IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

Abstract

West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons.

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

“…In the context of MAV-1-induced encephalitis our results indicate that IL-1 signaling has a protective role, as observed for WNV infection (11,25). Il1r1 Ϫ/Ϫ and Pycard Ϫ/Ϫ MAV-1-infected mice had lower survival than WT mice.…”

“…We observed a more pronounced effect on MAV-1 pathogenesis in Il1r1 Ϫ/Ϫ mice and higher brain viral loads in brains compared to the other mouse strains. This is different from WNV infection in mouse models, where not only Il1r1 Ϫ/Ϫ mice but also Pycard Ϫ/Ϫ mice have higher brain viral loads (11,25,30). During HSV-1-induced encephalitis, IL-1␤ also has a protective role against encephalitis (21).…”

Inflammasomes and its importance in viral infections

“…Furthermore, high mortality rates were observed in WNV-infected knockdown mice lacking functional Il-1r, Nlrp3, Casp-1, and Asc genes, while lower mortality rates were observed in WNV-infected wild-type mice [62,63]. Additionally, mice infected with other members of the family Flaviviridae, such as Japanese encephalitis virus, show IL-1b and IL-18 secretion and caspase-1 maturation in an NLRP3-dependent, K ?…”

Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells

“…NLRP3 recognizes a wide range of pathogen-and danger-associated molecular patterns (2,3). Specifically, this particular inflammasome can recognize both positive-and negative-sense RNA viruses, including influenza virus, Sendai virus, encephalomyocarditis virus (EMCV), vesicular stomatitis virus (VSV), and West Nile virus (7)(8)(9)(10)(11)(12)(13)(14)(15). However, the exact mechanism by which these pathogens activate the inflammasome is presently unknown.…”