Role of IFITM2 in SARS-CoV-2 infection: a potential new target for therapy

PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR)

Missione 4 - Componente 2 - Investimento 1.1

“Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN)” - Finanziato dall’Unione europea – NextGenerationEU

Bando PRIN 2022

D.D. n. 104 del 02.02.2022

Progetto “Role of IFITM2 in SARS-CoV-2 infection: a potential new target for therapy”

Codice Identificativo Progetto: 20229JZF8M- CUP: D53D23010620006

We have left behind a two-year pandemic that continues to pose a serious threat to public health in the near future; indeed, emerging virus variants may not respond to current preventive and therapeutic measures that need rapid adjustments and reformulations. Current strategies against SARS-CoV-2 are focused on the development of vaccines or monoclonal antibodies, both targeted at viral determinants to neutralize the infectious agent. Conversely - where applicable - an alternative strategy could exploit the neutralization of determinants on the host cell surface that modulate the viral entry. In this respect, we focused our studies on innate immune effectors that are hijacked during the viral entry into the target cells. The Interferon-induced transmembrane proteins (IFITMs), play a co-receptor role in the cell infection mechanism of different viruses. Among IFITM proteins, IFITM2 has been recently described as an essential factor for the efficient infection and replication of SARS-CoV-2 in human cells. However, the IFITM2- mediated mechanisms that promote SARS-CoV-2 entry into the host cells, is still under investigation, as well as the possible involvement of its ligand BAG3. BAG3 protein is induced by different types of stresses and is constitutively expressed in several primary tumors. We showed that BAG3 is also secreted by pancreatic cancer cells and mediates the release of pro-survival cytokines from tumor-associated macrophages and fibroblasts by binding IFITM2 expressed on the cell membrane of target cells. Apart from the well-known role of BAG3 secreted protein in tumors, little is known about secreted BAG3's impact in other situations, such as for viral infections. Indeed, our preliminary results showed that BAG3 is also secreted by Sars-CoV-2 infected cells. The proposed project is aimed at studying the role of IFITM2 and its ligand BAG3 in SARS-CoV-2 infection of human cells by investigating BAG3/IFITM2 regulated molecular pathways involved in the early steps of viral entry and its release into the host cells. Anti-IFITM2 and anti-BAG3 monoclonal antibodies will be tested in parallel to verify and evaluate their efficacy in preventing the virus entry and the viral burst. Furthermore, while IFITM3 variants have been linked to severe viral infections, little is known about the impact of IFITM2 variants in SARS-CoV-2 patients. As a consequence, the possible correlation between IFITM2 variants, BAG3 levels in serum, ​and disease severity in COVID-19 patients will be investigated. These data will allow us to shed light on the clinical implications of targeting the BAG3/IFITM2 axys in COVID-19 disease. The scientific team is already working on the development of proprietary anti-IFITM2 and anti-BAG3 monoclonal antibodies, whose run towards its clinical applications could be pushed forward by the completion of the basic and preclinical studies.