Chikungunya Virus Infects the Heart and Induces Heart-Specific Transcriptional Changes in an Immunodeficient Mouse Model of Infection

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen in family Togaviridae, genus Alphavirus. Although CHIKV is well known for its ability to cause debilitating rheumatoid-like arthritis, it has been also been observed to cause cardiovascular symptoms such as arrhythmias. Here, using samples from a previous study, we sequenced RNA from serum, kidney, skeletal muscle, and cardiac muscle from CHIKV- and mock-infected IFN-αR−/− mice using two sequencing techniques to investigate heart-specific changes in virus mutational profiles and host gene expression. Mutation rates were similar across muscle tissues although heart tissue carried heart-specific CHIKV minority variants, one of which had a coding change in the nsP3 gene and another in the 3′UTR. Importantly, heart-specific transcriptional changes included differential expression of genes critical for ion transport and muscle contraction. These results demonstrate that CHIKV replicates in the hearts of immunodeficient mice and induce heart-specific mutations and host responses with implications for cardiac pathologies.

Generation and Functional Analysis of Defective Viral Genomes during SARS-CoV-2 Infection

“…We used ViReMa to identify DVGs, as this algorithm has been developed and validated to faithfully identify recombination events in a range of plant viruses ( 65 – 67 ), insect viruses ( 68 , 69 ), arthropod-borne viruses (arboviruses) ( 70 – 72 ), human pathogens (influenza virus [ 73 ], reovirus [ 74 ], MERS-CoV, and SARS-CoV-2 [ 17 , 75 ]), and retroviruses (human immunodeficiency virus [HIV]) ( 76 ). It has also been validated independently by Alnaji et al ( 77 ) and Boussier et al ( 78 ) who provided a series of condition and parameter optimizations using simulated and experimental data to map RNA recombination events in DVGs of influenza A and B.…”

MAVS signaling is required for clearance of chikungunya heart infection and prevention of chronic inflammation in vascular tissue

“…Previous studies, including our own, reported the presence of infectious particles or viral RNA in the cardiac tissue of CHIKV-infected mice (Clavarino et al, 2012;Langsjoen et al, 2021;Noval et al, 2019). However, in these studies, mice were not perfused, thus confounding measurements due to the potential presence of the virus originating from serum in CHIKVinfected hearts.…”

Extra-articular Manifestations of Chikungunya

“…In some patients, cardiac symptoms are primarily related to CHIK infection; however, in others, cardiovascular disease may be secondary to pre-existing comorbidities 3 . Animal models have revealed active replication of CHIKV in the hearts of immunodeficient mice, and human biopsies have shown CHIKV in the myocardium, suggesting that direct viral infection plays a pathogenic role in CHIK cardiac disease 18,19 .…”