Cross-reactive Dengue virus-specific CD8+ T cells protect against Zika virus during pregnancy

Regla-Nava, José Ángel; Ngono, Annie Elong; Viramontes, Karla M.; Huynh, Anh-Thy; Wang, Ying-Ting; Nguyen, Anh-Viet; Salgado, Rebecca; Mamidi, Anila; Kim, Kenneth S.; Diamond, Michael S.; Shresta, Sujan

doi:10.1038/s41467-018-05458-0

Cited by 90 publications

(118 citation statements)

References 74 publications

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“…DENV-immune CD8 + T cells were required for this cross-protection. However, mice challenged 80 days after DENV priming were not protected, indicating the transient nature of cross-protection again 40 .…”

Section: Discussionmentioning

confidence: 99%

Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil

Carvalho

Freitas

Cruz

et al. 2020

Sci Rep

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Despite all the research done on the first Zika virus (ZIKV) epidemics, it was only after the Brazilian epidemic that the congenital Zika Syndrome was described. this was made possible due to the large number of babies born with microcephaly in the Northeast region (NE) in a narrow time. We hypothesize that the fivefold difference in the rate of microcephalic neonates between the NE and other regions is partially an effect of the population prior immunity against Dengue viruses (DENV), that cross-react with ZIKV. In this ecological study, we analysed the interaction between dengue fever epidemics from 2001 to 2014 and the 2015/2016 microcephaly epidemic in 400 microregions in Brazil using random-effects models under a Bayesian approach. The estimated effect of the time lag between the most recent large dengue epidemic (>400/100,000 inhabitants) and the microcephaly epidemic ranged from protection (up to 6 years prior) to an increased risk (from 7 to 12 years). This sustained window of protection, larger than described in previous longitudinal studies, is possibly an effect of herd immunity and of multiple exposures to DENV that could boost immunity.

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Section: Discussionmentioning

confidence: 99%

Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil

Carvalho

Freitas

Cruz

et al. 2020

Sci Rep

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“…Consequently, mice deficient in these molecules had increased viral burden 124,125 . Heterologous, memory T-cell responses also can have protective functions, as cross-reactive DENV-immune CD8 + T cells restrict ZIKV infection and disease, including in pregnancy 126,127 . Reciprocally, ZIKV-immune CD8 + T cells can protect against DENV infection in mice 128 .…”

Section: Immune Response To Flavivirus Infectionmentioning

confidence: 99%

“…Yet in another study in Ifnar1 -/-(A129) or Ifnar1 -/-Ifngr -/-(AG129) mice, whilst inactivated ZIKV vaccination enhanced dengue disease severity, ADE was not observed after ZIKV infection in animals that were passively immunized or pre-infected with DENV 181 . Apart from the contrasting results, a major caveat to the passive transfer of antibody model is that these mice lack immune, cross-reactive CD8 + T cells, which can limit the pathological effects of ADE in the context of DENV immunity and subsequent ZIKV infection, including during pregnancy 127,192 .…”

Section: Emerging and Re-emerging Threatsmentioning

confidence: 99%

The continued threat of emerging flaviviruses

Pierson

Diamond²

2020

Nat Microbiol

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730

627

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F laviviruses are single-stranded RNA viruses vectored principally by arthropods that cause severe illnesses in humans. The extensive global spread and epidemic transmission of flaviviruses during the last seven decades has been remarkable. The mosquito-borne dengue viruses (DENV) infect an estimated 400 million humans each year; more than a quarter of the world's population lives in areas where DENV is now endemic 1 . By comparison, only sporadic DENV epidemics were documented before the Second World War 2 . The introductions of West Nile (WNV) and Zika (ZIKV) viruses into the Western Hemisphere was followed by rapid geographical spread, large numbers of human infections and considerable morbidity 3,4 . Ongoing yellow fever virus (YFV) transmission and its encroachment on urban environments, despite the existence of an effective vaccine, poses a serious public health challenge 5-7 . Other flaviviruses present ongoing health risks or are beginning to emerge in different parts of the world, including Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Usutu virus (USUV).The epidemic potential of flaviviruses reflects many factors related to the unique characteristics of their insect vectors, the consequences of poorly planned urbanization that creates ideal arthropod breeding habitats, the geographical expansion of vectors, changing environmental conditions and extensive global travel 8,9 . Beyond arthropods and humans, flaviviruses are also known to infect a wide array of animal species and can be important veterinary pathogens that threaten economically important domesticated animals 10-14 . These vertebrate animal hosts may constitute important stable reservoirs and contribute to defining conditions that support the introduction of new viral species and transmission among humans 15 . The continued threat of flavivirus emergence and re-emergence highlights a need for a detailed fundamental understanding of the biology of these viruses, the immune responses that can contain them and the possible countermeasures that can blunt their impact on public health should new outbreaks occur. Flavivirus structure and replicationFlaviviruses are small (~50 nm) spherical virus particles that incorporate a single genomic RNA of positive-sense polarity encoding three structural and seven non-structural proteins (Fig. 1a). Our knowledge of the biology of flaviviruses has advanced considerably with the availability of high-resolution structures of viral structural proteins and of virions at different stages of the replication cycle or in complex with antibodies or host factors 16 . Crystal structures of the enzymatic non-structural proteins also have been solved, accelerating advances in an understanding of virus replication and pathogenesis [17][18][19] and enabling structure-guided drug discovery, as reviewed elsewhere 20 .Virion structure and morphogenesis. Flaviviruses are assembled using three viral structural proteins (C, prM and E), a host lipid envelope and the viral genomic RNA. The structure of ...

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“…The protective role of the cellular immune response controlling the viral burden of ZIKV in mice has been reported (76, 77). More recently mouse models have shown that prior DENV immunity can protect against ZIKV infection during pregnancy, and CD8+ T cells are sufficient for this cross-protection (78). Currently, it is well documented that pre-exposure to DENV both in macaques and humans results in a qualitative modification of the humoral and cellular immune response to ZIKV (24, 27-29) .…”

Section: Discussionmentioning

confidence: 99%

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

Serrano-Collazo

Pantoja

et al. 2019

Preprint

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29Prior exposure to a single serotype of dengue virus (DENV) predisposes individuals to severe 30 disease upon secondary heterologous DENV infection. Here we show that the length of time 31 between DENV/Zika (ZIKV) infections has a qualitative impact on controlling ZIKV replication. 32We identified limited but significant differences in the magnitude of the early humoral immune 33 response associated with a period of twelve months but not three months of DENV 34 convalescence. However, their role limiting ZIKV replication is not conclusive. There was no 35 evidence of in vivo antibody-dependent amplification of ZIKV by DENV immunity in any group. 36We are also showing that the significant differences among groups may be linked to a pre-37 existing polyfunctional CD4+ T cells response (increased IFN-g and Cd107a before ZIKV 38 infection) and to an early and continuous expansion of the CD4+ effector memory cells early on 39 after ZIKV infection. Those significant differences were associated with a period of 12 months 40 after DENV infection that were not observed in a span of 3-months. These results suggest that 41 there is a window of optimal cross-protection between ZIKV and DENV with significant 42 consequences. These results have pivotal implications while interpreting ZIKV pathogenesis in 43 flavivirus-experimented populations, diagnostic results interpretation and vaccine designs 44 among others. 45 46 Author Summary 47impact on controlling the ZIKV infection. In this study, as in our prior work we did not observe 100 evidence of ZIKV disease enhancement associated with prior DENV exposure. We also 101 confirmed that the significant differences among groups are mediated by the pre-existence of a 102 robust effector memory T cell (TEM) and cytotoxic activity mainly mediated by CD4 + T cells 103 more than qualitative differences in the humoral immune response. However, by conducting a 104 detailed study of the ZIKV-neutralizing titers vs. ZIKV RNAemia at early time points after 105 infection, we were able to determine a possible contribution of the neutralizing antibodies 106 limiting the ZIKV replication at 7 days after infection in the animals with 12 months but not 3 107 months of DENV immunity or in the control group. Overall, we demonstrated that exposure to 108 ZIKV 12 months after DENV infection afford a high level of T cell-mediated cross protection than 109 it was observed at the 3-month span. Based on our previous study we believe this protection 110 wanes as macaques exposed to ZIKV 2.8 years after DENV were not afforded this protection. 111These results suggest that there is a window of optimal T cell cross-protection between ZIKV 112 and DENV. 113 114 Results 115

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Cross-reactive Dengue virus-specific CD8+ T cells protect against Zika virus during pregnancy

Cited by 90 publications

References 74 publications

Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil

Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil

The continued threat of emerging flaviviruses

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

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