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

D Garrett Brown,Soumya Yandamuri,Laura Dickey,Joao Carlos Gomes-Neto,Charisse Petersen,Jason D Shepherd,W Zac Stephens,Rickesha Bell,Ryan M O'Connell,Thomas E Lane,Elissa D Pastuzyn,Raymond Soto,Kaitlin Buhrke,June L Round,Colleen Stone,Robert S Fujinami

doi:10.7554/elife.47117

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.

Highlights

Viral infection of the central nervous system (CNS) can cause permanent neurologic damage and psychiatric disorders (Bergmann et al, 2006; Koyuncu et al, 2013; van den Pol, 2009)
The microbiota protects from neurologic damage associated with viral infection To characterize the role of the microbiota in a model of viral-induced neurologic disease, 6- to 8week-old C57BL/6 specific-pathogen-free (SPF) or germ-free (GF) mice were infected intracranially (i. c.) with the neurotropic JHM strain of mouse hepatitis virus (JHMV)
Feeding toll-like receptor (TLR) ligands to GF mice suggests that these microbial products are sufficient to decrease neurologic disease, and our results show that TLR4 exposure may play a more prominent role than TLR2 signaling in this process

Summary

Introduction

Viral infection of the CNS can cause permanent neurologic damage and psychiatric disorders (Bergmann et al, 2006; Koyuncu et al, 2013; van den Pol, 2009). While Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, narcolepsy and other chronic neurologic diseases have unknown etiologies, initiation by CNS viral infection has been implicated (Itzhaki et al, 2016; Kakalacheva et al, 2011; Stoessl, 1999; Tesoriero et al, 2016; Virtanen and Jacobson, 2012). Viral infection of the CNS presents unique challenges to the immune system with regard to controlling and eliminating the invading pathogen. A significant hurdle encountered by infiltrating antigen-specific lymphocytes is to eliminate virus from infected cells while limiting damage that may have long-term detrimental consequences to the host. Defining antiviral host defense mechanisms within the CNS might highlight novel therapeutic interventions to prevent or treat many of these viral-induced neurologic disorders

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Conclusion