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Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

ABSTRACT: Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection in vitro by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes (ISGs) in response to ZIKV infection. In particular, we found that AZM upregulates the expression of MDA5 and RIG-I, pathogen recognition receptors (PRRs) induced by ZIKV infection, and increases the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulates phosphorylation of TBK1, without inducing phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and prevent ZIKV associated devastating clinical outcomes, such as congenital microcephaly.

SUBMITTER: Li C

PROVIDER: S-EPMC6879226 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

Li Chunfeng C Zu Shulong S Deng Yong-Qiang YQ Li Dapei D Parvatiyar Kislay K Quanquin Natalie N Shang Jingzhe J Sun Nina N Su Jiaqi J Liu Zhenyang Z Wang Min M Aliyari Saba R SR Li Xiao-Feng XF Wu Aiping A Ma Feng F Shi Yi Y Nielsevn-Saines Karin K Jung Jae U JU Qin Frank Xiao-Feng FX Qin Cheng-Feng CF Cheng Genhong G

Antimicrobial agents and chemotherapy 20190916 12

Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection <i>in vitro</i> by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and seve ...[more]

PMID: 31527024

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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.

Dataset Information

Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

Publications

Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

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