resCAPE – Virus evolution of SARS-CoV-2 under immunosuppressive treatment

• Applicant: Dr. Toni Luise Meister
• Subject Area: Clinical Infectiology and Tropical Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542328175

Viral infections are a major cause of disease, mortality and economic losses worldwide. Current estimates suggest that infections with viral pathogens account for about 6.6% of global mortality. Recent outbreaks of Zika, Ebola, and the current SARS-CoV-2 pandemic underscore the need to develop novel antiviral strategies as well as deepen our understandings which conditions favour the emergence of novel viral variants (i.e. SARS-CoV-2 Omicron). In particular, immunocompromised patients are at an increased risk of developing a more sever but also chronic prolonged phase of infection favouring the emergence of novel potentially harmful viral variants. Many people suffer from immunosuppression due to cancer, HIV infection, autoimmune conditions or having received solid organ transplantation. The later are eventually treated with immunosuppressive drugs. There are consistent reports about prolonged or chronic infections with SARS-CoV-2. Continuous replication of the virus potentially increases the risk of mutations and therefore the emergence of variants, as observed for chronic HCV and HEV infection. Moreover, immunocompromised patients eventually require pharmacological intervention to clear the infection, where in some cases the selective pressure imposed by the antiviral drug drives viral mutagenesis leading to the formation of intra-host populations that present with increased viral fitness eventually causing therapy failure. Interestingly, contradicting to its immunosuppressive features, MPA has been shown to successfully inhibit a variety of viruses. Thus, we passaged SARS-CoV-2 in the presence of physiologically relevant concentrations of MPA. Viral titres decreased when SARS-CoV-2 was propagated on MPA-treated cells compared to virus propagated on untreated cells (UTC). Further passaging resulted in a recovery of viral titres to counts similar to the virus harvested from the UTC. Additionally, the plaques from early passages (p2) were smaller and no differences were observed between virus propagated with or without MPA, while the plaques became larger at the time the virus had adapted to MPA treatment. These results suggest the emergence of one or more variants that are able to evade the selective pressure of MPA. RNA sequencing revealed multiple mutations across the viral genome. Similar observations were reported when SARS-CoV-2 was passaged in the presence of low-dose remdesivir. In fact, they reported mutations that are also found in variants of concern, demonstrating the power of in vitro adaptation studies. By gaining insight into how viruses adapt and mutate, researchers may be better equipped to predict and manage the spread of these variants on a larger scale. Moreover, the knowledge gained about the underlying mechanisms of viral mutagenesis during the study could be leveraged in the development of new antiviral drugs.

• DFG Programme: Research Grants