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

Abstract

Background Until 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. Methods Here, 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−/−). Results We 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. Conclusions Using 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.

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

“…For example, in IFNAR −/− mice ZIKV infection of astrocytes results in a breakdown of the blood-brain barrier, allowing an influx of CD8+ T cells into the central nervous system (CNS) where they mediate apoptosis of ZIKV-infected neurons, but also results in severe neuropathology (87). Similarly, CD8+ cellular infiltration was also found in the CNS following ZIKV infection in C57/BL6 neonatal mice who developed hind limb collapse, cerebellar degeneration (88) and in the case of adult wildtype C57BL/6 mice, encephalitis (89). Whilst the CD8+ T cell response may be detrimental in the CNS, in IFNAR −/− pregnant mice cross-reactive DENV-specific CD8+ cells are protective against ZIKV infection of the fetus, including the fetal central nervous system, and are associated with increased fetal growth and viability (90).…”

Castanospermine reduces Zika virus infection-associated seizure by inhibiting both the viral load and inflammation in mouse models

“…Encephalitis (inflammation of the brain), meningitis (Inflammation of membrane covering the brain), and myelitis (inflammation of spinal cord) are known to cause seizures. ZIKV infection causes encephalitis ( Hayashida et al, 2019 ). We thought that CST, with its anti-viral and anti-inflammatory activity, can be useful in reducing the seizure-related neuronal disorders apart from viral load reduction and, thus, the severity of the infection.…”

IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

“…In contrast to the notion of the protective role of IFN-I, studies conducted in Zika virus-induced encephalitis in mouse brain showed that IFN-I is insufficient to prevent the establishment of infection in mouse brain through innate immune response, rather adaptive response plays a major role in immunopathology [28]. Apart from innate responses to the pathogens, IFN-I plays an essential role in the development of CNS.…”