Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells

Journal of Neuroinflammation

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[1] 0000 0004 1936 834X, grid.1013.3, Discipline of Pathology, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Bosch Institute, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia;0000 0004 1936 834X, grid.1013.3, Discipline of Pathology, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Bosch Institute, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia;0000 0004 1936 834X, grid.1013.3, Sydney Cytometry Facility, The University of Sydney and the Centenary Institute, Sydney, Australia;0000 0004 1936 834X, grid.1013.3, School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia;0000 0004 1936 834X, grid.1013.3, School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia;0000 0004 1936 834X, grid.1013.3, School of Life and Environmental Sciences, The University of Sydney, Molecular Bioscience Bldg., Maze Crescent G08, 2006, Sydney, NSW, Australia;

关键词: Zika virus;    Microglia;    Monocyte;    Neutrophil;    Encephalitis;    Innate immunity;    Type I interferon;    Adaptive immunity;   

DOI  :  10.1186/s12974-019-1566-5

来源: publisher

【 摘 要 】

BackgroundUntil the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear.MethodsHere, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (Ifnar1−/−) and recombination-activating gene 1 (Rag1−/−).ResultsWe show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset.ConclusionsUsing intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.

【 授权许可】

CC BY