Innate, T-, and B-Cell Responses in Acute Human Zika Patients

Lai, Lilin; Rouphael, Nadine; Xu, Yongxian; Natrajan, Muktha S.; Beck, Allison; Hart, Mari; Feldhammer, Matthew; Feldpausch, Amanda; Hill, Charles E.; Wu, Henry M.; Fairley, Jessica K.; Lankford-Turner, Pamela; Kasher, Nicole; Rago, Patrick; Hu, Yi‐Juan; Edupuganti, Srilatha; Patel, Shital M.; Murray, Kristy O.; Mulligan, Mark J.; Team, Emory Zika Patient Study

doi:10.1093/cid/cix732

Cited by 72 publications

(109 citation statements)

References 37 publications

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“…Immune cells were phenotyped by using flow cytometry at baseline and on Days 1, 2, 7, 14, 28, and 56 as previously described [23] using an LSRII cell analyzer (BD Biosciences, Franklin Lakes, NJ, USA) and FlowJo Software (TreeStar, Ashland, OR, USA). All samples were gated to exclude dead cells, debris, and doublets.…”

Section: Cellular Phenotypingmentioning

confidence: 99%

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

et al. 2019

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Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses.

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Section: Cellular Phenotypingmentioning

confidence: 99%

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

et al. 2019

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“…In humans, virus‐specific antibodies are seen to develop as early as 3 days after the onset of fever, although in some studies IgM was not detectable until 8 days after symptom onset with IgG developing even later in flavivirus‐naive patients . Cross‐reactivity between ZIKV and antibodies to dengue virus has been observed, complicating both ZIKV diagnosis and assessment of vaccine‐induced immunity .…”

Section: Modeling Immune Control Of Viremiamentioning

confidence: 99%

Mathematical modeling of within‐host Zika virus dynamics

Best

Perelson

2018

Immunological Reviews

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Recent Zika virus outbreaks have been associated with severe outcomes, especially during pregnancy. A great deal of effort has been put toward understanding this virus, particularly the immune mechanisms responsible for rapid viral control in the majority of infections. Identifying and understanding the key mechanisms of immune control will provide the foundation for the development of effective vaccines and antiviral therapy. Here, we outline a mathematical modeling approach for analyzing the within-host dynamics of Zika virus, and we describe how these models can be used to understand key aspects of the viral life cycle and to predict antiviral efficacy.

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“…Previously Lai. et al confirmed that the early expansion of the antibody-secreting B cells secrets ZIKV-specific immunoglobulins G, A but also M (45). Moreover, germinal centers (GC) are responsible for generating long-lived, high-affinity Antibody Secreting Cells (ASC) that in turn are able to generate a better-quality response against re-infections (46).…”

Section: Discussionmentioning

confidence: 93%

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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Innate, T-, and B-Cell Responses in Acute Human Zika Patients

Abstract: Understanding the immune response during acute Zika in humans will aid vaccine design and testing. In 5 acute patients, including 2 pregnant women, viral levels and innate, T-, and B-cell responses against Zika or dengue viruses are described.

Cited by 72 publications

References 37 publications

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Mathematical modeling of within‐host Zika virus dynamics

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

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