Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, United Kingdom.
Molecular Biology Laboratory, Graduate Program in Health Science, University Hospital of the Federal University of Sergipe, Aracaju, Brazil.
Front Immunol. 2020 Feb 18;11:185. doi: 10.3389/fimmu.2020.00185. eCollection 2020.
There is an urgent need to understand the complex relationship between cross-reactive anti-viral immunity, disease susceptibility, and severity in the face of differential exposure to related, circulating Flaviviruses. Co-exposure to Dengue virus and Zika virus in Brazil is a case in point. A devastating aspect of the 2015-2016 South American Zika outbreak was the dramatic increase in numbers of infants born with microcephaly to mothers exposed to Zika virus during pregnancy. It has been proposed that this is more likely to ensue from Zika infection in women lacking cross-protective Dengue immunity. In this case series we measure the prevalence of Dengue immunity in a cohort of mothers exposed to Zika virus during pregnancy in the 2015-2016 Zika outbreak that gave birth to an infant affected by microcephaly and explore their adaptive immunity to Zika virus. Fifty women from Sergipe, Brazil who gave birth to infants with microcephaly following Zika virus exposure during the 2015-16 outbreak were tested for serological evidence of Dengue exposure and IFNγ ELISpot spot forming cell (SFC) response to Zika virus. The majority (46/50) demonstrated Dengue immunity. IFNγ ELISpot responses to Zika virus antigens showed the following hierarchy: Env>NS1>NS3>C protein. Twenty T cell epitopes from Zika virus Env were identified. Responses to Zika virus antigens Env and NS1 were polyfunctional with cells making IFNγ, TNFα, IL-4, IL-13, and IL-10. In contrast, responses to NS5 only produced the immune regulatory TGFβ1 cytokine. There were SFC responses against Zika virus Env (1-20) and variant peptide sequences from West Nile virus, Dengue virus 1-4 and Yellow Fever virus. Almost all the women in our study showed serological evidence of Dengue immunity, suggesting that microcephaly can occur in DENV immune mothers. T cell immunity to Zika virus showed a multifunctional response to the antigens Env and NS1 and immune regulatory responses to NS5 and C protein. Our data support an argument that different viral products may skew the antiviral response to a more pro or anti-inflammatory outcome, with an associated impact on immunopathogenesis.
面对相关循环黄病毒的不同暴露，了解交叉反应性抗病毒免疫、疾病易感性和严重程度之间的复杂关系至关重要。巴西登革热病毒和寨卡病毒的共同暴露就是一个很好的例子。2015-2016 年南美寨卡病毒爆发的一个破坏性方面是，在怀孕期间接触寨卡病毒的母亲所生的患有小头畸形的婴儿数量显著增加。据推测，这更有可能是由于缺乏交叉保护登革热免疫的妇女感染寨卡病毒所致。在本病例系列研究中，我们测量了在 2015-2016 年寨卡病毒爆发期间暴露于寨卡病毒的孕妇队列中登革热免疫的流行率，并探讨了她们对寨卡病毒的适应性免疫。 巴西塞尔希培州的 50 名妇女在 2015-16 年寨卡病毒爆发期间接触寨卡病毒后生下患有小头畸形的婴儿，她们接受了血清学检测以确定登革热暴露的证据，并进行了 IFNγ ELISpot 斑点形成细胞 (SFC) 对寨卡病毒的反应。大多数（46/50）显示出登革热免疫力。寨卡病毒抗原的 IFNγ ELISpot 反应显示出以下层次结构：Env>NS1>NS3>C 蛋白。从寨卡病毒 Env 中鉴定出 20 个 T 细胞表位。对寨卡病毒抗原 Env 和 NS1 的反应具有多功能性，细胞产生 IFNγ、TNFα、IL-4、IL-13 和 IL-10。相比之下，对 NS5 的反应仅产生免疫调节 TGFβ1 细胞因子。针对寨卡病毒 Env（1-20）和西尼罗河病毒、登革热病毒 1-4 和黄热病病毒的变体肽序列存在 SFC 反应。 我们研究中的几乎所有女性都显示出登革热免疫力的血清学证据，这表明 DENV 免疫的母亲也可能发生小头畸形。对寨卡病毒的 T 细胞免疫显示出对抗原 Env 和 NS1 的多功能反应，以及对 NS5 和 C 蛋白的免疫调节反应。我们的数据支持这样一种观点，即不同的病毒产物可能会使抗病毒反应偏向更促炎或抗炎的结果，从而对免疫发病机制产生影响。
