Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS.

L G Webb,D Bernal-Rubio,K A Stapleford,J Pintado-Silva,St P Reid,U Potla,J S Yount,T Zhu,S Aguirre,A Fernandez-Sesma,R Fenutria,L Zhang,T Mutetwa,D Figueroa,L Carrau,J Veloz,M V Rangel,John W Schoggins

doi:10.1371/journal.ppat.1008999

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.

Highlights

Chikungunya virus (CHIKV) is an arbovirus belonging to the genus Alphavirus (Family: Togaviridae) which is transmitted primarily by mosquitos of the Aedes spp[1, 2]
We show that CHIKV induces the accumulation of DNA in the cytoplasm of infected cells and that the virus blocks cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-Stimulator of Interferon Genes (STING) dependent innate immune sensing via degradation of cGAS
This work provides the first description of CHIKV mediated inhibition of DNA dependent innate immune sensing and expands upon our previous works by identifying and characterizing another RNA virus family able to counteract cGAS-STING mediated DNA sensing

Summary

Introduction

CHIKV is an arbovirus belonging to the genus Alphavirus (Family: Togaviridae) which is transmitted primarily by mosquitos of the Aedes spp[1, 2]. Between 2006– 2007, CHIKV was responsible for an outbreak on the island of La Reunion where more than one third of the island’s population was infected in the span of a few months[10]. Non-structural protein 1 (nsP1) of CHIKV has been shown to anchor viral replication complexes to cytosolic membranes through both an amphipathic helix as well as through palmitoylation of three cystine (Cys) residues 417–419[16, 17]. Mutations of these residues have been shown for both CHIKV and other alphaviruses to severely hamper viral replication kinetics and decrease pathogenicity in mouse models[18, 19]. Viral structural proteins are translated from the 26S RNA and processed threaded into the endoplasmic reticulum (ER) with exception of the capsid protein which remains in the cytosol prior to encapsidation of the viral genomic RNA[20]

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