Influenza a virus-triggered autophagy decreases the pluripotency of human-induced pluripotent stem cells

Ali Zahedi-Amiri,Sanjiv Dhingra,Kevin M Coombs,Glen L Sequiera

doi:10.1038/s41419-019-1567-4

Abstract

Maternal influenza infection during pregnancy was reported multiple times as the possible cause of many defects and congenital anomalies. Apart from several cases of influenza-related miscarriage during various trimesters of pregnancy, some epidemiological data suggest a link between maternal influenza infection and genetic abnormalities in offspring. However, there are no reports yet describing how maternal influenza alters cellular pathways at early stages of development to result in congenital defects in the fetus. In the present study, using proteomic approaches, we utilized human-induced pluripotent stem cells (hiPSCs) for modeling intrablastocyst infection with influenza virus to not only investigate the vulnerability and responses of pluripotent stem cells to this virus but also to determine the possible impacts of influenza on pluripotency and signaling pathways controlling differentiation and embryogenesis. Our data indicated viral protein production in influenza A virus (IAV)-infected hiPSCs. However, viral replication was restricted in these cells, but cell viability and pluripotency were negatively affected. These events occurred simultaneously with an excessive level of IAV-induced autophagy as well as cytopathic effects. Quantitative SOMAscan screening also indicated that changes in the proteome of hiPSCs corresponded to abnormal differentiation in these cells. Taken together, our results showed that IAV-modulated reduction in hiPSC pluripotency is associated with significant activation of autophagy. Further investigations are required to explore the role of IAV-induced autophagy in leading pluripotent stem cells toward abnormal differentiation and impaired development in early stages of embryogenesis.

Highlights

Some influenza pandemics and seasonal epidemics have shown high rates of fatalities in pregnant women and the fetus, suggesting that pregnancy puts both mother and offspring at higher risk of developing flu complications[1]
Influenza A/PR/8/34 replicates restrictively in Humaninduced pluripotent stem cells (hiPSCs) Unlike MDCK and A549 epithelial cells, which are permissive to influenza, influenza A virus (IAV) growth was restricted in hiPSCs at multiplicity of infection (MOI) of 0.1 and 1.0 (Fig. 1a, upper and middle panels)
We showed that IAV propagates restrictedly in hiPSCs

Summary

Introduction

Some influenza pandemics and seasonal epidemics have shown high rates of fatalities in pregnant women and the fetus, suggesting that pregnancy puts both mother and offspring at higher risk of developing flu complications[1]. Interactions of influenza proteins with themselves and with host cell proteins elicit substantial changes in the proteome to expand viral replication, as noticed by several virus-induced impairments in host cellular machinery affecting apoptosis and autophagy, immune responses, and protein synthesis[15,16,17,18,19,20,21]. None of these influenza-mediated alterations have been studied under the pluripotent state on a proteomic scale. We investigated the effects of IAV on the pluripotency and the proteome of hiPSCs

Methods

Results

Conclusion