SARS-CoV-2 Entry Genes Expression in Relation with Interferon Response in Cystic Fibrosis Patients.

Camilla Bitossi,Fabio Midulla,Guido Antonelli,Alessandra Pierangeli,Federica Frasca,Gabriella D’Ettorre,Laura Belloni,Giuseppe Cimino,Valeria Pietropaolo,Mirko Scordio,Giuseppe Oliveto,Agnese Viscido,Maria Trancassini,Massimo Gentile,Carolina Scagnolari

doi:10.3390/microorganisms9010093

Abstract

The expression rate of SARS-CoV-2 entry genes, angiotensin-converting enzyme 2 (ACE2), the main viral receptor and the proteases, furin and transmembrane serine protease 2 (TMPRSS2) in cystic fibrosis (CF) individuals is poorly known. Hence, we examined their levels in upper respiratory samples of CF patients (n = 46) and healthy controls (n = 45). Moreover, we sought to understand the interplay of type I interferon (IFN-I) with ACE2, furin and TMPRSS2 by evaluating their gene expression with respect to ISG15, a well-known marker of IFN activation, in upper respiratory samples and after ex vivo IFNβ exposure. Lower ACE2 levels and trends toward the reduction of furin and TMPRSS2 were found in CF patients compared with the healthy controls; decreased ACE2 amounts were also detected in CF individuals with pancreatic insufficiency and in those receiving inhaled antibiotics. Moreover, there was a strong positive correlation between ISG15 and ACE2 levels. However, after ex vivo IFNβ stimulation of nasopharyngeal cells, the truncated isoform (dACE2), recently demonstrated as the IFN stimulated one with respect to the full-length isoform (flACE2), slightly augmented in cells from CF patients whereas in those from healthy donors, dACE2 levels showed variable levels of upregulation. An altered expression of SARS-COV-2 entry genes and a poor responsiveness of dACE2 to IFN-I stimulation might be crucial in the diffusion of SARS-CoV-2 infection in CF.

Highlights

Introduction censeeMDPI, Basel, Switzerland.The impact of SARS-CoV-2 infection in cystic fibrosis (CF) patients remains not well characterized.Despite the fact that the CF condition could represent a risk of worse outcomes than the general population, an apparently low spread of SARS-CoV-2 has been reported in CF patients [1,2,3] as well as a wide range of clinical symptoms from completely asymptomatic to acute respiratory distress [2,3]
As there are contrasting results on the relationship between IFN-I and angiotensin-converting enzyme 2 (ACE2) isoforms expression [13,14], we aimed to study the relationship of ACE2, furin and TMPRSS2 with IFN stimulated gene 15 (ISG15), a well-established ISG that acts as a potential modifier of CF severity, as well as
Lower ACE2 levels were found in CF patients compared with those in the control group (p = 0.034); a decreased but not statistically significant expression of furin and TMPRSS2 was observed in CF individuals (Table 1)

Summary

Introduction

Despite the fact that the CF condition could represent a risk of worse outcomes than the general population, an apparently low spread of SARS-CoV-2 has been reported in CF patients [1,2,3] as well as a wide range of clinical symptoms from completely asymptomatic to acute respiratory distress [2,3]. In this scenario, we previously found no case of SARS-CoV-2 infection in CF patients who attended clinic visits at the Regional (Lazio) CF. A novel, transcriptionally independent truncated isoform of ACE2, which was designated as ∆ACE2 (dACE2) but not the full-length ACE2 (flACE2), was demonstrated to be an IFN stimulated gene (ISG) [12]

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