Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

Herrera, Bobby Brooke; Tsai, Wen-Yang; Chang, Charlotte A.; Hamel, Donald J.; Wang, Wei‐Kung; Lu, Yichen; Mboup, Souleymane; Kanki, Phyllis J.

doi:10.1128/jvi.01992-17

Cited by 31 publications

(51 citation statements)

References 54 publications

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“…Unexpectedly, we did not observe T cell responses that were significantly higher in magnitude in individuals with prior DENV exposure. These results are in contrast to our data on African ZIKV infections, which showed that previous flavivirus exposure was associated with enhanced T cell responses (27). One possibility is that the proportion of HIV infection among those with prior DENV exposure was higher compared with DENV-naïve in this study (90.5% versus 50% comparing sDENV and pDENV cases; 83.3% versus 60% comparing ZIKVwpDENV and pZIKV cases).…”

Section: Discussioncontrasting

confidence: 99%

“…We recently reported the development of a LFn ELISPOT assay based on NS3 protease and helicase to distinguish DENV and African ZIKV human infections (27). To assess the ability of the assay to distinguish infection by DENV and Asian ZIKV, we performed DENV and ZIKV homologous and heterologous LFn-NS3 protease and helicase stimulation of date-matched late convalescent-phase PBMCs in an IFN-γ and TNF-α ELISPOT among the serological-validated pDENV, pZIKV, sDENV, and ZIKVwpDENV, and undetermined cases.…”

Section: Resultsmentioning

confidence: 99%

“…While CD8 + T cell responses against DENV target nonstructural (NS) proteins such as NS3, NS4B, and NS5, ZIKV-specific CD8 + T cell responses target the structural proteins, capsid (C), premembrane (prM), and E (10, 26). We previously developed a modified anthrax toxin (LFn)-based enzyme-linked immunospot (ELISPOT) assay, which revealed long-term T cell responses that were ZIKV- and DENV-specific to NS3 protease but cross-reactive to NS3 helicase in individuals infected with DENV and African ZIKV (27). The impact of cross-reactive immune responses in protection or development of ZIKV-mediated neuropathology remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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T cell responses to nonstructural protein 3 distinguish infections by Dengue and Zika viruses

Herrera

Tsai

Brites

et al. 2018

Preprint

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WORD COUNT: 229 24 25 TEXT WORD COUNT: 3,409 26 27 (ZIKV) epidemic in the Americas and the Caribbean 49 demonstrates that clinical assays to detect, distinguish, and characterize immune 50 responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are 51 mosquito-transmitted flaviviruses sharing overlapping geographical distribution and 52have significant sequence similarity that can increase the potential for antibody and T 53 cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent 54 assays (ELISAs), we determine the serostatus of individuals living in a DENV-and 55 ZIKV-endemic region in Brazil, identifying individuals with primary DENV (pDENV) and 56 ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV 57 (sDENV) infections; pDENV and pZIKV were further confirmed by neutralization tests. 58Development of an enzyme-linked immunospot (ELISPOT) assay for DENV and ZIKV 59 structural and nonstructural (NS) protein antigens enables us to distinguish infections by 60 these viruses based on T cells and to characterize those responses. We find that IFN-γ 61 and TNF-α T cell responses to NS3 differentiates DENV and ZIKV infections with 94% 62 sensitivity and 92% specificity. In general, we also show that pDENV and sDENV cases 63 and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns, and that HIV-64 infected individuals have T cell responses that are lower in magnitude compared to HIV-65 negative individuals. These results have important implications for DENV and ZIKV 66 diagnostic and vaccine development and provide critical insights into the T cell 67 response in individuals with multiple flaviviral infections. 68 69 4 IMPORTANCE 70 71 The potential for antibody and T cell cross-reaction to DENV and ZIKV, 72 flaviviruses that co-circulate and can sequentially infect individuals, has complicated 73 diagnostic and vaccine development. Our serological data show that antibodies to 74 nonstructural protein 1 can distinguish sequential human infections by DENV and ZIKV. 75 The development of a simple and inexpensive assay also enables the differentiation of 76 DENV and ZIKV infections based on the characterization of T cell responses. Our T cell 77 data reveals strong response patterns that are similar in nature in individuals with one or 78 multiple DENV infections and in individuals with only primary ZIKV infection and ZIKV-79 infected individuals with previous DENV exposure. The characterization of T cell 80 responses in a serologically-validated group of individuals is of relevance to the 81 development of vaccines and immunotherapeutics against these global threats. 82 83 84 85 86 87 88 89 90 91 92 93 94 Aedes mosquitoes transmit globally relevant flaviviruses including dengue virus 95 (DENV) and Zika virus (ZIKV). DENV exists as four antigenic serotypes, DENV1 to 96 DENV4 (1). These viruses have a wide geographic distribution with approximately 390 97 million infections annually and more than a quarter of the world's population at risk (2)...

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T cell responses to nonstructural protein 3 distinguish infections by Dengue and Zika viruses

Herrera

Tsai

Brites

et al. 2018

Preprint

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“…In fact, NS3 and NS5 represent the main targets of the CD8 + T cell response to flaviviruses (34, 35). One study reported more cross-reactive T cell responses to full length NS3 helicase, because of higher sequence homology, than that to the protease region alone (36). Also, a homologous analysis based on the NS5 protein would place ZIKV closer to the JEV serocomplex than to DENVs (37).…”

Section: Discussionmentioning

confidence: 99%

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Wang

Zhen

Turtle

et al. 2020

Preprint

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24Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related 25 mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in 26 the Chinese national Expanded Program on Immunization since 2007. The recent 27 recognition of severe disease syndromes associated with ZIKV, and the identification of 28 ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential 29 interaction between the two. In this study, we showed that SA14-14-2 is protective against 30 ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive 31 immune responses to ZIKV; however, it was cellular immunity that predominantly 32 mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not 33 result in significant cross-protection, but did mediate antibody dependent enhancement in 34 vitro, though this did not have an adverse impact on survival. This study suggests that 35 SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. 36This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected 37 regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising 38 avenue into developing a novel bivalent vaccine against both ZIKV and JEV. 40Importance 43 Japanese encephalitis is a controllable disease in many countries in Asia, especially in 44 China, where many people have Japanese encephalitis virus (JEV) immunity due to 45 extensive JEV vaccination campaigns or natural exposure. Live-attenuated SA14-14-2 46 strain is a safe and effective vaccine recommended by the World Health Organization and 47 has been vaccinated more than 600 million doses since 1989. As the prevalence of Zika 48 virus (ZIKV) and rising risk in above regions, the cross-reactive immune response 49 between these two antigenically closely related flaviviruses, JEV and ZIKV, should also be 50 fully recognized, which is presumed to be based on those ambiguous cross-reactive 51 immunity between dengue virus and ZIKV. In this study, we found that JEV SA14-14-2 52 vaccine conferred cross-protection against ZIKV challenge in mice, which is mainly due to 53 cellular immunity rather than neutralizing antibody response. However, specific protective 54 components or cooperation between components warrant to be explored in subsequent 55 experiments. In conclusion, this study can provide important evidence for those who live in 56 JEV-endemic areas and are at risk for ZIKV infection.57 4 Introduction 58 Recently, Zika virus (ZIKV) has caused devastating outbreaks of fetal congenital 59 malformations in South and Central America and now transmitted in more than 70 60 countries, including many previously unaffected regions. ZIKV infection during pregnancy 61 increases the risk of neurological disorders in newborns (1), such as microcephaly. In 62 adults, ZIKV causes Guillain-Barré syndrome and other neurologic disorders (2). So far, 63 no specific vaccine or antiviral for prevention and treatment of Z...

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“…In the same study it was shown that in two large cohorts from Sri Lanka and Nicaragua (54), the imprint of previous DENV exposure is clearly detectable, and that the resulting T cell response to Asian ZIKV was biased toward the non-structural proteins (Figure 4). Similarly, evidence of pre-existing flavivirus immunity has been shown to result in enhanced T cell responses directed to NS3 of DENV and African ZIKV (69). Whether such responses are protective is unknown, but two studies have demonstrated that short-term T cell cultures of flavivirus specific T cells are capable of killing targets pulsed with peptides that are found in ZIKV, indicating that they likely have anti-viral function ( Figure 5) (20,70).…”

Section: Denv/zikv T Cell Cross-reactivitymentioning

confidence: 98%

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

et al. 2020

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Dengue virus (DENV, family Flaviviridae, genus Flavivirus) exists as four distinct serotypes. Generally, immunity after infection with one serotype is protective and lifelong, though exceptions have been described. However, secondary infection with a different serotype can result in more severe disease for a minority of patients. Host responses to the first DENV infection involve the development of both cross-reactive antibody and T cell responses, which, depending upon their precise balance, may mediate protection or enhance disease upon secondary infection with a different serotype. Abundant evidence now exists that responses elicited by DENV infection can cross-react with other members of the genus Flavivirus, particularly Zika virus (ZIKV). Cohort studies have shown that prior DENV immunity is associated with protection against Zika. Cross-reactive antibody responses may enhance infection with flaviviruses, which likely accounts for the cases of severe disease seen during secondary DENV infections. Data for T cell responses are contradictory, and even though cross-reactive T cell responses exist, their clinical significance is uncertain. Recent mouse experiments, however, show that cross-reactive T cells are capable of mediating protection against ZIKV. In this review, we summarize and discuss the evidence that T cell responses may, at least in part, explain the cross-protection seen against ZIKV from DENV infection, and that T cell antigens should therefore be included in putative Zika vaccines.

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Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

Abstract: responses to African ZIKV and DENV is of relevance to vaccine development.

Cited by 31 publications

References 54 publications

T cell responses to nonstructural protein 3 distinguish infections by Dengue and Zika viruses

T cell responses to nonstructural protein 3 distinguish infections by Dengue and Zika viruses

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

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