A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity upon Viral Infection and Advanced Age
Basma H Joma1,2, Nalat Siwapornchai1, Vijay K Vanguri3
1Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.
Abstract:
Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx (NP) but 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 coinfection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2-month-old) mice, coinfection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease, and mortality in a fraction of mice. In aged mice (18 to 24 months), coinfection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted alpha interferon (IFN-α) production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden, likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and coinfection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.
Insights
Influenza A virus and aging worsen Streptococcus pneumoniae infections by impairing immune responses and promoting bacterial spread. This study reveals how coinfection drives pneumococcus from colonizer to pathogen, impacting antiviral defenses.
Area of Science:
- Immunology
- Microbiology
- Pathogenesis
Background:
- Streptococcus pneumoniae asymptomatically colonizes the nasopharynx but can cause severe disease.
- Viral infections and aging are known risk factors for invasive pneumococcal disease.
- Existing models did not fully replicate severe coinfection outcomes.
Purpose of the Study:
- To investigate the impact of influenza A virus (IAV) coinfection on pneumococcal pathogenesis in young and aged mice.
- To elucidate the mechanisms by which aging and IAV influence pneumococcal disease severity.
- To explore the bidirectional interactions between pneumococcus, IAV, and host immunity.
Main Methods:
- Established a multistep murine model: initial pneumococcal colonization followed by IAV inoculation.
- Compared disease progression, bacterial burdens, and pulmonary inflammation in young and aged mice.
- Assessed neutrophil function and interferon-alpha (IFN-α) production ex vivo.
Main Results:
- Coinfection led to pneumococcal dispersal, inflammation, and mortality, with exacerbated disease in aged mice.
- Aging and IAV infection impaired neutrophil bacterial killing.
- Both aging and pneumococcal colonization reduced IFN-α production and increased IAV burden.
Conclusions:
- IAV promotes pneumococcal pathogenicity by altering bacterial behavior and host immunity.
- Aging exacerbates pneumococcal disease severity through enhanced inflammation and impaired immune cell function.
- Pneumococcal infections can compromise antiviral responses, increasing viral burden.
