Susceptibility and cytokine responses of human neuronal cells to multiple circulating EV-A71 genotypes in India

Madhu Chhanda Mohanty,Swapnil Yashavant Varose,Vinay Kumar Saxena

doi:10.1038/s41598-021-97166-x

Madhu Chhanda Mohanty, Swapnil Yashavant Varose + Show 1 more

Open Access

https://doi.org/10.1038/s41598-021-97166-x

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Abstract

Enterovirus-A71 (EV-A71) associated Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting children in Asia–Pacific region and has become a major threat to public health. Although several EV-A71 genotypes (C, D, and G) were isolated in India in recent years, no recognizable outbreak of EV-A71 caused HFMD, Acute Flaccid paralysis (AFP) or encephalitis have been reported so far. It is essential to study the pathogenicity or cell tropism of these Indian isolates in order to understand their tendency to cause disease. We investigated the susceptibility and cytokine responses of indigenous EV-A71 genotypes (D and G) isolated from cases of AFP and genotype C viruses isolated from cases of HFMD and encephalitis, in human cells in-vitro. Although all three EV-A71 genotypes could infect and replicate in human muscle and neuronal cells, the genotype D virus showed a delayed response in human neuronal cells. Quantification of cytokine secretion in response to these isolates followed by confirmation with gene expression assays in human neuronal cells revealed significantly higher secretion of pro-inflammatory cytokines TNF-α IL-8, IL-6, IP-10 (p < 0.001) in G genotype infected cells as compared to pathogenic C genotypes whereas the genotype D virus could not induce any of the inflammatory cytokines. These findings will help to better understand the host response to indigenous EV-A71 genotypes for management of future EV-A71 outbreaks in India, if any.

Highlights

Enterovirus-A71 (EV-A71) associated Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting children in Asia–Pacific region and has become a major threat to public health
EV-A71 strain D and G are indigenous to India and not isolated in any other countries, but so far there is no recognizable outbreak of either HFMD or meningo-encephalitis has been caused by these strains
To understand whether the Indian genotypes infects human neuronal cells, SK-N-SH cells and RD-A cells were infected with all the three genotypes of EV-A71 (C, D, G) with 1 MOI

Summary

Introduction

Enterovirus-A71 (EV-A71) associated Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting children in Asia–Pacific region and has become a major threat to public health. Quantification of cytokine secretion in response to these isolates followed by confirmation with gene expression assays in human neuronal cells revealed significantly higher secretion of pro-inflammatory cytokines TNF-α IL-8, IL-6, IP-10 (p < 0.001) in G genotype infected cells as compared to pathogenic C genotypes whereas the genotype D virus could not induce any of the inflammatory cytokines These findings will help to better understand the host response to indigenous EV-A71 genotypes for management of future EV-A71 outbreaks in India, if any. EV-A71 commonly causes Hand, Foot and Mouth Disease (HFMD) in children, but can result in neurological complications such as AFP, aseptic meningitis, encephalitis and cardiorespiratory complications in severe cases It is the second most important enterovirus of public health after poliovirus.

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