The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling

Abstract

Symbiotic microbes impact the function and development of the central nervous system (CNS); however, little is known about the contribution of the microbiota during viral-induced neurologic damage. We identify that commensals aid in host defense following infection with a neurotropic virus through enhancing microglia function. Germfree mice or animals that receive antibiotics are unable to control viral replication within the brain leading to increased paralysis. Microglia derived from germfree or antibiotic-treated animals cannot stimulate viral-specific immunity and microglia depletion leads to worsened demyelination. Oral administration of toll-like receptor (TLR) ligands to virally infected germfree mice limits neurologic damage. Homeostatic activation of microglia is dependent on intrinsic signaling through TLR4, as disruption of TLR4 within microglia, but not the entire CNS (excluding microglia), leads to increased viral-induced clinical disease. This work demonstrates that gut immune-stimulatory products can influence microglia function to prevent CNS damage following viral infection.

Microglia influence host defense, disease, and repair following murine coronavirus infection of the central nervous system

“…Furthermore, there was a small population of Galectin+ microglia in spinal cords in control mice yet not in PLX5622-treated mice and previous studies argue for a role for certain isoforms of Galectin in potentially contributing to demyelination in patients with multiple sclerosis (MS) ( de Jong et al, 2018) while other isoforms are considered important in driving oligodendrocyte differentiation associated with remyelination (Thomas & Pasquini, 2018). Our findings that spinal cord demyelination was significantly increased in PLX5622-treated mice supports an emerging role for microglia in restricting the severity of white matter and this is consistent with a recent study from our group indicating that microglia influence the severity of demyelination in JHMVinfected mice (Brown et al, 2019). While we are currently exploring the molecular and cellular mechanisms by which microglia may modulate the CNS microenvironment in mice persistently infected with JHMV, evidence presented in the current study indicates that PLX5622 treatment resulted in increased expression of transcripts encoding for Osteopontin, APOE, and TREM2 all of which have been implicated in contributing to demyelination (Chabas et al, 2001;Krasemann et al, 2017;Ulrich & Holtzman, 2016).…”

Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

“…Further, loss of intestinal flora reduces the percentage of total microglia, the number of microglia cells expressing major histocompatibility complex (MHC) molecules, and costimulatory molecules, such as CD86 and CD40, required for antigen presentation. Indeed, the TLR ligands produced by intestinal flora are recognized by the intestinal immune system and trigger antigen presentation by microglia, contributing to TLR4 signal transduction in microglia, achieving the highest level of MHC-I and MHC-II upregulation to inhibit viral diseases (84,85).…”

Intestinal microbiota: a new force in cancer immunotherapy

“…PRRs recognize pathogenassociated molecular patterns (PAMPs) and damagerelated molecular patterns (DAMPs) that affect the colonization of the intestinal microbiota. Among the more typical PRRs associated with microbial homeostasis are Toll-like receptors (TLRs) and NOD-like receptors (NLRs) [13,14]. TLRs bind to cell membranes and effect signal transduction through myeloid differentiation of primary response protein 88 (MYD88) and TIR-domaincontaining adapter-inducing interferon-β (TRIF) [15].…”