 2014;5:58-62. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028407/ http://www.ncbi.nlm.nih.gov/pubmed/24584035?tool=bestpractice.com 它在种系进化方面不同于所有之前已知的 β 冠状病毒属病毒,包括人类冠状病毒 HKU1 和 OC43、严重急性呼吸综合征 (severe acute respiratory syndrome, SARS) 冠状病毒和蝙蝠冠状病毒 HKU4、HKU5 和 HKU9。[3]Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522. http://www.ncbi.nlm.nih.gov/pubmed/25810418?tool=bestpractice.com
MERS-CoV 基因组分为 2 个进化枝:进化枝 A(最早感染的群,即 EMC/2012 和 Jordan N3/2012)和进化枝 B(基因上不同于进化枝 A 的新群)。[35]Cotten M, Watson SJ, Zumla AI, et al. Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus. MBio. 2014;5:e01062-13. http://mbio.asm.org/content/5/1/e01062-13.full http://www.ncbi.nlm.nih.gov/pubmed/24549846?tool=bestpractice.com
动物宿主
人们认为单峰骆驼是 MERS-CoV 的主要动物宿主。[36]Omrani AS, Shalhoub S. Middle East respiratory syndrome coronavirus (MERS-CoV): what lessons can we learn? J Hosp Infect. 2015;91:188-196. http://www.ncbi.nlm.nih.gov/pubmed/26452615?tool=bestpractice.com
多项研究均在阿拉伯半岛及其周边国家/地区的骆驼血清中发现了这种病毒的抗体,其中一些研究可追溯到 20 世纪 90 年代。[37]Reusken CB, Haagmans BL, Muller MA, et al. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis. 2013;13:859-866. http://www.ncbi.nlm.nih.gov/pubmed/23933067?tool=bestpractice.com [38]Reusken CB, Ababneh M, Raj VS, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) serology in major livestock species in an affected region in Jordan, June to September 2013. Euro Surveill. 2013;18:20662. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20662 http://www.ncbi.nlm.nih.gov/pubmed/24342516?tool=bestpractice.com [39]Perera RA, Wang P, Gomaa MR, et al. Seroepidemiology for MERS coronavirus using microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in dromedary camels in Egypt, June 2013. Euro Surveill. 2013;18:20574. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20574 http://www.ncbi.nlm.nih.gov/pubmed/24079378?tool=bestpractice.com [40]Muller MA, Corman VM, Jores J, et al. MERS coronavirus neutralizing antibodies in camels, Eastern Africa, 1983-1997. Emerg Infect Dis. 2014;20:2093-2095. https://wwwnc.cdc.gov/eid/article/20/12/14-1026_article http://www.ncbi.nlm.nih.gov/pubmed/25425139?tool=bestpractice.com [41]Meyer B, Muller MA, Corman VM, et al. Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg Infect Dis. 2014;20:552-559. https://wwwnc.cdc.gov/eid/article/20/4/13-1746_article http://www.ncbi.nlm.nih.gov/pubmed/24655412?tool=bestpractice.com [42]Hemida MG, Perera RA, Wang P, et al. Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Euro Surveill. 2013;18:20659. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20659 http://www.ncbi.nlm.nih.gov/pubmed/24342517?tool=bestpractice.com [43]Corman VM, Jores J, Meyer B, et al. Antibodies against MERS coronavirus in dromedary camels, Kenya, 1992-2013. Emerg Infect Dis. 2014;20:1319-1322. https://wwwnc.cdc.gov/eid/article/20/8/14-0596_article http://www.ncbi.nlm.nih.gov/pubmed/25075637?tool=bestpractice.com [44]Alagaili AN, Briese T, Mishra N, et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio. 2014;5:e00884-14. http://mbio.asm.org/content/5/2/e00884-14.full http://www.ncbi.nlm.nih.gov/pubmed/24570370?tool=bestpractice.com [45]Alexandersen S, Kobinger GP, Soule G, et al. Middle East respiratory syndrome coronavirus antibody reactors among camels in Dubai, United Arab Emirates, in 2005. Transbound Emerg Dis. 2014;61:105-108. http://onlinelibrary.wiley.com/doi/10.1111/tbed.12212/full http://www.ncbi.nlm.nih.gov/pubmed/24456414?tool=bestpractice.com [46]Ferguson NM, Van Kerkhove MD. Identification of MERS-CoV in dromedary camels. Lancet Infect Dis. 2014;14:93-94. http://www.ncbi.nlm.nih.gov/pubmed/24355867?tool=bestpractice.com [47]Hemida MG, Chu DK, Poon LL, et al. MERS coronavirus in dromedary camel herd, Saudi Arabia. Emerging Infect Dis. 2014;20:1231-1234. https://wwwnc.cdc.gov/eid/article/20/7/14-0571_article http://www.ncbi.nlm.nih.gov/pubmed/24964193?tool=bestpractice.com [48]Hemida MG, Elmoslemany A, Al-Hizab F, et al. Dromedary camels and the transmission of Middle East respiratory syndrome coronavirus (MERS-CoV). Transbound Emerg Dis. 2017;64:344-353. http://www.ncbi.nlm.nih.gov/pubmed/26256102?tool=bestpractice.com [49]Hemida MG, Perera RA, Al Jassim RA, et al. Seroepidemiology of Middle East respiratory syndrome (MERS) coronavirus in Saudi Arabia (1993) and Australia (2014) and characterisation of assay specificity. Euro Surveill. 2014;19:20828. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20828 http://www.ncbi.nlm.nih.gov/pubmed/24957744?tool=bestpractice.com [50]Nowotny N, Kolodziejek J. Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels, Oman, 2013. Euro Surveill. 2014;19:20781. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20781 http://www.ncbi.nlm.nih.gov/pubmed/24786259?tool=bestpractice.com
在这些骆驼的鼻腔和粪便样本中还分离出了 MERS-CoV RNA 以及可存活的病毒。[44]Alagaili AN, Briese T, Mishra N, et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio. 2014;5:e00884-14. http://mbio.asm.org/content/5/2/e00884-14.full http://www.ncbi.nlm.nih.gov/pubmed/24570370?tool=bestpractice.com [51]Yusof MF, Eltahir YM, Serhan WS, et al. Prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels in Abu Dhabi Emirate, United Arab Emirates. Virus Genes. 2015;50:509-513. http://www.ncbi.nlm.nih.gov/pubmed/25653016?tool=bestpractice.com [52]Farag EA, Reusken CB, Haagmans BL, et al. High proportion of MERS-CoV shedding dromedaries at slaughterhouse with a potential epidemiological link to human cases, Qatar 2014. Infect Ecol Epidemiol. 2015;5:28305. http://www.tandfonline.com/doi/full/10.3402/iee.v5.28305 http://www.ncbi.nlm.nih.gov/pubmed/26183160?tool=bestpractice.com [53]Briese T, Mishra N, Jain K, et al. Middle East respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in Saudi Arabia. MBio. 2014;5:e01146-14. http://mbio.asm.org/content/5/3/e01146-14.full http://www.ncbi.nlm.nih.gov/pubmed/24781747?tool=bestpractice.com 骆驼可能没有感染征象,但仍然会在鼻腔分泌液、粪便、乳汁或尿液中排出病毒。
针对骆驼诱发的实验性 MERS-CoV 感染可导致轻度呼吸道感染和轻度发热。[54]Adney DR, van Doremalen N, Brown VR, et al. Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis. 2014;20:1999-2005. https://wwwnc.cdc.gov/eid/article/20/12/14-1280_article http://www.ncbi.nlm.nih.gov/pubmed/25418529?tool=bestpractice.com
蝙蝠也被视作 MERS-CoV 的早期宿主;然而,这一点尚未得到证实。[55]Anthony SJ, Gilardi K, Menachery VD, et al. Further evidence for bats as the evolutionary source of Middle East respiratory syndrome coronavirus. MBio. 2017;8:e00373-17. http://mbio.asm.org/content/8/2/e00373-17.long http://www.ncbi.nlm.nih.gov/pubmed/28377531?tool=bestpractice.com
动物与人之间的传播
确切的传播方式尚不清楚,人们认为传播途径为直接或间接接触单峰骆驼(例如挤骆驼奶,接触骆驼鼻腔分泌物、尿液或粪便)或食用骆驼产品(例如未经巴氏消毒的骆驼奶,未加工或未煮熟的骆驼肉)。
在沙特阿拉伯、卡塔尔和阿拉伯联合酋长国,从与流行病相关的单峰骆驼和人类病例中分离出了几乎相同的病毒株。[31]Memish ZA, Cotten M, Watson SJ, et al. Community case clusters of Middle East respiratory syndrome coronavirus in Hafr Al-Batin, Kingdom of Saudi Arabia: a descriptive genomic study. Int J Infect Dis. 2014;23:63-68. http://www.ijidonline.com/article/S1201-9712(14)01451-9/fulltext http://www.ncbi.nlm.nih.gov/pubmed/24699184?tool=bestpractice.com [56]Haagmans BL, Al Dhahiry SH, Reusken CB, et al. Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. Lancet Infect Dis. 2014;14:140-145. http://www.ncbi.nlm.nih.gov/pubmed/24355866?tool=bestpractice.com [57]Al Hammadi AM, Chu DKW, Eltahir YM, et al. Asymptomatic MERS-CoV infection in humans possibly linked to infected dromedaries imported from Oman to United Arab Emirates, May 2015. Emerg Infect Dis. 2015;21:2197-2200. https://wwwnc.cdc.gov/eid/article/21/12/15-1132_article http://www.ncbi.nlm.nih.gov/pubmed/26584223?tool=bestpractice.com 骆驼与人之间的传播最有力证据来自沙特阿拉伯的一项研究,该研究从患者和他的一只骆驼中分离出病毒,发现基因组几乎相同。[58]Memish ZA, Cotten M, Meyer B, et al. Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg Infect Dis. 2014;20:1012-1015. https://wwwnc.cdc.gov/eid/article/20/6/14-0402_article http://www.ncbi.nlm.nih.gov/pubmed/24857749?tool=bestpractice.com [59]Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med. 2014;370:2499-2505. http://www.nejm.org/doi/full/10.1056/NEJMoa1401505#t=article http://www.ncbi.nlm.nih.gov/pubmed/24896817?tool=bestpractice.com 然而,骆驼与人之间传播方面也存在不一致性,因此需要通过更多数据来更好地理解传播原理。[60]Hemida MG, Al-Naeem A, Perera RA, et al. Lack of Middle East respiratory syndrome coronavirus transmission from infected camels. Emerg Infect Dis. 2015;21:699-701. https://wwwnc.cdc.gov/eid/article/21/4/14-1949_article http://www.ncbi.nlm.nih.gov/pubmed/25811546?tool=bestpractice.com
一项病例对照研究发现,与骆驼接触是感染 MERS-CoV 的一个危险因素。[61]Alraddadi BM, Watson JT, Almarashi A, et al. Risk factors for primary Middle East respiratory syndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerg Infect Dis. 2016;22:49-55. https://wwwnc.cdc.gov/eid/article/22/1/15-1340_article http://www.ncbi.nlm.nih.gov/pubmed/26692185?tool=bestpractice.com
人与人之间的传播
大多数病例是人际间传播(而非骆驼与人之间传播)的结果,确诊病例的高峰出现于医院暴发期间。[6]Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah - a link to health care facilities. N Engl J Med. 2015;372:846-854. http://www.nejm.org/doi/full/10.1056/NEJMoa1408636#t=article http://www.ncbi.nlm.nih.gov/pubmed/25714162?tool=bestpractice.com [7]Assiri A, McGeer A, Perl TM, et al. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013;369:407-416. http://www.nejm.org/doi/full/10.1056/NEJMoa1306742#t=article http://www.ncbi.nlm.nih.gov/pubmed/23782161?tool=bestpractice.com [27]Alenazi TH, Al Arbash H, El-Saed A, et al. Identified transmission dynamics of Middle East respiratory syndrome coronavirus infection during an outbreak: implications of an overcrowded emergency department. Clin Infect Dis. 2017;65:675-679. http://www.ncbi.nlm.nih.gov/pubmed/28575307?tool=bestpractice.com 尽管如此,通常认为人际间传播效率较低。
病毒通过感染者的呼吸道飞沫(如咳嗽、打喷嚏)或与感染者密切接触而发生传播。但不排除通过空气传播或污染物传播的可能性。[62]Kim SH, Chang SY, Sung M, et al. Extensive viable Middle East respiratory syndrome (MERS) coronavirus contamination in air and surrounding environment in MERS isolation wards. Clin Infect Dis. 2016;63:363-369. https://academic.oup.com/cid/article/63/3/363/2595016/Extensive-Viable-Middle-East-Respiratory-Syndrome http://www.ncbi.nlm.nih.gov/pubmed/27090992?tool=bestpractice.com 潜伏期为 2 至 14 天,传播发生在有症状阶段或潜伏阶段。[8]Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013;13:752-761. http://www.ncbi.nlm.nih.gov/pubmed/23891402?tool=bestpractice.com [63]Centers for Disease Control and Prevention. MERS clinical features. September 2017 [internet publication]. http://www.cdc.gov/coronavirus/mers/clinical-features.html
据病例记录显示,传播呈现家族聚集性。[17]Abroug F, Slim A, Ouanes-Besbes L, et al. Family cluster of Middle East respiratory syndrome coronavirus infections, Tunisia, 2013. Emerg Infect Dis. 2014;20:1527-1530. http://www.ncbi.nlm.nih.gov/pubmed/25148113?tool=bestpractice.com [28]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309-318. https://academic.oup.com/cid/article/58/3/309/340555/Executive-Summary-2013-IDSA-Clinical-Practice http://www.ncbi.nlm.nih.gov/pubmed/24421306?tool=bestpractice.com [29]Memish ZA, Zumla AI, Al-Hakeem RF, et al. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med. 2013;368:2487-2494. http://www.nejm.org/doi/full/10.1056/NEJMoa1303729#t=article http://www.ncbi.nlm.nih.gov/pubmed/23718156?tool=bestpractice.com 然而,报告显示,更常见的传播形式为医院内(例如血液透析室、重症监护病房、内科病房)暴发。[6]Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah - a link to health care facilities. N Engl J Med. 2015;372:846-854. http://www.nejm.org/doi/full/10.1056/NEJMoa1408636#t=article http://www.ncbi.nlm.nih.gov/pubmed/25714162?tool=bestpractice.com [7]Assiri A, McGeer A, Perl TM, et al. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013;369:407-416. http://www.nejm.org/doi/full/10.1056/NEJMoa1306742#t=article http://www.ncbi.nlm.nih.gov/pubmed/23782161?tool=bestpractice.com [29]Memish ZA, Zumla AI, Al-Hakeem RF, et al. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med. 2013;368:2487-2494. http://www.nejm.org/doi/full/10.1056/NEJMoa1303729#t=article http://www.ncbi.nlm.nih.gov/pubmed/23718156?tool=bestpractice.com [30]Omrani AS, Matin MA, Haddad Q, et al. A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J Infect Dis. 2013;17:e668-e672. http://www.ijidonline.com/article/S1201-9712(13)00225-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/23916548?tool=bestpractice.com [31]Memish ZA, Cotten M, Watson SJ, et al. Community case clusters of Middle East respiratory syndrome coronavirus in Hafr Al-Batin, Kingdom of Saudi Arabia: a descriptive genomic study. Int J Infect Dis. 2014;23:63-68. http://www.ijidonline.com/article/S1201-9712(14)01451-9/fulltext http://www.ncbi.nlm.nih.gov/pubmed/24699184?tool=bestpractice.com [32]Al-Abdallat MM, Payne DC, Alqasrawi S, et al. Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description. Clin Infect Dis. 2014;59:1225-1233. https://academic.oup.com/cid/article/59/9/1225/419021/Hospital-Associated-Outbreak-of-Middle-East http://www.ncbi.nlm.nih.gov/pubmed/24829216?tool=bestpractice.com 这可能由多个因素造成,包括发现感染较晚、院内患者过度拥挤,以及感染控制预防措施不足。[6]Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah - a link to health care facilities. N Engl J Med. 2015;372:846-854. http://www.nejm.org/doi/full/10.1056/NEJMoa1408636#t=article http://www.ncbi.nlm.nih.gov/pubmed/25714162?tool=bestpractice.com [26]Saad M, Omrani AS, Baig K, et al. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis. 2014;29:301-306. http://www.ijidonline.com/article/S1201-9712(14)01622-1/fulltext http://www.ncbi.nlm.nih.gov/pubmed/25303830?tool=bestpractice.com [28]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309-318. https://academic.oup.com/cid/article/58/3/309/340555/Executive-Summary-2013-IDSA-Clinical-Practice http://www.ncbi.nlm.nih.gov/pubmed/24421306?tool=bestpractice.com [30]Omrani AS, Matin MA, Haddad Q, et al. A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J Infect Dis. 2013;17:e668-e672. http://www.ijidonline.com/article/S1201-9712(13)00225-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/23916548?tool=bestpractice.com [64]Park HY, Lee EJ, Ryu YW, et al. Epidemiological investigation of MERS-CoV spread in a single hospital in South Korea, May to June 2015. Euro Surveill. 2015;20:21169. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21169 http://www.ncbi.nlm.nih.gov/pubmed/26132766?tool=bestpractice.com 患者周边环境大面积污染,以及该病毒在塑料和金属表面长期存活的能力,为疫情的暴发创造了条件。[65]van Doremalen N, Bushmaker T, Munster VJ. Stability of Middle East respiratory syndrome coronavirus (MERS-CoV) under different environmental conditions. Euro Surveill. 2013;18:20590. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20590 http://www.ncbi.nlm.nih.gov/pubmed/24084338?tool=bestpractice.com [66]Bin SY, Heo JY, Song MS, et al. Environmental contamination and viral shedding in MERS patients during MERS-CoV outbreak in South Korea. Clin Infect Dis. 2016;62:755-760. http://www.ncbi.nlm.nih.gov/pubmed/26679623?tool=bestpractice.com
有效生殖数量小于一时,除非病毒发生突变,否则目前感染的流行潜力很低。[67]Cauchemez S, Van Kerkhove MD, Riley S, et al. Transmission scenarios for Middle East respiratory syndrome coronavirus (MERS-CoV) and how to tell them apart. Euro Surveill. 2013;18:20503. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20503 http://www.ncbi.nlm.nih.gov/pubmed/23787162?tool=bestpractice.com [68]Cauchemez S, Fraser C, Van Kerkhove MD, et al. Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility. Lancet Infect Dis. 2014;14:50-56. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895322/ http://www.ncbi.nlm.nih.gov/pubmed/24239323?tool=bestpractice.com [69]Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet. 2013;382:694-699. http://www.ncbi.nlm.nih.gov/pubmed/23831141?tool=bestpractice.com 与 SARS 相比,此病毒疫情暴发更受SARS 相比,此病毒疫情暴发更受限制。尚未报道超级传播者事件;然而,未来病毒的适应可能会增加人际传播或病毒毒力。
[Figure caption and citation for the preceding image starts]: 中东呼吸综合征冠状病毒 (MERS-CoV) 的薄层电子显微照片,显示受感染细胞胞浆内的球形颗粒美国疾病预防控制中心 (CDC) [Citation ends].
病理生理学
发病机制尚不完全清楚。病毒主要通过感染者的呼吸道飞沫传播,飞沫通过呼吸道粘膜进入人体。[70]Zumla A, Hui DS. Infection control and MERS-CoV in health-care workers. Lancet. 2014;383:1869-1871. http://www.ncbi.nlm.nih.gov/pubmed/24857701?tool=bestpractice.com 该病毒与宿主细胞(例如,I 型和 II 型肺泡细胞、纤毛和无纤毛支气管上皮、内皮、肺泡巨噬细胞、白细胞)表面的功能受体二肽基肽酶-4(DPP4,也称为 CD26)结合。此结合过程由病毒表面刺突 (S) 蛋白 S1 亚单位上的受体结合域介导。[71]Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495:251-254. http://www.ncbi.nlm.nih.gov/pubmed/23486063?tool=bestpractice.com [72]Belouzard S, Millet JK, Licitra BN, et al. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4:1011-1033. http://www.mdpi.com/1999-4915/4/6/1011/htm http://www.ncbi.nlm.nih.gov/pubmed/22816037?tool=bestpractice.com S2 亚单位通过 2 个七肽重复序列结构域(HR1 和 HR2)和 1 个融合蛋白的作用来协助膜融合过程和病毒进入细胞。[73]Xia S, Liu Q, Wang Q, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res. 2014;194:200-210. http://www.ncbi.nlm.nih.gov/pubmed/25451066?tool=bestpractice.com [74]Bosch BJ, Raj VS, Haagmans BL. Spiking the MERS-coronavirus receptor. Cell Res. 2013;23:1069-1070. https://www.nature.com/cr/journal/v23/n9/full/cr2013108a.html http://www.ncbi.nlm.nih.gov/pubmed/23938293?tool=bestpractice.com 该病毒还可以与几个物种(例如骆驼、兔、绵羊、山羊、非人灵长类动物)中的 DPP4 受体结合。
DPP4 可在大多数人体器官(例如肾、肝、肠)的上皮细胞和内皮细胞上表达。这可以解释感染的多系统临床表现,包括重症(有时为致死性)肺炎、急性呼吸窘迫综合征和多器官功能衰竭。[75]Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015;386:995-1007.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721578/
http://www.ncbi.nlm.nih.gov/pubmed/26049252?tool=bestpractice.com
[Figure caption and citation for the preceding image starts]: 负染色电子显微镜检查显示中东呼吸综合征冠状病毒 (MERS-CoV) 颗粒的病毒包膜上有典型的杆状刺突美国疾病预防控制中心 (CDC) [Citation ends].
分类
病毒分类学
MERS-CoV 属于冠状病毒科(目:网巢病毒目;亚科:冠状病毒亚科;属:乙型冠状病毒属),谱系 C 组。[1]Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814-1820. http://www.nejm.org/doi/full/10.1056/NEJMoa1211721#t=article http://www.ncbi.nlm.nih.gov/pubmed/23075143?tool=bestpractice.com [2]Raj VS, Osterhaus AD, Fouchier RA, et al. MERS: emergence of a novel human coronavirus. Curr Opin Virol. 2014;5:58-62. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028407/ http://www.ncbi.nlm.nih.gov/pubmed/24584035?tool=bestpractice.com 它在种系进化方面不同于所有之前已知的 β 冠状病毒属病毒,包括人类冠状病毒 HKU1 和 OC43、严重急性呼吸综合征 (severe acute respiratory syndrome, SARS) 冠状病毒和蝙蝠冠状病毒 HKU4、HKU5 和 HKU9。[3]Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522. http://www.ncbi.nlm.nih.gov/pubmed/25810418?tool=bestpractice.com
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