• Thu. Sep 21st, 2023

Tun MM, Aoki K, Senba M, Buerano CC, Shirai K, Suzuki R, Morita K, Hayasaka D, Protective role of TNF-alpha, IL-10 and IL-2 in mice infected with the Oshima strain of Tick-borne encephalitis virus


Jan 23, 2022

Tun MM, Aoki K, Senba M, Buerano CC, Shirai K, Suzuki R, Morita K, Hayasaka D, Protective role of TNF-alpha, IL-10 and IL-2 in mice infected with the Oshima strain of Tick-borne encephalitis virus. barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to contamination, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand the mechanism by which innate and adaptive immune cells thwart neuroinvasion by vesicular stomatitis virus (VSV), a potentially lethal virus that uses olfactory sensory neurons A2AR-agonist-1 to enter the brain after nasal contamination. Fate-mapping studies exhibited that infected CNS neurons were cleared non-cytolytically, yet specific deletion of MHC I from these neurons unexpectedly had no effect on viral control. Intravital A2AR-agonist-1 imaging studies of calcium signaling in virus-specific CD8+ T cells revealed instead that brain resident microglia were the relevant source of viral peptide-MHC I complexes. Microglia were not infected by the virus but were found to cross-present antigen following acquisition A2AR-agonist-1 from adjacent neurons. Microglia depletion interfered with T cell calcium signaling and antiviral control in the brain after nasal contamination. Collectively, these data demonstrate that microglia provide a front-line defense against a neuroinvasive nasal contamination by cross-presenting antigen to antiviral T cells that non-cytolytically cleanse neurons. Disruptions in this innate defense likely render the brain susceptible to neurotropic viruses like VSV that attempt to enter the CNS via the nose. One Sentence Summary: Microglia safeguard the brain from an intranasal VSV contamination by cross-presenting A2AR-agonist-1 neuronal antigen to antiviral CD8+ T cells. INTRODUCTION Viral infections of the central nervous system (CNS) can be devastating when not properly contained (1, 2). Because the CNS contains irreplaceable post-mitotic cells, it is protected by several physical barriers that limit pathogen access into the CNS, including the blood brain barrier (BBB), blood cerebrospinal fluid barrier (B-CSF), and skull, among others. In addition, immune responses in this compartment are heavily regulated (3). Viruses in turn use several approaches to bypass these barriers such as direct contamination of the BBB, invasion of peripheral nerves followed by transport into the CNS, and trojan horse entry via surveying immune cells (4). One especially vulnerable route that viruses use to invade the CNS is usually via olfactory sensory neurons (OSNs) within the nasal cavity. OSNs lie within the mucosal upper airway surface, which is constantly exposed to environmental pathogens. However, the olfactory epithelium (OE) lining the nasal turbinates is unique in that this mucosal surface provides access for viruses to enter the CNS. Unlike the neighboring respiratory epithelium, the OE contains thousands to millions of OSNs (depending on the species) that are the predominant cell type within the olfactory neuroepithelial surface. While the OSN cell bodies lie beneath a layer of supporting or sustentacular cells, they extend a ciliated dendrite into the mucus lined airway space. Odorant information gathered from the external environment is usually conveyed via OSN axons within the turbinates through the specialized cribriform plate at the front of the skull Slit3 and into the olfactory bulb of the brain (5). However, this anatomical arrangement also results in OSNs serving as a direct single cell route for neuroinvasion. Pathogens that infect OSNs can be shuttled intracellularly along OSN axons directly into the brain. The intracellular passage via OSNs into the brain allows invading pathogens to tunnel under the castle wall and evade classical CNS barriers that typically shield the brain. Thus, the olfactory route of contamination is especially vulnerable to neurotropic viruses (6, 7). The immune response to viruses must be appropriately balanced between pathogen clearance and limiting tissue damage. This balance is especially important in the CNS because most neurons are unable to regenerate, and damage can A2AR-agonist-1 result in permanent damage to neural networks (1). While virus-induced cytopathology poses a serious concern to the CNS, immune-mediated cellular damage via perforin/granzyme poses a similar threat to neuronal integrity. Therefore, noncytolytic viral clearance via.