A Murine Model for the Transition of Streptococcus pneumoniae from Asymptomatic Colonizer to Systemic Pathogen

(pneumococcus) resides asymptomatically in the nasopharynx but, as a pathobiont, can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human co-infection. We built upon this model by establishing pneumococcal nasopharyngeal colonization in mice, then inoculating both the nasopharynx and lungs with IAV. In young (2 months) mice, co-infection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, concomitant disease and mortality in a fraction of mice. Although neutrophils are critical for pneumococcal clearance, IAV infection was associated with inefficient killing of pneumococci by neutrophils and these cells were dispensable for host resistance during co-infection. In old mice (20-22 months), co-infection resulted in earlier and more severe disease compared to young mice. Aging was not associated with greater bacterial spread from the nasopharynx to the lungs or bloodstream. Rather, old mice displayed a more rapid proinflammatory cytokine response, earlier pulmonary neutrophil influx, lung damage and abrogated neutrophil function. Thus, in this model, IAV fosters the transition of pneumococci from commensals to pathogens through modifying bacterial behavior in the nasopharynx, enhancing pulmonary infection, and compromising neutrophil function. This model faithfully replicates age-associated susceptibility and can provide insight into factors that influence pathobiont behavior in different hosts.