Strong CD4 T Cell Responses to Zika Virus Antigens in a Cohort of Dengue Virus Immune Mothers of Congenital Zika Virus Syndrome Infants

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 Reynolds et al. CD4 Immunity in ZIKV Infection 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.

Evaluation of the Expression of CCR5 and CX3CR1 Receptors and Correlation with the Functionality of T Cells in Women infected with ZIKV during Pregnancy

“…In contrast, their responses to NS5 ZIKV peptides only produced the immune regulatory TGF-β1 cytokine. Thus, these authors' 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 [48].…”

Protective and enhancing interactions among dengue viruses 1-4 and Zika virus

“…In contrast to DENV, ZIKV CD4 + T cells mostly target structural proteins, and following primary and secondary ZIKV infection, a low proportion of the CD4 + T cell response was reactive to DENV E protein [67,103]. Some studies suggest ZIKV may skew the CD4 + T cell response and bias future DENV infections toward pathogenesis in mice and severe outcomes, including microcephaly, in humans [105,106].…”

A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage

“…It has been shown that there is an 11%–13% risk of microcephaly born to Brazilian women infected with ZIKV during pregnancy, particularly in the first trimester of pregnancy ( de Araújo et al, 2018 ; Brady et al, 2019 ; Johansson et al, 2016 ; Regla-Nava et al, 2018 ). A recent study showed that the ZIKV-induced microcephaly occurred in the DENV-immune mothers ( Reynolds et al, 2020 ), suggesting that T cell immunity does not provide sufficient cross-protection among ZIKV and DENV serotypes. The protection may be dependent on the numbers of cross-reacting CTLs and neutralizing antibodies (if any) at the time of ZIKV infection.…”