Klebsiella pneumoniaeAlleviates Influenza-Induced Acute Lung Injury via Limiting NK Cell Expansion

Abstract

A protective effect induced by bacterial preinfection upon a subsequent lethal influenza virus infection has been observed, but the underlying immune mechanisms have not yet been fully elucidated. In this study, we used a mouse model of Klebsiella pneumoniae preinfection to gain insight into how bacterial preinfection influences the subsequent lethal influenza virus infection. We found that K. pneumoniae preinfection significantly attenuated lung immune injury and decreased mortality during influenza virus infection, but K. pneumoniae–specific immunity was not involved in this cross-protection against influenza virus. K. pneumoniae preinfection limited NK cell expansion, which was involved in influenza-induced immune injury and death. Furthermore, K. pneumoniae preinfection could not control NK cell expansion and death during influenza virus infection in Rag1−/− mice, but adoptive transfer of T cells from wild-type mice was able to restore this protective effect. Our data suggest that the adaptive immune response activated by bacterial infection limits the excessive innate immune response induced by a subsequent influenza infection, ultimately protecting mice from death.

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

“…Similarly, infection of mice with Klebsiella pneumoniae prior to PR8 protects against morbidity and mortality, which is associated with both reduced inflammation and viral load in the lungs of coinfected mice (58). In this coinfection system, K. pneumoniae was shown to reduce PR8-induced NK cell responses, which are known to promote disease pathology during PR8 infection (53,58). Thus, the order of coinfecting pathogens is a critical determinant in disease outcomes across pathogen types and experimental systems.…”

“…Several studies have evaluated stimulation of innate immunity in providing protection against influenza virus infections. As described above, bacterial pathogens given prior to influenza viruses can stimulate innate immunity that reduces the severity of influenza (56,58). Infection of mice with nonpathogenic bacteria or with a parasite that causes a chronic infection has also been shown to reduce the severity of influenza infections (34,(62)(63)(64)(65).…”

“…Bacterial pneumolysin was shown to be required for protection by preventing IAV-mediated depletion of alveolar macrophages (56). Similarly, infection of mice with Klebsiella pneumoniae prior to PR8 protects against morbidity and mortality, which is associated with both reduced inflammation and viral load in the lungs of coinfected mice (58). In this coinfection system, K. pneumoniae was shown to reduce PR8-induced NK cell responses, which are known to promote disease pathology during PR8 infection (53,58).…”

“…Bacterial infections secondary to IAV infection have been widely shown to have worse disease outcomes than either IAV or the bacterial infection alone (7,56,57). However, when these same bacterial pathogens are given to mice prior to IAV, they can reduce the severity of IAV (56,58). This protective effect has been seen when Streptococcus pneumoniae was given to mice 10 days prior to PR8 and was associated with reduced inflammation in the lung without impacting viral loads.…”

Natural Killer Cells in the Lungs

“…In mice, lung NK cells promote host defense against K. pneumoniae by IL-22 and IFN-γ production (13, 14). On the other hand, Wang et al (112) demonstrated that K. pneumoniae pre-infection alleviated influenza virus-induced death and acute lung injury by inhibiting lung NK cell expansion. These findings suggest a complex role of NK cells in response to various pathogens.…”