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

Ingo Riederer,Daniella Arêas Mendes-Da-Cruz,Mariane Talon Menezes,Wilson Savino,Alexandra Gerber,Guilherme Cordenonsi Da Fonseca,Joseane Biso De Carvalho,Gillian Butler-Browne,Mariela Natacha González,Myrna Cristina Bonaldo,Cássia Rocha,Lidiane Menezes Souza Raphael,Otavio Brustolini,Vinicius Cotta-De-Almeida,Guilherme Loss,Vincent Mouly,Ana Tereza Ribeiro De Vasconcelos

doi:10.1371/journal.pntd.0010166

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.

Highlights

The Zika virus (ZIKV) is an arthropod-borne virus from the Flaviviridae family and genus Flavivirus, which includes dengue, yellow fever, and West Nile viruses
The ZIKV was responsible for a large pandemic surge between 2015 and 2016; Brazil was the epicenter with very high numbers of congenital ZIKV syndrome that included microcephaly, myalgia, among other manifestations
We have observed in previous work that muscle progenitor cells are infected by ZIKV, while differentiated cells do not present viral proteins

Summary

Introduction

The ZIKV is an arthropod-borne virus (arbovirus) from the Flaviviridae family and genus Flavivirus, which includes dengue, yellow fever, and West Nile viruses. Congenital ZIKV infection results in a range of neurological abnormalities in children, collectively defined as congenital Zika syndrome [1,2], comprising, among others, microcephaly, decreased brain tissue, absence of brain structures, eye abnormalities, as well as congenital contractures such as arthrogryposis [3]. Several studies have described the tropism of ZIKV for different cell types of the central nervous system like microglia, neural stem cells, and progenitor cells, as well as in other tissues such as skin, blood, placenta, retina, thymus, as well as smooth and skeletal muscle [4,5,6,7,8,9,10]. A spectrum of neurological outcomes was described in toddlers and preschoolers that have been congenitally infected by the ZIKV [11]. Children were separated into groups termed corticospinal or neuromuscular based on their clinical signs, with or without dyskinetic findings. Infants can develop features consistent with fetal immobility, ranging from dimples, distal hand/finger contractures and foot mispositioning to generalized arthrogryposis [12]

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Conclusion