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.

• Authors: Hilario J Ramos, Marion C Lanteri, Gabriele Blahnik, Amina Negash, Mehul S Suthar, Margaret M Brassil, Khushbu Sodhi, Piper M Treuting, Michael P Busch, Philip J Norris, Michael Gale Jr
• Journal: PLoS pathogens (PLoS Pathog) Vol. 8 Issue 11 Pg. e1003039 ( 2012) ISSN: 1553-7374 [Electronic] United States
• PMID: 23209411 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• IL1B protein, human
• Inflammasomes
• Interferon Type I
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Carrier Proteins (genetics, immunology, metabolism)
• Central Nervous System (immunology, metabolism, virology)
• Female
• Humans
• Inflammasomes (genetics, immunology, metabolism)
• Interferon Type I (genetics, immunology, metabolism)
• Interleukin-1beta (blood, genetics, immunology)
• Male
• Mice
• Mice, Mutant Strains
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neurons (immunology, metabolism, virology)
• Signal Transduction (immunology)
• Virus Replication (immunology)
• West Nile Fever (blood, genetics, immunology)
• West Nile virus (physiology)