Identification of Protective CD8 T Cell Responses in a Mouse Model of Zika Virus Infection

Hassert, Mariah; Harris, Madison G.; Brien, James D.; Pinto, Amelia K.

doi:10.3389/fimmu.2019.01678

Cited by 45 publications

(83 citation statements)

References 68 publications

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“…5C and S6). In line with the recent ndings that CD8 + T cells protected against ZIKV infection in the CNS [31,47,48], our study suggests that IL-22 may contribute to ZIKV encephalitis pathogenesis by modulating periphery CD8 + T cell responses. Additional evidence is that IL-22 de ciency did not in uence WNV burdens in the spleen [15]; however, IL-22 −/− mice had lower viral loads in the spleen following ZIKV infection (Fig.…”

Section: Discussionsupporting

confidence: 91%

IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

Liang

et al. 2020

Preprint

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Background The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is unknown. Methods The cellular source of IL-22 was identified in IFNAR−/− mice and WT neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old wild-type (WT) and IL-22−/− mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, we infected mouse primary astrocytes in vitro, and characterized the reactive astrocyte phenotype. Human glial cell line was also infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression and viral loads. Results We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 days post-infection (dpi), and ultimately succumbed to infection at 16–19 dpi. Surprisingly, IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. ZIKV infection facilitated a neurotoxic polarization of A1-prone astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a marginal effect on glial cells in vitro, IL-22−/− mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain. Conclusions Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

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Section: Discussionsupporting

confidence: 91%

IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

Liang

et al. 2020

Preprint

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“…With this result, we chose to use our SARS-CoV-2 murine model to identify the SARS-CoV-2-specific CD8 + and CD4 + T cell responses using a peptide library screening method (Figures 3 and 4). We chose this approach, as it has worked previously for identifying Zika virus (ZIKV) T cell epitopes using a ZIKV peptide library in C57BL/6 mice [36,48]. Table 1).…”

Section: Sars-cov-2 Cd8 + and Cd4 + T Cell Epitope Identificationmentioning

confidence: 99%

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2

Hassert

Geerling

Stone

et al. 2020

Preprint

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The novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic resulting in nearly 20 million infections across the globe, as of August 2020. Critical to the rapid evaluation of vaccines and antivirals is the development of tractable animal models of infection. The use of common laboratory strains of mice to this end is hindered by significant divergence of the angiotensin-converting enzyme 2 (ACE2), which is the receptor required for entry of SARS-CoV-2. In the current study, we designed and utilized an mRNA-based transfection system to induce expression of the hACE2 receptor in order to confer entry of SARS-CoV-2 in otherwise non-permissive cells. By employing this expression system in an in vivo setting, we were able to interrogate the adaptive immune response to SARS-CoV-2 in type 1 interferon receptor deficient mice. In doing so, we showed that the T cell response to SARS-CoV-2 is enhanced when hACE2 is expressed during infection. Moreover, we demonstrated that these responses are preserved in memory and are boosted upon secondary infection. Interestingly, we did not observe an enhancement of SARS-CoV-2 specific antibody responses with hACE2 induction. Importantly, using this system, we functionally identified the CD4+ and CD8+ peptide epitopes targeted during SARS-CoV-2 infection in H2b restricted mice. Antigen-specific CD8+ T cells in mice of this MHC haplotype primarily target peptides of the spike and membrane proteins, while the antigen-specific CD4+ T cells target peptides of the nucleocapsid, membrane, and spike proteins. The functional identification of these T cell epitopes will be critical for evaluation of vaccine efficacy in murine models of SARS-CoV-2. The use of this tractable expression system has the potential to be used in other instances of emerging infections in which the rapid development of an animal model is hindered by a lack of host susceptibility factors.

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“…Virus-specific CD8 + T cells have the capacity to lyse virally-infected cells and produce cytokines, creating an environment that supports viral clearance and protection from severe disease (reviewed in [72]). For ZIKV, we showed that there is a broad CD8 + T cell response generated against the pathogen and that T cell response is required for protection against a lethal ZIKV challenge [19].…”

Section: Discussionmentioning

confidence: 99%

“…The ZIKV strain PRVABC59 used was a kind gift of Robert Lanciotti (CDC). The ZIKV used was grown in Vero cells from the American Type Culture Collection (ATCC CCL-81) and stored at −80 • C, as described previously [19,22,49]. The human serum samples were obtained from the University of North Carolina/ National Institute of Health (UNC/NIH) Traveler Study through BEI Resources, NIAID, NIH: human convalescent plasma.…”

Section: Viruses Human Serum and Cellsmentioning

confidence: 99%

“…To assess the ability of the hAd5-ZKV vaccine to induce a CD8 + T cell response eight days post immunization with the hAd5-ZKV, a subset of vaccinated mice was euthanized and ZIKV antigen-specific CD8 + T cell responses were evaluated by intracellular cytokine staining. Splenic CD8 + T cells were stimulated with the immunodominant ZIKV peptide E 294 (aa294-302) [19], and the intracellular levels of the effector cytokine interferon gamma (IFNγ were determined. A representative flow plot with our gating strategy for the detection of the of IFNγ-CD8 + T cells is shown in Figure S1.…”

Section: Immunogenicity Of Had5-zkv Vaccinementioning

confidence: 99%

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Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

et al. 2020

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Zika virus (ZIKV) is a significant public health concern due to the pathogen's ability to be transmitted by either mosquito bite or sexual transmission, allowing spread to occur throughout the world. The potential consequences of ZIKV infection to human health, specifically neonates, necessitates the development of a safe and effective Zika virus vaccine. Here, we developed an intranasal Zika vaccine based upon the replication-deficient human adenovirus serotype 5 (hAd5) expressing ZIKV pre-membrane and envelope protein (hAd5-ZKV). The hAd5-ZKV vaccine is able to induce both cell-mediated and humoral immune responses to ZIKV epitopes. Importantly, this vaccine generated CD8 + T cells specific for a dominant ZIKV T cell epitope and is shown to be protective against a ZIKV challenge by using a pre-clinical model of ZIKV disease. We also demonstrate that the vaccine expresses pre-membrane and envelope protein in a confirmation recognized by ZIKV experienced individuals. Our studies demonstrate that this adenovirus-based vaccine expressing ZIKV proteins is immunogenic and protective in mice, and it encodes ZIKV proteins in a conformation recognized by the human antibody repertoire.The development of a ZIKV vaccine is urgent due to the speed of ZIKV spread in susceptible populations, as well as the range of diseases caused by infection [5]. According to the World Health Organization (WHO), a majority of individuals who are infected with ZIKV are asymptomatic, but those with a mild clinical form of the disease report symptoms including fever, rash, conjunctivitis, and muscle and joint pain, all of which typically last less than a week. While these symptoms are rarely debilitating, complications of Zika virus disease can include Guillain-Barré syndrome. Zika-induced microcephaly and congenital abnormalities are generally classified as congenital Zika syndrome (CZS), which is also a potential complication in the developing fetuses of pregnant women [4,6-10]. These risks, combined with the explosive outbreaks that occurred at Yap Island in 2007 [11], French Polynesia in 2013 [12], and Brazil in 2015-16 [13], underscore the need to control the spread of ZIKV. However, there are no current FDA-approved vaccines available to control infection.Harnessing the power of both arms of the adaptive immune response improves vaccine potency and efficacy while reducing opportunities of viral escape. Current data from both naturally acquired human infection and mouse models of ZIKV disease indicate that protection from disease is multi-faceted (reviewed in [14][15][16][17][18]). Both small and large animal models of ZIKV infection have demonstrated that the Zika-specific CD8 + and CD4 + T cell response is necessary and sufficient to protect against a lethal ZIKV challenge [19][20][21][22]. As has been demonstrated previously for multiple flavivirus infections [23-25], ZIKV-specific polyclonal and monoclonal neutralizing antibody responses can protect mice and nonhuman primates from mortality and severe disease. There is also a role fo...

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Identification of Protective CD8 T Cell Responses in a Mouse Model of Zika Virus Infection

Cited by 45 publications

References 68 publications

IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

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