Flagellin From Pseudomonas aeruginosa Modulates SARS-CoV-2 Infectivity in Cystic Fibrosis Airway Epithelial Cells by Increasing TMPRSS2 Expression.

Maëlle Givelet,Jeanne Bigot,Manon Ruffin,Andrés Pizzorno,Olivier Terrier,Claire Calmel,Loïc Guillot,Viviane Balloy,Manuel Rosa-Calatrava,Harriet Corvol,Justine Oliva,Julia Mercier

doi:10.3389/fimmu.2021.714027

Abstract

In the coronavirus disease 2019 (COVID-19) health crisis, one major challenge is to identify the susceptibility factors of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in order to adapt the recommendations for populations, as well as to reduce the risk of COVID-19 development in the most vulnerable people, especially patients with chronic respiratory diseases such as cystic fibrosis (CF). Airway epithelial cells (AECs) play a critical role in the modulation of both immune responses and COVID-19 severity. SARS-CoV-2 infects the airway through the receptor angiotensin-converting enzyme 2, and a host protease, transmembrane serine protease 2 (TMPRSS2), plays a major role in SARS-CoV-2 infectivity. Here, we show that Pseudomonas aeruginosa increases TMPRSS2 expression, notably in primary AECs with deficiency of the ion channel CF transmembrane conductance regulator (CFTR). Further, we show that the main component of P. aeruginosa flagella, the protein flagellin, increases TMPRSS2 expression in primary AECs and Calu-3 cells, through activation of Toll-like receptor-5 and p38 MAPK. This increase is particularly seen in Calu-3 cells deficient for CFTR and is associated with an intracellular increased level of SARS-CoV-2 infection, however, with no effect on the amount of virus particles released. Considering the urgency of the COVID-19 health crisis, this result may be of clinical significance for CF patients, who are frequently infected with and colonized by P. aeruginosa during the course of CF and might develop COVID-19.

Highlights

As of October 30, 2021, the coronavirus disease 2019 (COVID19) pandemic, caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, has infected nearly 245 million people globally and led to >4.9 million deaths
At baseline, similar angiotensin-converting enzyme-2 (ACE2) and FURIN mRNA expression levels were observed in non-cystic fibrosis (CF) and CF primary hAECs (Figure 1A), whereas TMPRSS2 expression was significantly higher in CF primary hAECs (Figures 1A, B)
We showed that exposure of airway epithelial cells (AECs) to flagellin from P. aeruginosa induces an increase in TMPRSS2 expression, which is dependent on Toll-like receptor-5 (TLR5) and p38 mitogen-activated protein kinase (MAPK) activation

Summary

Introduction

As of October 30, 2021, the coronavirus disease 2019 (COVID19) pandemic, caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, has infected nearly 245 million people globally and led to >4.9 million deaths (https://covid19. who.int). In this health crisis, one of the major challenges is to identify the susceptibility factors of the infecting virus in order to adapt public health recommendations and to reduce the risk of getting COVID-19, in the case of the most vulnerable people: patients with common chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease, and patients with less common or rare chronic respiratory diseases such as cystic fibrosis (CF). One of the major challenges is to identify the susceptibility factors of the infecting virus in order to adapt public health recommendations and to reduce the risk of getting COVID-19, in the case of the most vulnerable people: patients with common chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease, and patients with less common or rare chronic respiratory diseases such as cystic fibrosis (CF) Given their lung impairments, patients with chronic respiratory diseases can reasonably be expected to face an elevated risk of developing severe COVID-19, but the magnitude of this risk remains uncertain [1]. The most recent multinational report identified 181 cases of pwCF infected by SARS-CoV-2, and recorded 7 deaths [3]; among the 181 pwCF, 82% were symptomatic, 47% were hospitalized, and 51% showed airway infection by P. aeruginosa

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Conclusion