A Mouse Model for the Transition of <em>Streptococcus pneumoniae</em> from Colonizer to Pathogen upon Viral Co-Infection Recapitulates Age-Exacerbated Illness

Abstract

Streptococcus pneumoniae (pneumococcus) is an asymptomatic colonizer of the nasopharynx in most individuals but can progress to a pulmonary and systemic pathogen upon influenza A virus (IAV) infection. Advanced age enhances host susceptibility to secondary pneumococcal pneumonia and is associated with worsened disease outcomes. The host factors driving those processes are not well defined, in part due to a lack of animal models that reproduce the transition from asymptomatic colonization to severe clinical disease. This paper describes a novel mouse model that recreates the transition of pneumococci from asymptomatic carriage to disease upon viral infection. In this model, mice are first intranasally inoculated with biofilm-grown pneumococci to establish asymptomatic carriage, followed by IAV infection of both the nasopharynx and lungs. This results in bacterial dissemination to the lungs, pulmonary inflammation, and obvious signs of illness that can progress to lethality. The degree of disease is dependent on the bacterial strain and host factors.Importantly, this model reproduces the susceptibility of aging, because compared to young mice, old mice display more severe clinical illness and succumb to disease more frequently. By separating carriage and disease into distinct steps and providing the opportunity to analyze the genetic variants of both the pathogen and the host, this S. pneumoniae/IAV co-infection model permits the detailed examination of the interactions of an important pathobiont with the host at different phases of disease

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

“…Mice were infected intratracheally with 10 7 CFU of S. pneumoniae serotype 4 (TIGR4) or serotype 19F (EF3030) using the tongue pull method as previously described (12, 37). Twenty-four hours following infection, mice were euthanized for enumeration of bacterial burden.…”

“…A separate set of mice (for TIGR4 only) was monitored for 7 days post infection. Mice were blindly assessed for clinical signs of disease progression including breathing, posture, weight, activity, grooming, and respiration ranging from 0 (healthy) to 21 (severely sick) as previously described (12, 32, 35, 37).…”

“…9A). This difference in protection was reflected in their clinical scores at 24 hours post infection, which are a set of criteria that determine disease severity and include assessment of weight loss, posture, activity and respiration (37). While a small percentage of vaccinated female mice had a score higher than 0, nearly all vaccinated male mice were sick, with >75% of them displaying signs of disease (Fig.…”

“…Mice were infected intratracheally with 10 7 CFU of S. pneumoniae serotype 4 (TIGR4) or serotype 19F (EF3030) using the tongue pull method as previously described (12,37).…”