COVID-19: role of co-infections, and drug repurposing for treament

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Experimental Medicine

Abstract

Clinical studies have reported co-infections in at least 20% of Covid-19 patients. This figure is likely underestimated because ICU mechanical ventilation results in up to 75% of patients developing nosocomial pneumonia. Moreover, pathological analysis of post-mortem biopsies of lung from patients who died of severe COVID-19 revealed histopathologic findings consistent with superimposed bacterial pneumonia in some patients. Alarmingly, this occurs in a scenario of a limited arsenal of antibiotics to target these infections.Nothing is known on the effect of co-infections in SARS-CoV-2-induced pathophysiology. It is also unknown whether SARS-CoV-2 infection may affect the pathophysiology of nosocomial infections. Addressing this knowledge gap is critical if we are to develop therapeutics; otherwise, treatments may tip the balance from one infection to the other. This happens in a scenario of a limited arsenal of antibiotics to target nosocomial infections. We will investigate the interface between SARS-CoV-2 and bacterial infections (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus) by exploiting relevant translational research models: well-differentiated primary human airway epithelial cell cultures (WD-PAECs), excellent surrogates of human airway epithelium in vivo, and PBMCs, reflecting the complexity of the human immune system. Single-cell RNA seq and multiplexed single-cell mass cytometry (CyTOF) will reveal cell-type specific immune pathways associated with the infections. These responses might be suitable for therapeutic manipulation. Cytopathogenesis, viral and bacterial replication in co-infection, and cytokines/chemokines will be additional read-outs. The effect of SARS-CoV-2 and bacteria on each other's virulence will be analysed by determining the transcriptome of exposed bacteria, and investigating viral and bacterial infection parameters upon infection of WD-PAECs and PMBCs. We will screen a panel of FDA-approved drugs affecting host-pathogen interactions to identify drugs against SARS-CoV-2 in the co-infection interface. These drugs shall be considered as new therapeutics entering clinical trials.

Publications

10 25 50