Targeting AR-dependent TMPRSS2 expression in the hypoxia environment of SARS-CoV-2 target cells
Recent evidence indicates that male patients with SARS-CoV-2 disease have a worse prognosis than women. The mechanism behind this gender discrepancy is unknown. This project aims to shed light onto this aspect of the disease. We will test how male sex hormones influence the expression of a gene, the trans-membrane serine protease 2 (TMPRSS2), whose function is essential for viral entry into target cells. Importantly, TMPRSS2 expression is regulated by male sex hormones, i.e. the androgens testosterone (T) and dihydrotestosterone, which perform their function by binding to their natural receptor, the androgen receptor (AR). The AR-T complex in fact activates the expression of the TMPRSS2 gene, thus increasing the amount of protein produced and consequently the risk of viral infection. Furthermore, since the effect of the AR-T complex is associated with an increase in circulating neutrophil leukocytes, it could also be responsible for the cytokine storm syndrome found in patients with SARS-CoV-2. In light of this, it is plausible to hypothesize a key role of the AR receptor in SARS-CoV-2 pathology.
The function of the AR gene is modulated by a CAG triplet present in exon 1, varying in number from 5 to 36 in the normal population. CAG expansions> 38 cause a specific male disease, spinal and bulbar muscular atrophy (SBMA), associated with an increased risk of pneumonia and respiratory infections throughout life. Leveraging on our experience and experimental tools developed over the past 15 years to study SBMA, we will combine a clinical, experimental and computational approach to identify the causal link between AR CAG length and risk of infection and severity of clinical manifestations from SARS. -CoV-2. This hypothesis will be tested on lung, kidney and intestinal cells. Research costs: salary of a fellow 25,000 euros, costs for lab reagents 25,000 euros.