病因学
寨卡病毒是黄病毒科(黄病毒属)的单链 RNA 病毒,且与登革热、黄热病、西尼罗河病毒和日本脑炎病毒相关。[45]Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009 Sep;15(9):1347-50. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819875/ http://www.ncbi.nlm.nih.gov/pubmed/19788800?tool=bestpractice.com 寨卡病毒的三维结构图显示,寨卡病毒与西尼罗河病毒、日本脑炎病毒和登革热病毒结构相似。[46]Sirohi D, Chen Z, Sun L, et al. The 3.8 Å resolution cryo-EM structure of Zika virus. Science. 2016 Apr 22;352(6284):467-70. http://science.sciencemag.org/content/early/2016/04/01/science.aaf5316.full http://www.ncbi.nlm.nih.gov/pubmed/27033547?tool=bestpractice.com 非结构蛋白 5 (NS5) 的结构也进行了报道,为将来的药物治疗提供了重要靶向。[47]Zhao B, Yi G, Du F, et al. Structure and function of the Zika virus full-length NS5 protein. Nat Commun. 2017 Mar 27;8:14762. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378950/ http://www.ncbi.nlm.nih.gov/pubmed/28345656?tool=bestpractice.com 已经对亚洲和非洲谱系病毒的全基因组进行了测序。[48]Ladner JT, Wiley MR, Prieto K, et al. Complete genome sequences of five Zika virus isolates. Genome Announc. 2016 May 12;4(3). pii: e00377-16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866861/ http://www.ncbi.nlm.nih.gov/pubmed/27174284?tool=bestpractice.com [49]Díaz-Quiñonez JA, Peña-Alonso R, Mendieta-Condado E, et al. Complete genome sequence of Zika virus isolated in Mexico, 2016. Genome Announc. 2016 Aug 4;4(4). pii: e00750-16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974310/ http://www.ncbi.nlm.nih.gov/pubmed/27491989?tool=bestpractice.com 当前主要有两个谱系的病毒:非洲谱系(仅在非洲有病例报道)和亚洲谱系(在亚洲、西太平洋区域、美洲,和佛得角共和国有病例报道)。种系发生分析显示目前的流行株已在其亚洲来源基础上积累了多种替代病毒株,使得现在的病毒株对人类的毒性更强。[50]Yuan L, Huang XY, Liu ZY, et al. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science. 2017 Nov 17;358(6365):933-36. http://science.sciencemag.org/content/early/2017/09/27/science.aam7120.full http://www.ncbi.nlm.nih.gov/pubmed/28971967?tool=bestpractice.com
主要通过已感染伊蚊的叮咬传播给人类。最常由分布于热带地区的埃及伊蚊传播,但也可由分布于温带地区的白纹伊蚊携带。[45]Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009 Sep;15(9):1347-50. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819875/ http://www.ncbi.nlm.nih.gov/pubmed/19788800?tool=bestpractice.com [51]Fauci AS, Morens DM. Zika virus in the Americas - yet another arbovirus threat. N Engl J Med. 2016 Feb 18;374(7):601-4. http://www.nejm.org/doi/full/10.1056/NEJMp1600297 http://www.ncbi.nlm.nih.gov/pubmed/26761185?tool=bestpractice.com 这些同种的蚊子也传播基孔肯雅热、登革热和西尼罗河病毒,不过库蚊是西尼罗河病毒的主要传播媒介。越来越多的证据表明,寨卡病毒也可由致倦库蚊传播。[52]Aliota MT, Peinado SA, Osorio JE, et al. Culex pipiens and Aedes triseriatus mosquito susceptibility to Zika virus. Emerg Infect Dis. 2016 Oct;22(10):1857-9. http://wwwnc.cdc.gov/eid/article/22/10/16-1082_article http://www.ncbi.nlm.nih.gov/pubmed/27434194?tool=bestpractice.com 不过这还存在争议。[53]Huang YS, Ayers VB, Lyons AC, et al. Culex species mosquitoes and Zika virus.Vector Borne Zoonotic Dis. 2016 Oct;16(10):673-6. http://www.ncbi.nlm.nih.gov/pubmed/27556838?tool=bestpractice.com [54]Amraoui F, Atyame-Nten C, Vega-Rúa A, et al. Culex mosquitoes are experimentally unable to transmit Zika virus. Euro Surveill. 2016 Sep 1;21(35):30333. http://www.ncbi.nlm.nih.gov/pubmed/27605159?tool=bestpractice.com [55]Boccolini D, Toma L, Di Luca M, et al. Experimental investigation of the susceptibility of Italian Culex pipiens mosquitoes to Zika virus infection. Euro Surveill. 2016 Sep 1;21(35):30328. http://www.ncbi.nlm.nih.gov/pubmed/27605056?tool=bestpractice.com 非人类和人类等灵长类种属可能是病毒的主要宿主,并且在暴发期间会发生人源性(人-媒介-人)传播。
也有非蚊媒传播事件(例如,围产期传播、[56]Besnard M, Lastere S, Teissier A, et al. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. 2014 Apr 3;19(13). pii: 20751. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20751 http://www.ncbi.nlm.nih.gov/pubmed/24721538?tool=bestpractice.com 宫内传播、[57]Ventura CV, Maia M, Ventura BV, et al. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol. 2016 Feb;79(1):1-3. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27492016000100002&lng=en&nrm=iso&tlng=en http://www.ncbi.nlm.nih.gov/pubmed/26840156?tool=bestpractice.com [58]Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible association between Zika virus infection and microcephaly - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016 Jan 29;65(3):59-62. http://dx.doi.org/10.15585/mmwr.mm6503e2 http://www.ncbi.nlm.nih.gov/pubmed/26820244?tool=bestpractice.com 性传播、[56]Besnard M, Lastere S, Teissier A, et al. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. 2014 Apr 3;19(13). pii: 20751. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20751 http://www.ncbi.nlm.nih.gov/pubmed/24721538?tool=bestpractice.com [59]Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011 May;17(5):880-2. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21529401/ http://www.ncbi.nlm.nih.gov/pubmed/21529401?tool=bestpractice.com 以及经输血传播[60]Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014 Apr 10;19(14). pii: 20761. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20761 http://www.ncbi.nlm.nih.gov/pubmed/24739982?tool=bestpractice.com [61]Vasquez AM, Sapiano MR, Basavaraju SV, et al. Survey of blood collection centers and implementation of guidance for prevention of transfusion-transmitted Zika virus infection - Puerto Rico, 2016. MMWR Morb Mortal Wkly Rep. 2016 Apr 15;65(14):375-8. http://www.cdc.gov/mmwr/volumes/65/wr/mm6514e1.htm?s_cid=mm6514e1_w http://www.ncbi.nlm.nih.gov/pubmed/27078190?tool=bestpractice.com [62]Barjas-Castro ML, Angerami RN, Cunha MS, et al. Probable transfusion-transmitted Zika virus in Brazil. Transfusion. 2016 Jul;56(7):1684-8. http://onlinelibrary.wiley.com/doi/10.1111/trf.13681/full http://www.ncbi.nlm.nih.gov/pubmed/27329551?tool=bestpractice.com )的报道。[63]Petersen E, Wilson ME, Touch S, et al. Rapid spread of Zika virus in the Americas - implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games. Int J Infect Dis. 2016 Mar;44:11-5. http://www.ncbi.nlm.nih.gov/pubmed/26854199?tool=bestpractice.com 巴西报道了经输注血小板引起的传播。[64]Motta IJ, Spencer BR, Cordeiro da Silva SG, et al. Evidence for transmission of Zika virus by platelet transfusion. N Engl J Med. 2016 Sep 15;375(11):1101-3. http://www.nejm.org/doi/full/10.1056/NEJMc1607262 http://www.ncbi.nlm.nih.gov/pubmed/27532622?tool=bestpractice.com 一小部分接受肝肾移植的患者也患有感染,[65]Nogueira ML, Estofolete CF, Terzian AC, et al. Zika virus infection and solid organ transplantation: a new challenge. Am J Transplant. 2017 Mar;17(3):791-5. http://www.ncbi.nlm.nih.gov/pubmed/27629942?tool=bestpractice.com 且一位儿科患者在接受造血干细胞移植后,出现了格林-巴利综合征,高度怀疑该患者感染了寨卡病毒。[66]Raboni SM, Bonfim C, Almeida BM, et al. Flavivirus cross-reactivity in serological tests and Guillain-Barré syndrome in a hematopoietic stem cell transplant patient: a case report. Transpl Infect Dis. 2017 Aug;19(4). http://www.ncbi.nlm.nih.gov/pubmed/28306183?tool=bestpractice.com 需对这些传播方式进行进一步研究。[67]Levi ME. Zika virus: a cause of concern in transplantation? Curr Opin Infect Dis. 2017 Aug;30(4):340-5. http://www.ncbi.nlm.nih.gov/pubmed/28632511?tool=bestpractice.com
几乎所有经性传播的病例,均涉及与正表现出急性寨卡病毒感染症状的男性、症状发作前不久或症状刚消失的男性的经阴道性交或肛交。然而,也有从无症状男性传播给女性的病例,同时有女性通过性传播将病毒传播至其性伴侣的报道,[68]Davidson A, Slavinski S, Komoto K, et al. Suspected female-to-male sexual transmission of Zika virus - New York City, 2016. MMWR Morb Mortal Wkly Rep. 2016 Jul 22;65(28):716-7. http://www.cdc.gov/mmwr/volumes/65/wr/mm6528e2.htm http://www.ncbi.nlm.nih.gov/pubmed/27442327?tool=bestpractice.com 也有男性之间的性传播。[69]Deckard DT, Chung WM, Brooks JT, et al. Male-to-male sexual transmission of Zika virus - Texas, January 2016. MMWR Morb Mortal Wkly Rep. 2016 Apr 15;65(14):372-4. http://www.cdc.gov/mmwr/volumes/65/wr/mm6514a3.htm http://www.ncbi.nlm.nih.gov/pubmed/27078057?tool=bestpractice.com 亦有通过精液而经口传播病毒的可能。[70]D'Ortenzio E, Matheron S, Yazdanpanah Y, et al. Evidence of sexual transmission of Zika virus. N Engl J Med. 2016 Jun 2;374(22):2195-8. http://www.ncbi.nlm.nih.gov/pubmed/27074370?tool=bestpractice.com 有证据显示,病毒在精液和尿液中存留的时间要长于血液或唾液。[71]World Health Organization. Laboratory testing for Zika virus infection: interim guidance. March 2016 [internet publication]. http://www.who.int/csr/resources/publications/zika/laboratory-testing/en/ [72]Rozé B, Najioullah F, Fergé JL, et al; GBS Zika Working Group. Zika virus detection in urine from patients with Guillain-Barré syndrome on Martinique, January 2016. Euro Surveill. 2016;21(9):30154. http://www.ncbi.nlm.nih.gov/pubmed/26967758?tool=bestpractice.com [73]Petersen LR, Jamieson DJ, Powers AM, et al. Zika virus. N Engl J Med. 2016 Apr 21;374(16):1552-63. http://www.nejm.org/doi/full/10.1056/NEJMra1602113 http://www.ncbi.nlm.nih.gov/pubmed/27028561?tool=bestpractice.com 症状发作后,通过精液培养检出感染性寨卡病毒的最长时间为 69 天。[74]World Health Organization. WHO guidelines for the prevention of sexual transmission of Zika virus. WHO/RHR/19.4. 2019 [internet publication]. https://www.who.int/reproductivehealth/zika/prevention-guidelines-sexual-transmission-summary/en/ 一项关于 184 位确诊感染的症状性男性的队列研究发现,症状发作后 30 天内采集的精液样本中有 61% 检测到寨卡病毒 RNA,这一数据在症状发作后 31-60 天内采集的精液样本中为 43%,在 61-90 天内的样本中为 21%。在症状发作 90 天之后采集的样本中只有不到 7% 可检测到寨卡病毒 RNA。[75]Mead PS, Duggal NK, Hook SA, et al. Zika virus shedding in semen of symptomatic infected men. N Engl J Med. 2018 Apr 12;378(15):1377-1385. https://www.nejm.org/doi/full/10.1056/NEJMoa1711038 http://www.ncbi.nlm.nih.gov/pubmed/29641964?tool=bestpractice.com 然而,这可能并不表明存在传染性病毒,也不说明存在性传播的可能性。有多个病例报告称,精液中检测到寨卡病毒存留的时间长:一名免疫功能正常男性在症状发作后 370 天检测到寨卡病毒 RNA,而一名罕见风湿性疾病免疫抑制患者在症状发作后 >900 天仍可检测到该病毒。[76]Petridou C, Bonsall D, Ahmed A, et al. Prolonged Zika virus RNA detection in semen of immunosuppressed patient. Emerg Infect Dis. 2019 Aug;25(8):1598-1600. https://wwwnc.cdc.gov/eid/article/25/8/18-1543_article http://www.ncbi.nlm.nih.gov/pubmed/31310210?tool=bestpractice.com
在除血液和精液外的其他体液中也检测到寨卡病毒 RNA,包括羊水、脑脊液(cerebrospinal fluid, CSF)、尿液、唾液、阴道分泌物和眼部液体;然而,经这些体液的传播方式还未被完全阐明。[58]Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible association between Zika virus infection and microcephaly - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016 Jan 29;65(3):59-62. http://dx.doi.org/10.15585/mmwr.mm6503e2 http://www.ncbi.nlm.nih.gov/pubmed/26820244?tool=bestpractice.com [77]Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015 Feb;21(2):359-61. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313657/ http://www.ncbi.nlm.nih.gov/pubmed/25625872?tool=bestpractice.com [78]Musso D, Roche C, Nhan TX, et al. Detection of Zika virus in saliva. J Clin Virol. 2015 Jul;68:53-5. http://www.ncbi.nlm.nih.gov/pubmed/26071336?tool=bestpractice.com [79]Gourinat AC, O'Connor O, Calvez E, et al. Detection of Zika virus in urine. Emerg Infect Dis. 2015 Jan;21(1):84-6. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25530324/ http://www.ncbi.nlm.nih.gov/pubmed/25530324?tool=bestpractice.com [80]Sun J, Wu, Zhong H, et al. Presence of Zika virus in conjunctival fluid. JAMA Ophthalmol. 2016 Nov 1;134(11):1330-2. http://archopht.jamanetwork.com/article.aspx?articleid=2552685 http://www.ncbi.nlm.nih.gov/pubmed/27632055?tool=bestpractice.com [81]Murray KO, Gorchakov R, Carlson AR, et al. Prolonged detection of Zika virus in vaginal secretions and whole blood. Emerg Infect Dis. 2017 Jan;23(1):99-101. http://wwwnc.cdc.gov/eid/article/23/1/16-1394_article http://www.ncbi.nlm.nih.gov/pubmed/27748649?tool=bestpractice.com [82]Heck E, Cavanagh HD, Robertson DM. Zika virus RNA in an asymptomatic donor's vitreous: risk for transmission? Am J Transplant. 2017 Aug;17(8):2227-8. http://www.ncbi.nlm.nih.gov/pubmed/28452113?tool=bestpractice.com 病毒在血液中可存留长达 83 天,[83]Paz-Bailey G, Rosenberg ES, Doyle K, et al. Persistence of Zika virus in body fluids - final report. N Engl J Med. 2017 Feb 14;379(13):1234-43. https://www.nejm.org/doi/full/10.1056/NEJMoa1613108 http://www.ncbi.nlm.nih.gov/pubmed/28195756?tool=bestpractice.com 且在血液中存留时间长于血清。[84]Mansuy JM, Mengelle C, Pasquier C, et al. Zika virus infection and prolonged viremia in whole-blood specimens. Emerg Infect Dis. 2017 May;23(5):863-5. https://wwwnc.cdc.gov/eid/article/23/5/16-1631_article http://www.ncbi.nlm.nih.gov/pubmed/28257281?tool=bestpractice.com 已在一位已感染女性的生殖道中检测到病毒,这可能会对垂直传播有所影响。[85]Prisant N, Bujan L, Benichou H, et al. Zika virus in the female genital tract. Lancet Infect Dis. 2016 Sep;16(9):1000-1. http://www.ncbi.nlm.nih.gov/pubmed/27427201?tool=bestpractice.com 据报道,阴道分泌物的病毒脱落期最长可达 6 个月。[86]Reyes Y, Bowman NM, Becker-Dreps S, et al. Prolonged shedding of zika virus RNA in vaginal secretions, Nicaragua. Emerg Infect Dis. 2019 Apr;25(4):808-10. https://www.doi.org/10.3201/eid2504.180977 http://www.ncbi.nlm.nih.gov/pubmed/30882329?tool=bestpractice.com 也曾在胚胎组织中检测到病毒。在一位出生后至少 67 天的新生儿中出现病毒血症。[87]Oliveira DB, Almeida FJ, Durigon EL, et al. Prolonged shedding of Zika virus associated with congenital infection. N Engl J Med. 2016 Sep 22;375(12):1202-4. http://www.nejm.org/doi/full/10.1056/NEJMc1607583 http://www.ncbi.nlm.nih.gov/pubmed/27653589?tool=bestpractice.com 虽然曾在母乳中检测到病毒,但目前还没有经母乳传播的报道。[88]Colt S, Garcia-Casal MN, Peña-Rosas JP, et al. Transmission of Zika virus through breast milk and other breastfeeding-related bodily-fluids: a systematic review. PLoS Negl Trop Dis. 2017 Apr 10;11(4):e0005528. http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005528 http://www.ncbi.nlm.nih.gov/pubmed/28394887?tool=bestpractice.com
医务人员可能通过经皮损伤(例如,针刺伤)或与黏膜(或破损皮肤)的血液、组织或其他获得感染的体液直接接触,而造成职业暴露。[89]Centers for Disease Control and Prevention. Interim guidance for managing occupational exposures to Zika virus for healthcare personnel. January 2019 [internet publication]. https://www.cdc.gov/zika/hc-providers/infection-control/managing-occupational-exposures.html
美国疾病预防控制中心 (CDC) 调查了与犹他州一位死于寨卡病毒感染的患者有过接触的家庭如何感染寨卡病毒。死亡患者血液循环内的病毒水平非常高,并且家庭成员与患者曾有过亲密接触(即,亲吻和拥抱)。传播途径的机制仍不明确,但可能是由于家庭成员与先证者之间人与人的传播所引发。[90]Krow-Lucal ER, Novosad SA, Dunn AC, et al. Zika virus infection in patient with no known risk factors, Utah, USA, 2016. Emerg Infect Dis. 2017 Aug;23(8):1260-7. https://wwwnc.cdc.gov/eid/article/23/8/17-0479_article http://www.ncbi.nlm.nih.gov/pubmed/28726601?tool=bestpractice.com
有病毒血症的旅行者(通常无症状)将病毒引入存在易受感染的伊蚊的国家,这些感染的伊蚊引发并延续了当地的传播。[91]Bogoch II, Brady OJ, Kraemer MU, et al. Anticipating the international spread of Zika virus from Brazil. Lancet. 2016 Jan 23;387(10016):335-6. http://www.ncbi.nlm.nih.gov/pubmed/26777915?tool=bestpractice.com
有报道称有可能混合感染登革热和基孔肯雅热病毒。[92]Villamil-Gomez WE, Gonzalez-Camargo O, Rodriguez-Ayubi J, et al. Dengue, chikungunya and Zika co-infection in a patient from Colombia. J Infect Public Health. 2016 Sep-Oct;9(5):684-6. http://www.ncbi.nlm.nih.gov/pubmed/26754201?tool=bestpractice.com [93]Fernanda Estofolete C, Terzian AC, Parreira R, et al. Clinical and laboratory profile of Zika virus infection in dengue suspected patients: a case series. J Clin Virol. 2016 Aug;81:25-30. http://www.ncbi.nlm.nih.gov/pubmed/27289428?tool=bestpractice.com [94]Sardi S, Somasekar S, Naccache SN, et al. Co-infections from Zika and chikungunya virus in Bahia, Brazil identified by metagenomic next-generation sequencing. J Clin Microbiol. 2016 Sep;54(9):2348-53. http://jcm.asm.org/content/early/2016/07/12/JCM.00877-16.long http://www.ncbi.nlm.nih.gov/pubmed/27413190?tool=bestpractice.com [95]Cherabuddi K, Iovine NM, Shah K, et al. Zika and chikungunya virus co-infection in a traveller returning from Colombia, 2016: virus isolation and genetic analysis. JMM Case Rep. 2016 Dec 19;3(6):e005072. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343122/ http://www.ncbi.nlm.nih.gov/pubmed/28348794?tool=bestpractice.com 有一例同时感染寨卡、基孔肯雅热和登革热这三种病毒的病例。[96]Villamil-Gómez WE, Rodríguez-Morales AJ, Uribe-García AM, et al. Zika, dengue, and chikungunya co-infection in a pregnant woman from Colombia. Int J Infect Dis. 2016 Oct;51:135-8. http://www.ncbi.nlm.nih.gov/pubmed/27497951?tool=bestpractice.com
巴西政府正在调查是否有除寨卡病毒感染之外的因素(如卫生条件差、同时感染其他病毒)与小头畸形的出现有关,因为巴西小头畸形病例并非如预期分布,且分布不均。[97]Collucci C. Brazil to investigate if other factors act with Zika to cause congenital defects. BMJ. 2016 Aug 11;354:i4439. http://www.bmj.com/content/354/bmj.i4439.long http://www.ncbi.nlm.nih.gov/pubmed/27515384?tool=bestpractice.com
病理生理学
病毒侵入后的潜伏期在 3 至 14 天之间。[98]Krow-Lucal ER, Biggerstaff BJ, Staples JE. Estimated incubation period for Zika virus disease. Emerg Infect Dis. 2017 May;23(5):841-5. https://wwwnc.cdc.gov/eid/article/23/5/16-1715_article http://www.ncbi.nlm.nih.gov/pubmed/28277198?tool=bestpractice.com 感染的发病机制还未明确;但一般认为黄病毒最初是在接种部位旁的树突细胞处复制,然后播散至血液和淋巴结。[99]Buckley A, Gould EA. Detection of virus-specific antigen in the nuclei or nucleoli of cells infected with Zika or Langat virus. J Gen Virol. 1988 Aug;69(Pt 8):1913-20. http://www.ncbi.nlm.nih.gov/pubmed/2841406?tool=bestpractice.com 在有临床症状的患者中,病毒血症一般会持续长达 1 周的时间。
寨卡病毒是一种嗜神经病毒,已显示其可攻击神经祖细胞,同时也可攻击不同分化阶段的神经元,但程度较轻。[7]Costello A, Dua T, Duran P, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ. 2016 Jun 1;94(6):406-406A. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890216/ http://www.ncbi.nlm.nih.gov/pubmed/27274588?tool=bestpractice.com 在一项体外试验中,一株寨卡病毒先后被接种到猴和蚊的细胞中,并有效的感染了源于诱导多能干细胞的人神经祖细胞。寨卡病毒感染加剧了细胞死亡和细胞周期进程失调,导致细胞生长缓慢。[100]Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016 May 5;18(5):587-90. https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)00106-5 http://www.ncbi.nlm.nih.gov/pubmed/26952870?tool=bestpractice.com 另一项研究发现病毒可感染人皮质祖细胞,通过引起细胞凋亡和自噬,而导致细胞死亡。[101]Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016 Jun 9;534(7606):267-71. http://www.ncbi.nlm.nih.gov/pubmed/27279226?tool=bestpractice.com
尽管临床症状轻微,但妊娠期感染寨卡病毒与胎儿死亡、胎盘功能不全、胎儿生长受限和中枢神经系统(central nervous system, CNS)损伤有关。[102]Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016 Dec 15;375(24):2321-34. http://www.nejm.org/doi/full/10.1056/NEJMoa1602412#t=article http://www.ncbi.nlm.nih.gov/pubmed/26943629?tool=bestpractice.com 基于平均足月妊娠的孕期,从寨卡病毒暴发高峰至小头畸形出现高峰的 24 周时长提示,在早期妊娠和中期妊娠早期时感染寨卡病毒,患小头畸形的风险最高。[103]Cuevas EL, Tong VT, Rozo N, et al. Preliminary report of microcephaly potentially associated with Zika virus infection during pregnancy - Colombia, January-November 2016. MMWR Morb Mortal Wkly Rep. 2016 Dec 16;65(49):1409-13. https://www.cdc.gov/mmwr/volumes/65/wr/mm6549e1.htm http://www.ncbi.nlm.nih.gov/pubmed/27977645?tool=bestpractice.com 然而,也有报道称中枢神经系统异常可由晚至妊娠 39 周的暴露所导致。[104]Brasil P, Pereira JP Jr, Moreira ME, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016 Dec 16;65(49):1409-13. http://www.nejm.org/doi/full/10.1056/NEJMoa1602412#t=article http://www.ncbi.nlm.nih.gov/pubmed/26943629?tool=bestpractice.com 一份病例报道发现,胎儿小头畸形可能是妊娠中期胎儿脑部由于细胞凋亡机制而丢失中分化的迁移后神经元所引致。[105]Driggers RW, Ho CY, Korhonen EM, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med. 2016 Jun 2;374(22):2142-51. http://www.nejm.org/doi/full/10.1056/NEJMoa1601824#t=article http://www.ncbi.nlm.nih.gov/pubmed/27028667?tool=bestpractice.com 有人提出胚胎生发基质是该病毒的主要攻击目标。[106]Guillemette-Artur P, Besnard M, Eyrolle-Guignot D, et al. Prenatal brain MRI of fetuses with Zika virus infection. Pediatr Radiol. 2016 Jun;46(7):1032-9. http://rd.springer.com/article/10.1007/s00247-016-3619-6/fulltext.html http://www.ncbi.nlm.nih.gov/pubmed/27090801?tool=bestpractice.com 关于小鼠的研究提供了寨卡病毒感染和小头畸形间存在直接因果关系的证据:寨卡病毒可引起细胞周期阻滞、细胞凋亡以及对神经前体细胞的抑制。[107]Malkki H. CNS infections: mouse studies confirm the link between Zika virus infection and microcephaly. Nat Rev Neurol. 2016 Jul;12(7):369. https://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2016.78.html http://www.ncbi.nlm.nih.gov/pubmed/27231186?tool=bestpractice.com [108]Li C, Xu D, Ye Q, et al. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell. 2016 Jul 7;19(1):120-6. https://www.sciencedirect.com/science/article/pii/S1934590916300844 http://www.ncbi.nlm.nih.gov/pubmed/27179424?tool=bestpractice.com [109]Hofer U. Viral pathogenesis: tracing the steps of Zika virus. Nat Rev Microbiol. 2016 Jul;14(7):401. http://www.ncbi.nlm.nih.gov/pubmed/27211788?tool=bestpractice.com [110]Mysorekar IU, Diamond MS. Modeling Zika virus infection in pregnancy. N Engl J Med. 2016 Aug 4;375(5):481-4. http://www.nejm.org/doi/full/10.1056/NEJMcibr1605445 http://www.ncbi.nlm.nih.gov/pubmed/27433842?tool=bestpractice.com 病毒似乎在大脑发育的关键时期触发了一些细胞行为,使得正常细胞增殖和神经祖细胞存活均有所改变。[111]Merfeld E, Ben-Avi L, Kennon M, et al. Potential mechanisms of Zika-linked microcephaly. Wiley Interdiscip Rev Dev Biol. 2017 Jul;6(4):e273. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516183/ http://www.ncbi.nlm.nih.gov/pubmed/28383800?tool=bestpractice.com 胎盘在小头畸形中的作用还不明确,但有假设提出,胎盘可能促进了病毒传播给胎儿的过程,或者也可能造成破坏性的免疫应答。[112]Adibi JJ, Marques ET Jr, Cartus A, et al. Teratogenic effects of the Zika virus and the role of the placenta. Lancet. 2016 Apr 9;387(10027):1587-90. http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)00650-4/fulltext http://www.ncbi.nlm.nih.gov/pubmed/26952548?tool=bestpractice.com 其中一个假设是,病毒通过直接感染胎盘细胞,从而破坏胎盘屏障,侵入胎儿。[113]Quicke KM, Bowen JR, Johnson EL, et al. Zika virus infects human placental macrophages. Cell Host Microbe. 2016 Jul 13;20(1):83-90. http://www.ncbi.nlm.nih.gov/pubmed/27247001?tool=bestpractice.com 有数据表明,病毒要侵入胎儿,必须躲避滋养层源性干扰素 λ-1。[114]Bayer A, Lennemann NJ, Ouyang Y, et al. Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe. 2016 May 11;19(5):705-12. http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(16)30100-7 http://www.ncbi.nlm.nih.gov/pubmed/27066743?tool=bestpractice.com 另一项研究发现胎盘感染可引起细胞增殖,主要是绒毛膜绒毛霍夫包尔细胞的增生。[115]Rosenberg AZ, Yu W, Hill DA, et al. Placental pathology of Zika virus: viral infection of the placenta induces villous stromal macrophage (Hofbauer cell) proliferation and hyperplasia. Arch Pathol Lab Med. 2017 Jan;141(1):43-8. http://www.archivesofpathology.org/doi/10.5858/arpa.2016-0401-OA?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed http://www.ncbi.nlm.nih.gov/pubmed/27681334?tool=bestpractice.com 病毒可在胎儿出生后继续在大脑中复制,且可在胎盘中存留数月。[116]Centers for Disease Control and Prevention. Study finds Zika virus replicates and persists in fetal brains and placentas. December 2016 [internet publication]. https://www.cdc.gov/media/releases/2016/p1213-zika-virus-replicates.html 小头畸形的风险增加与各种因素有关,包括孕龄、遗传因素、社会经济状况和既往暴露于其他黄病毒。最近一项研究发现,小头畸形风险增加与母体抗体的特定特征之间存在相关性,这些抗体会增强寨卡病毒进入细胞的能力,这或许可以解释为什么寨卡病毒感染会导致一些婴儿出现出生缺陷,而其他婴儿则不会。[117]Robbiani DF, Olsen PC, Costa F, et al. Risk of Zika microcephaly correlates with features of maternal antibodies. J Exp Med. 2019 Oct 7;216(10):2302-15. https://www.doi.org/10.1084/jem.20191061 http://www.ncbi.nlm.nih.gov/pubmed/31413072?tool=bestpractice.com 还需进一步的研究以探究寨卡病毒相关的全部先天性异常疾病谱及其发病机制,包括对胎儿和新生儿尸检组织以及有小头畸形活婴胎盘组织的系统性检查。[118]Solomon IH, Milner DA, Folkerth RD. Neuropathology of Zika virus infection. Neuroinfect Dis. 2016 Jun;7(2):220. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982465/ http://www.ncbi.nlm.nih.gov/pubmed/27525286?tool=bestpractice.com
一例病例报告中,在血清中仍有寨卡病毒时即出现格林-巴利综合征,说明病毒的嗜神经性可能表现为直接神经损伤,或对该病毒产生快速细胞介导反应,对周围神经具有交叉反应性。入侵神经的过程还未充分明了,仍需进一步研究。[119]Siu R, Bukhari W, Todd A, et al. Acute Zika infection with concurrent onset of Guillain-Barré syndrome. Neurology. 2016 Jun;7(2):220. http://www.neurology.org/content/early/2016/07/27/WNL.0000000000003038.long http://www.ncbi.nlm.nih.gov/pubmed/27466468?tool=bestpractice.com 小鼠的研究表明,成人神经干细胞同样容易受到寨卡病毒的神经病理学影响。[120]Li H, Saucedo-Cuevas L, Regla-Nava JA, et al. Zika virus infects neural progenitors in the adult mouse brain and alters proliferation. Cell Stem Cell. 2016 Nov 3;19(5):593-8. http://www.sciencedirect.com/science/article/pii/S1934590916302521 http://www.ncbi.nlm.nih.gov/pubmed/27545505?tool=bestpractice.com
动物模型研究表明,抗其他黄病毒抗体的存在可能会加重寨卡病毒感染,从而导致更严重的感染。[121]Bardina SV, Bunduc P, Tripathi S, et al. Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science. 2017 Apr 14;356(6334):175-80. http://www.ncbi.nlm.nih.gov/pubmed/28360135?tool=bestpractice.com 有限的人类和非人类灵长类动物研究表明,与没有登革病毒感染史的患者相比,在有登革热病毒接触史的患者中,寨卡病毒血症的发病率出现了小幅且无统计学意义的上升;然而,没有证据表明这种病毒血症的增加与寨卡病毒表型的改变有关。[122]Masel J, McCracken MK, Gleeson T, et al. Does prior dengue virus exposure worsen clinical outcomes of Zika virus infection? A systematic review, pooled analysis and lessons learned. PLoS Negl Trop Dis. 2019 Jan;13(1):e0007060. https://www.doi.org/10.1371/journal.pntd.0007060 http://www.ncbi.nlm.nih.gov/pubmed/30682026?tool=bestpractice.com 有一些流行病学数据表明,多型登革热病毒免疫对先天性寨卡病毒综合征具有交叉保护作用。[123]Pedroso C, Fischer C, Feldmann M, et al. Cross-protection of dengue virus infection against congenital Zika syndrome, Northeastern Brazil. Emerg Infect Dis. 2019 Aug;25(8):1485-93. https://www.doi.org/10.3201/eid2508.190113 http://www.ncbi.nlm.nih.gov/pubmed/31075077?tool=bestpractice.com
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