Determinants of host cell tropism, viral innate immune evasion and attenuation in SARS-CoV-2

SARS-CoV-2, the beta coronavirus responsible for COVID-19, infects the epithelium of the lung and the gastrointestinal tract. Despite a generally mild disease in most, the virus can cause devastating illness and mortality in the elderly and those with chronic inflammatory conditions. Severe COVID-19 is normally associated with extensive immune dysregulation that can lead to overt inflammatory responses, viral spread beyond the respiratory tract, and a life-threatening cytokine storm.



Since it was first sequenced in early 2020, SARS-CoV-2 has acquired numerous mutations giving rise to new lineages known as variants of concern (VOCs) such as a, b, g, and D. Acquired SARS-CoV-2 mutations have been linked to enhanced binding affinity to its receptor ACE2, more efficient cell entry, higher viral titres and escape from monoclonal antibody (mAb) therapy. However, mutations can also alter sensitivity to host-derived antiviral factors (1), such as type-I interferons, which has important implications for immune control. Together, this highlights not only the importance of effective immune control in clearing SARS-CoV-2 infection, but also the need to understand how the virus antagonizes host innate immune defences which is of paramount importance for the understanding of viral pathogenesis and the search for novel therapeutics.



At the cellular level, type I interferons govern the antiviral response by upregulating IFN-stimulated genes (ISGs) that restrict viral growth by interfering with various aspects of the viral lifecycle. ISGs with known activity against SARS-CoV-2 include the IFN-induced transmembrane proteins (IFITMs) as shown by the Neil Lab (2). These IFITMs are localized to either the plasma membrane or endosome and are known to have broad antiviral activity against several viruses. In the case of SARS-CoV-2 we found that IFITM2 is predominantly restrictive in a manner governed by route of viral entry.



An intriguing and emerging area of viral research is the interplay between immune control and metabolism. Metabolic rewiring during viral infection is a well-observed phenomenon with important consequences in immune-mediated viral control due to the role metabolic pathways have in regulating inflammation, immune cell differentiation, and IFN production. In the case of SARS-CoV-2 pathogenesis, studies analysing mild, moderate, and severe COVID-19 patients have identified distinct metabolic signatures that can stratify patients, with perturbations in amino acid and lipid metabolism frequently detected (3-8). This is in line with other metabolomic studies identifying serum reductions in TCA metabolites, indicating that the switch from oxidative phosphorylation to glycolysis as the main ATP source, also known as the 'Warburg effect', is a likely hallmark of SARS-CoV-2 infection.



However, it's unclear how SARS-CoV-2 rewires the cellular metabolome to influence immunity and there are several important questions that need to be addressed. Firstly, the mechanistic basis of metabolic rewiring remains unknown. Determining how SARS-CoV-2 rewires the metabolome of infected cells would extend current metabolic research from correlational analyses and towards cause and effect. Furthermore, identifying specific viral factors required for metabolic rewiring will provide druggable targets. No study to date has investigated if there are lineage-specific metabolome alterations.



On that note, during rotation 1, as part of a collaboration with the Institute of Pharmaceutical Science, we identified three compounds of interest (rapamycin, rosiglitazone, and tesevatinib) with differential effects on SARS-CoV-2 replication. SARS-CoV-2 was exquisitely sensitive to both rosiglitazone and tesevatinib, whereas rapamycin was found to enhance infectivity. Interestingly, rosiglitazone and rapamycin have dual roles within metabolism and immunity.