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Testosterone protects mice against zika virus infection and suppresses the inflammatory response in the brain.

ABSTRACT: Testosterone is essential to human growth and development as well as immune regulation. Zika virus (ZIKV), an emerging arbovirus associated with neurological complications including neuroinflammation, can also cause testicular damage and decrease testosterone secretion. However, whether the dysregulation of testosterone plays a role in the process of neuroinflammation during ZIKV pathogenesis is still unclear. In this study, we found that ZIKV infection caused testicular damage and decreased testosterone secretion in male mice, and testosterone supplementation after ZIKV infection reduced their mortality and attenuated the pathological symptoms. Further investigation revealed that testosterone treatment after ZIKV infection alleviated inflammation and nerve injury in the mouse brain. Additionally, reduced CD8⁺ T cell infiltration and interferon-gamma production were observed in brains of testosterone-treated mice. Overall, our results demonstrated that testosterone plays a protective role in ZIKV-infected mice, and thus it can be developed as a potential therapeutic drug against ZIKV infection.

SUBMITTER: Zheng B

PROVIDER: S-EPMC9593801 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Testosterone protects mice against zika virus infection and suppresses the inflammatory response in the brain.

Zheng Bohan B Sun Jiajun J Luo Haoran H Yang Ling'en L Li Qi Q Zhang Luping L Si Youhui Y Cao Shengbo S Ye Jing J

iScience 20221006 11

Testosterone is essential to human growth and development as well as immune regulation. Zika virus (ZIKV), an emerging arbovirus associated with neurological complications including neuroinflammation, can also cause testicular damage and decrease testosterone secretion. However, whether the dysregulation of testosterone plays a role in the process of neuroinflammation during ZIKV pathogenesis is still unclear. In this study, we found that ZIKV infection caused testicular damage and decreased tes ...[more]

PMID: 36304103

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Project description:Zika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms, but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. Creating an effective vaccine against ZIKV is a public health priority. We describe the protective effect of an already licensed attenuated yellow fever vaccine (YFV, 17DD) in type-I interferon receptor knockout mice (A129) and immunocompetent BALB/c and SV-129 (A129 background) mice infected with ZIKV. YFV vaccination provided protection against ZIKV, with decreased mortality in A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in BALB/c mice. The A129 mice that were challenged two and three weeks after the first dose of the vaccine were fully protected, whereas partial protection was observed five weeks after vaccination. In all cases, the YFV vaccine provoked a substantial decrease in the cerebral viral load. YFV immunization also prevented hippocampal synapse loss and microgliosis in ZIKV-infected mice. Our vaccine model is T cell-dependent, with AG129 mice being unable to tolerate immunization (vaccination is lethal in this mouse model), indicating the importance of IFN-γ in immunogenicity. To confirm the role of T cells, we immunized nude mice that we demonstrated to be very susceptible to infection. Immunization with YFV and challenge 7 days after booster did not protect nude mice in terms of weight loss and showed partial protection in the survival curve. When we evaluated the humoral response, the vaccine elicited significant antibody titers against ZIKV; however, it showed no neutralizing activity in vitro and in vivo. The data indicate that a cell-mediated response promotes protection against cerebral infection, which is crucial to vaccine protection, and it appears to not necessarily require a humoral response. This protective effect can also be attributed to innate factors, but more studies are needed to strengthen this hypothesis. Our findings open the way to using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak.

Project description:BackgroundZika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV.Methodology/principle findingsWe have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge.Conclusions/significanceThese studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

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Testosterone protects mice against zika virus infection and suppresses the inflammatory response in the brain.

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Testosterone protects mice against zika virus infection and suppresses the inflammatory response in the brain.

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