Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia

Xiaofang Wang; Hui Wang; Panpan Yi; Coleman Baker; Gonzales Casey; Xuping Xie; Huanle Luo; Jiyang Cai; Xuegong Fan; Lynn Soong; Haitao Hu; Pei-Yong Shi; Yuejin Liang; Jiaren Sun

doi:10.1016/j.intimp.2023.110512

Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia

Int Immunopharmacol. 2023 Aug:121:110512. doi: 10.1016/j.intimp.2023.110512. Epub 2023 Jun 19.

Authors

Xiaofang Wang¹, Hui Wang², Panpan Yi³, Coleman Baker⁴, Gonzales Casey², Xuping Xie⁵, Huanle Luo⁶, Jiyang Cai⁷, Xuegong Fan³, Lynn Soong⁸, Haitao Hu⁹, Pei-Yong Shi¹⁰, Yuejin Liang¹¹, Jiaren Sun¹²

Affiliations

¹ Department of Infectious Disease, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, China; Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
² Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
³ Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁴ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁶ School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
⁷ Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁸ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁹ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹⁰ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹¹ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: yu2liang@utmb.edu.
¹² Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: jisun@utmb.edu.

PMID: 37343373
DOI: 10.1016/j.intimp.2023.110512

Abstract

The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances.

Keywords: Inflammation; Interferon; Metformin; Microglia; Viral infection; ZIKV.

MeSH terms

Down-Regulation
Humans
Infant, Newborn
Metformin*
Microglia
Virus Replication
Zika Virus Infection*
Zika Virus*

Substances

Metformin

Abstract

MeSH terms

Substances

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