Molecular Determinants of Viral Pathogenesis

To date, it is still unclear why some people are completely asymptomatic or pauci-symptomatic upon SARS-CoV-2 infection, while others require hospitalization and intensive care treatments. Indeed, the presence of co-morbidities correlates with an increased chance of develop severe COVID-19. In addition, several studies have shown that rare genetic mutations, especially linked with the innate immune response, correlates with an increased risk of infection, hospitalization, and death upon SARS-CoV-2 infection. As such, to understand COVID-19 physiopathology it is essential to identify potential genetic risk factors that might lead to severe manifestation of the infection. To this aim, in collaboration with Cacchiarelli group, we will analyze the host transcriptome directly from SARS-CoV-2-positive nasal swabs to identify specific genetic signatures and correlate them with infection outcome. This will allow to shed light on the molecular mechanisms defining SARS-CoV-2 pathogenesis.
It has been shown that the presence of underlying medical conditions increases the risk of severe COVID-19. This is especially true for comorbidities affecting the respiratory tract, such as chronic lung diseases. Interestingly, patients with cystic fibrosis (CF), a genetic disease that severely affects the respiratory system, with increased sensitivity to bacterial and viral infections, do not appear particularly at risk of a severe form of COVID-19. This observation suggests that the intrinsic genetic defect, i.e. the alteration of innate defense mechanisms caused by CFTR gene mutations, and/or the chronic inflammatory process associated with CF lung diseases, generate a “protective” status against SARS-CoV-2. Therefore, together with the Galietta group, we will characterize how the epithelium of cystic fibrosis patients reacts in vitro to SARS-CoV-2 infection. These experiments will be done under resting conditions, following treatments that restore CFTR protein expression and function, and by exposing the epithelia to stimuli that mimic CF inflammation.  This study will allow the identification of potential protective mechanisms regulating the response of the lungs to viral infections. This may have important implications to devise novel strategies to limit viral infections in CF patients as well as in the general population.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.