Abstract
Background: 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.Results: 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.Conclusion: 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.
Highlights
There was considerable alarm caused by the Zika virus (ZIKV) epidemic which spread across more than 70 countries, especially the Americas, during 2015–2016
For 15 individuals, the timing of onset of ZIKV infection was specified as during the 1st or 2nd trimester, one was infected during the 3rd trimester, and the remainder were unable to specify the exact timing of onset of ZIKVrelated symptoms
4 tested negative by Dengue virus (DENV)-specific IgG by ELISA (Table 1). This commercial NS1 ELISA is validated for clinical use in Brazil under a working assumption that ZIKV IgG indicates ZIKV immunity and a result for DENV IgG, DENV immunity; the authors acknowledge that there is uncertainty on this point in the field
Summary
There was considerable alarm caused by the Zika virus (ZIKV) epidemic which spread across more than 70 countries, especially the Americas, during 2015–2016. There is a need to understand the complex relationship between human immunity and disease susceptibility in the face of differential exposure and immune memory to these viruses for which the patterns of immune cross-reactivity are as yet poorly mapped Overlaid on these unknowns are the additional issues of Aedes population dynamics and the variable impact of climate, posing multi-faceted, and unresolved dilemmas [3]. 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
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