Zika virus disrupts gene expression in human myoblasts and myotubes: Relationship with susceptibility to infection

Abstract

The tropism of Zika virus (ZIKV) has been described in the nervous system, blood, placenta, thymus, and skeletal muscle. We investigated the mechanisms of skeletal muscle susceptibility to ZIKV using an in vitro model of human skeletal muscle myogenesis, in which myoblasts differentiate into myotubes. Myoblasts were permissive to ZIKV infection, generating productive viral particles, while myotubes controlled ZIKV replication. To investigate the underlying mechanisms, we used gene expression profiling. First, we assessed gene changes in myotubes compared with myoblasts in the model without infection. As expected, we observed an increase in genes and pathways related to the contractile muscle system in the myotubes, a reduction in processes linked to proliferation, migration and cytokine production, among others, confirming the myogenic capacity of our system in vitro. A comparison between non-infected and infected myoblasts revealed more than 500 differentially expressed genes (DEGs). In contrast, infected myotubes showed almost 2,000 DEGs, among which we detected genes and pathways highly or exclusively expressed in myotubes, including those related to antiviral and innate immune responses. Such gene modulation could explain our findings showing that ZIKV also invades myotubes but does not replicate in these differentiated cells. In conclusion, we showed that ZIKV largely (but differentially) disrupts gene expression in human myoblasts and myotubes. Identifying genes involved in myotube resistance can shed light on potential antiviral mechanisms against ZIKV infection.

Zika virus infection of retinal cells and the developing mouse eye induces host responses that contrasts to the brain and dengue virus infection

“…In contrast, CfD was the highest mRNA induced by DENV, suggesting a more local acting, complement driven response to infection. Both DENV and ZIKV induced a major upregulation of Myl2, a gene typically associated with cardiac growth, previously reported to be upregulated in ZIKV-infected myeloblasts (Riederer et al 2022 ), and the relationship of this to non-muscle myosin and growth processes in the brain remains to be defined. Markers such as CD40, CD86, and CCL5 were increased, while induction of IFN-γ was not detected by NanoString, and CD4 and CD8 mRNA could not be detected by RT-PCR (data is not shown).…”

Skin muscle is the initial site of viral replication for arboviral bunyavirus infection

“…Other arboviruses have been shown to infect skeletal muscle, but primarily skeletal muscle of the limbs and smooth muscle of the heart 11,13,26,27 . Indeed, Chikungunya, Dengue, and Zika have all been reported to infect skeletal muscle across animal models and human samples 13,26,[28][29][30][31] . Approximately 25% of clinical human DENV and CHIKV patients have myocardial involvement, indicating that arboviral infections can readily occur in the heart 32 .…”

Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies

“…Similarly, it was demonstrated in vitro that human myoblasts could be infected by Zika virus, whereas myotubes are resistant to infection [ 177 , 178 ]. Zika-virus infected myogenic cells undergo a profound modulation of gene expression related to cytokine production, cell death, and immune response [ 179 ]. Furthermore, viral replication can also occur within muscle following infection with Ross River virus, Chikungunya virus, Mayaro virus, and Zika virus [ 171 ].…”