Identification of the molecular origins of comorbidity in COVID-19 patients

• Applicant: Professor Dr. Carl Herrmann, since 2/2022
• Subject Area: Virology ; Bioinformatics and Theoretical Biology ; Immunology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458633366

The SARS-CoV-2 outbreak has already claimed 700,000 related deaths worldwide and as of August 2020 has infected at least 18 million people. While the mechanism of the immune reaction leading to varying severity stages of the disease are beginning to be well understood, it remains unclear why certain people are more at risk than others. It is well established that populations above 65 years old and people with chronic conditions (e.g. cancers) are more susceptible to develop a more severe pathology. Epidemiological studies have demonstrated the high comorbidity of COVID-19 with different tumor types affecting organs other than the lung. These observations suggest that to fully understand host susceptibility and the pathomechanisms in these high-risk populations, we need to characterize virus replication and spread and the viral induced inflammation not only in the lung but also in other organs. By performing an extensive computational analysis, we have identified several genes which could act as restriction or virulence factors that we hypothesize as being responsible for the comorbidity in high risk patients. In this project, we propose to focus on SPINT2 which is an inhibitor of the serine protease TMPRSS2, a key cellular factor required for SARS-CoV-2 entry into cells. Our preliminary data already show that downregulation of SPINT2 leads to an increase in viral replication which is consistent with the observation that SPINT2 is downregulated in cancer patients and may be a leading cause for the observed comorbidity. In Aim 1 of this proposal, we will build on our expertise and our already established SARS-CoV-2 culture models to address how expression levels of SPINT2 impacts SARS-CoV-2 replication, de novo virus production and spread. We will address whether decreased levels of SPINT2, which favor virus replication, will lead to a higher immune response which in turn will fuel inflammation and disease severity. In Aim 2, we will exploit COVID-19 patient-derived tissues to correlate in vivo SPINT2 levels (and other identified susceptibility factors), SARS-CoV-2 replication levels, and disease severity.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Steeve Boulant, until 1/2022