Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Abstract

Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-␤) production. Our findings highlight the importance of IFN-␤ production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCECoronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-␤ by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion.T he blood-brain barrier (BBB) is a highly selective barrier critical for central nervous system (CNS) homeostasis in controlling peripheral blood-brain exchange and preventing neurotoxins and pathogens from access to the CNS. The functional and structural integrity of the BBB mainly relies on specific features of the brain microvascular endothelial cells (BMECs) lining the brain capillaries. These cells are tightly connected by a unique assembly of adherens junctions composed of transmembrane cadherin and tight-junction complexes (e.g., claudins and occludin) anchored to actin filaments via adaptor molecules, such as zona occlu...

Type I interferon pathway in CNS homeostasis and neurological disorders

“…The BBB is known to provide significant protection against the hematogenous spread of viruses into the CNS, as several viruses inoculated in periphery were shown to induce neuropathology only after mechanically or chemically mediated disruption of the BBB. The infection of BMECs reduced their barrier protective IFN-b production and resulted in BBB breakdown, allowing the virus to invade the brain tissue (Bleau, Filliol, Samson, & Lamontagne, 2015). An extremely virulent subtype of the mouse hepatitis virus (MHV) was able to invade the brain by breakdown of the BMEC barrier.…”

Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance

“…[89] In contrast, the non-pathogenic strain isolated from persistently infected YAC lymphoid cell line (YAC-MHV3) does not induce an acute lethal disease but only subclinical infection in mice. [92] Recent data evidenced the invasion of MHV in the brain microvasculature by impairment of IFN-β production [93] or by sustained CXCL1 expression. [94] The pathogenic infection by MHV3 in mice up-regulated expression of IL-33 in the liver along with other pro-inflammatory cytokines such as IL-6, TNF-α, IL-1β, and IFN-γ.…”

¿Es esperable que haya cuadros neurológicos por la pandemia por SARS-CoV-2?

“…Las cepas neurotrópicas de MHV pueden invadir el SNC por inoculación intranasal en ratones 60 y también por vía sanguínea, y ello se ha observado también en primates 61 . El paso por la barrera hematoencefalica se ha relacionado con la producción de interferón-beta por las células epiteliales de la microcirculación cerebral 62 . La infección por MHV-CoV desencadena una encefalomielitis aguda asociada con áreas focales de desmielinización, y se ha analizado el papel de la respuesta inmune en su evolución 63 .…”