The Staphylococcus aureus iron-regulated surface determinant A (IsdA) increases SARS CoV-2 replication by modulating JAK-STAT signaling

Abstract

The emergence and spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) and the associated Coronavirus disease (COVID-19) pandemic have affected millions globally. Like other respiratory viruses, a significant complication of COVID-19 infection is secondary bacterial co-infection, which is seen in approximately 25% of severe cases. The most common organism isolated from co-infection is the Gram-positive bacterium Staphylococcus aureus. Here, we developed an in vitro co-infection model where both CoV-2 and S. aureus replication kinetics can be examined. We demonstrate CoV-2 infection does not alter how S. aureus attaches to or grows in host epithelial cells. In contrast, the presence of replicating S. aureus enhances the replication of CoV-2 by 10-15-fold. We identify this pro-viral activity is due to the S. aureus iron-regulated surface determinant A (IsdA) and this effect is mimicked across different SARS CoV-2 permissive cell lines infected with multiple viral variants. Analysis of co-infected cells demonstrated an IsdA dependent modification of host transcription. Using chemical inhibition, we determined S. aureus IsdA modifies host Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) signalling, ultimately leading to increased viral replication. These findings provide key insight into the molecular interactions that occur between host cells, CoV-2 and S. aureus during co-infection. ImportanceBacterial co-infection is a common and significant complication of respiratory viral infection, including in patients with COVID-19, and leads to increased morbidity and mortality. The relationship between virus, bacteria and host is largely unknown, which makes it difficult to design effective treatment strategies. In the present study we created a model of co-infection between SARS CoV-2 and Staphylococcus aureus, the most common species identified in COVID-19 patients with co-infection. We demonstrate that the S. aureus protein IsdA enhances the replication of SARS CoV-2 in vitro by modulating host cell signal transduction pathways. The significance of this finding is in identifying a bacterial component that enhances CoV-2 pathogenesis, which could be a target for the development of co-infection specific therapy in the future. In addition, this protein can be used as a tool to decipher the mechanisms by which CoV-2 manipulates the host cell, providing a better understanding of COVID-19 virulence.