Research Projects

Coronaviruses (CoVs) usually cause the common cold in humans. The recent outbreaks of the severe acute respiratory syndrome (SARS), however, demonstrate that zoonotic transmission occasionally introduces more dangerous viruses into the human population. Due to their large genome size and adaptability, CoVs have a wide host tropism and can infect a wide range of animals, birds, and mammals, including humans. The recently emerged Middle East respiratory syndrome (MERS)-, Severe Acute respiratory syndrome (SARS), and SARS-2 CoVs cause severe lower respiratory illness in humans. The SARS-CoV emerged from a Cevet cat, and the MERS-CoV emerged from a dromedary camel in the Middle East, close relatives of SARS and MERS identified in bats replicate in human cells. Moreover, antibodies to MERS-CoV found in camels from the Middle East and beyond, including Pakistan, Ethiopia, and Kenya, suggest that a MERS or SARS-related virus outbreak may occur in the near future. To tackle emergency situations there is a need for preparedness to tackle outbreak situations. Effective prevention and eradication of viral outbreaks are only possible once the biology of the virus is known, especially the host cell entry mechanism. Drugs targeting the host factors would be an early preventive measure. CoVs initiate their infection cycle by binding the spike protein to their respective receptor(s), DPP4 or ACE2 and fusing it into host cells mainly via the clathrin-mediated endocytosis pathway. However, the internalization process and signalling post-attachment to the receptor is not clear for coronaviruses. For instance, in HCV or HIV, after binding the envelope protein to the primary receptor, the virus uses multiple co-factors or receptors to initiate the endocytic pathways. Similarly, coronavirus viruses may use multiple host factors to enter the host cell, which has not been investigated yet. Recently, we and others have shown that ACE2 (published) or DPP4 (unpublished) cytoplasmic domain signaling is not essential for the entry of SARS-CoV-2/MERS-CoV, which shows the usage of another host factor(s) other than host proteases (e.g., TMPRS) for their entry. In addition, we identified a novel SARS-like virus (BtCoV05) from India and the entry mechanism of BtCoV05 is not clear. Identifying which cellular elements or co-factors are used by CoVs for their attachment or internalization might provide insights into viral pathogenesis and transmission and help to develop therapeutic targets. The proposed research aims to characterize extracellular interactions between MERS-CoV/BtCoV05 virus and their host(s) that are relevant for virus entry, host range, and virus pathogenesis. Ultimately, we aim to gain insights into fundamental coronavirus biology and extracellular determinants of severe coronavirus disease and entry mechanism, while orienting the design of therapeutic intervention strategies.