Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

Abstract

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus that can cause debilitating, acute febrile illness and potentially result in encephalitis. Currently, there are no FDA-licensed vaccines or specific therapeutics for VEEV. Previous studies have demonstrated that VEEV infection results in increased blood-brain barrier (BBB) permeability that is mediated by matrix metalloproteinases (MMPs). Furthermore, after subarachnoid hemorrhage in mice, MMP-9 is upregulated in the brain and mediates BBB permeability in a toll-like receptor 4 (TLR4)-dependent manner. Here, we demonstrate that disease in C3H mice during VEEV TC-83 infection is dependent on TLR4 because intranasal infection of C3H/HeN (TLR4 WT ) mice with VEEV TC-83 resulted in mortality as opposed to survival of TLR4-defective C3H/HeJ (TLR4 mut ) mice. In addition, BBB permeability was induced to a lesser extent in TLR4 mut mice compared with TLR4 WT mice during VEEV TC-83 infection as determined by sodium fluorescein and fluorescently-conjugated dextran extravasation. Moreover, MMP-9, MMP-2, ICAM-1, CCL2 and IFN-γ were all induced to significantly lower levels in the brains of infected TLR4 mut mice compared with infected TLR4 WT mice despite the absence of significantly different viral titers or immune cell populations in the brains of infected TLR4 WT and TLR4 mut mice. These data demonstrate the critical role of TLR4 in mediating BBB permeability and disease in C3H mice during VEEV TC-83 infection, which suggests that TLR4 is a potential target for the development of therapeutics for VEEV.

A review of the mechanisms of blood–brain barrier disruption during COVID‐19 infection

“…Furthermore, TLR4 activation, aberrant TLR4 signaling, and hyperinflammation may be to blame for SARS‐CoV‐2‐induced myocarditis and multiple organ injury in COVID‐19 patients. In addition, the study conducted by Hollidge et al (2021) revealed that TLR4 plays a crucial role in modulating the permeability of the BBB and the pathogenesis of encephalitis in C3H mice following infection with the Venezuelan equine encephalitis virus TC‐83 (Hollidge et al, 2021). According to the study, TLR4 has been identified as a promising candidate for the advancement of therapeutic interventions for Venezuelan equine encephalitis virus.…”

SARS-CoV-2: is there neuroinvasion?

“…The TLR2/4 is expressed in the choroid plexus and circumventricular organs [ 45 ]. Equine encephalitis virus interacts with TLR4 and disrupt BBB permeability [ 46 ]. It is tempting to think that SARS-CoV-2 can also interact with these receptors.…”

Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses

“…VEEV and EEEV are also highly stable and retain infectivity as aerosols, which greatly increases the possibility of encephalitic disease in infected individuals. VEEV or EEEV exposures due to deliberate aerosol dissemination pose encephalitis concerns because of their ability to establish a quick infection in the central nervous system (CNS) through the olfactory neuron, by-passing the blood–brain barrier (BBB) [ 10 , 11 , 12 , 13 , 14 ]. The establishment of a robust productive infection in the CNS triggers a strong inflammatory response that impacts the integrity of the BBB and contributes to encephalitic disease [ 15 , 16 , 17 , 18 ].…”