Filamentous Influenza A Virus Infection Predisposes Mice to Fatal Septicemia following Superinfection with Streptococcus pneumoniae Serotype 3

Abstract

Previous studies have demonstrated that animals exposed to Streptococcus pneumoniae while recovering from influenza A virus infection exhibit exacerbated disease symptoms. However, many of the current animal models exploring dual viral and bacterial synergistic exacerbations of respiratory disease have utilized mouse-adapted influenza virus and strains of Streptococcus pneumoniae that in themselves are highly lethal to mice. Here we describe a mouse model of bacterial superinfection in which a mild, self-limiting influenza virus infection is followed by mild, self-limiting superinfection with S. pneumoniae serotype 3. S. pneumoniae superinfection results in rapid dissemination of the bacterium from the respiratory tract and systemic spread to all major organs of the mice, resulting in fatal septicemia. This phenomenon in mice was observed in superinfected animals undergoing an active viral infection as well as in mice that had completely cleared the virus 7 to 8 days prior to superinfection. Neutrophils were the predominant cellular inflammatory infiltrate in the lungs of superinfected mice compared to singly infected animals. Among other cytokines and chemokines, the neutrophil activator granulocyte colony-stimulating factor (G-CSF) was found to be significantly overexpressed in the spleens, lungs, and brains of superinfected animals. High G-CSF protein levels were observed in sera and lung lavage fluid from superinfected animals, suggesting that G-CSF is a major contributor to synergistic exacerbation of disease leading to fatal septicemia.

Infection with Human Metapneumovirus Predisposes Mice to Severe Pneumococcal Pneumonia

“…Our study demonstrated that challenge with inactivated hMPV did not enhance clinical symptoms or pneumococcal replication in the lung, suggesting that active hMPV replication is required for exacerbated pneumococcal disease. Delayed pneumococcus superinfection 14 days after hMPV infection led to similar results, confirming that the enhancing effect of pneumococcus is driven primarily by replicating hMPV and much less by a long-lasting associated host response to hMPV, which contrasts with the response to influenza virus (41). Thus, our results show that despite similar clinical outcomes, hMPV and influenza virus use different mechanisms to enhance pneumococcus replication in the lung.…”

“…Activated neutrophils also produce antimicrobial agents, such as hydrogen peroxide, superoxide anion, and nitric oxide (13). Thus, the enhanced bacterial colonization of the lungs following virus infection may lead to the sustained production of toxic compounds by neutrophils, resulting in tissue destruction (41). In addition, levels of G-CSF, which regulates the maturation, differentiation, and proliferation of neutrophils, were highly elevated in the lungs of superinfected animals.…”

“…The synergistic interaction between the influenza A virus (a member of the Orthomyxoviridae family) and pneumococcus is well documented in humans (31) and has been extensively studied in animal models (39,41). We used a well-established experimental murine model to validate our hypothesis that hMPV, like influenza virus, increases pneumococcus replication in lungs and enhances host immunological responses.…”

“…Additionally, it has been suggested that the pathogenesis of severe hMPV-associated lower respiratory tract infections in South African children involves coinfection with pneumococcus, since vaccination with a 9-valent pneumococcal conjugate vaccine prevented hMPV-related hospitalizations (27). Similarly, pulmonary bacterial coinfections have been reported for children with severe hRSV bronchiolitis (45), and recent hospitalization for hRSV infection has been shown to increase the risk of invasive pneumococcal disease (42).The synergistic interaction between the influenza A virus (a member of the Orthomyxoviridae family) and pneumococcus is well documented in humans (31) and has been extensively studied in animal models (39,41). We used a well-established experimental murine model to validate our hypothesis that hMPV, like influenza virus, increases pneumococcus replication in lungs and enhances host immunological responses.…”

Parapneumonic Empyema Deaths during Past Century, Utah

“…Experimental as well as epidemiologic data support the association between serious S. pneumoniae infections and infl uenza. Studies by McCullers and others have shown that infl uenza virus infection preferentially predisposes mice to fatal infections with S. pneumoniae (25)(26)(27). Recent studies have demonstrated a clear temporal association between seasonal infl uenza and invasive pneumococcal disease in children (28).…”