Animal models of SARS-CoV-2 bacterial Coinfection

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The COVID-19 pandemic has infected over 26 million and killed at least 450,000 Americans as of 4 February 2021. Early reports show coinfections are possibly the greatest predictor of disease severity. Mixed viral/bacterial pneumonias are notoriously difficult to treat. The most extensively researched respiratory coinfection is influenza and Streptococcus pneumoniae, which contribute significant morbidity and mortality during normal respiratory infection seasons. Despite nearly two decades of vaccination with the highly effective pneumococcal conjugate vaccine (PCV), S. pneumoniae (Spn or the pneumococcus) remains a significant cause of community acquired pneumonia, sepsis, and meningitis. Much pneumococcal morbidity and mortality occurs during seasonal and pandemic flus. The physiological reasons for this are incompletely understood despite extensive investigation into this critical aspect of pneumococcal pathogenesis. Anti-viral immunological shifts, “activation” signals, proinflammatory upregulation of adhesins, and sialic acid availability have all been implicated. The general host responses observed during flu (fever, strong inflammatory cytokine profile, and release of DAMPS) are recapitulated during COVID-19. Spn is a normal colonizer of the human nasopharynx and a febrile state has been shown to lead to invasive pneumococcal disease by “activating” pneumococci. This also occurs with respiratory viruses other than flu and is likely to occur during COVID-19-associated fever, promoting the development of secondary bacterial pneumonia. A recent single-site study found S. pneumoniae to be the most common coinfection in SARS-CoV-2 infected individuals and a significant source of mortality in the aged. Although much work has been conducted with influenza/Spn coinfections, essentially nothing is known about SARS-CoV-2/Spn coinfections. As the world braces for multiple waves of SARS-CoV-2, it is of paramount importance to understand how these pathogens interact to promote severe disease. The long-term goal of this research program is to understand the interaction between SARS-CoV-2 and the pneumococcus; the objective here is to investigate the mechanisms of SARS-CoV-2 + pneumococcal disease pathogenesis during mixed infections and to model disease in appropriate animal models. The overarching hypothesis is that the host response to SARS-CoV-2 promotes invasive pneumococcal disease (IPD), ultimately resulting in increased disease severity including mixed pneumonia. More specifically, we hypothesize the inflammatory milieu created by SARS-CoV-2 infection upregulates pIGr, PafR, LamininR, and K-10, adhesins utilized by Spn to facilitate IPD. We further hypothesize that common COVID-19 treatments could impact the severity of coinfection.