The overall objective of this proposed project is to understand the mechanisms responsible for enhanced susceptibility to Streptococcus pneumoniae that follows influenza infection. Despite being a recognized clinical problem that causes many, if not the majority of deaths during human influenza pandemics, including the 1918 pandemic, we still know only very little about the reasons for this microbial synergy. Taking advantage of influenza and pneumococcal mouse infection models that are established in the PI's laboratory, we have now shown that during the recovery phase of influenza infection, when IFN-3+ T cells migrate into the lung, there is significant inhibition of the MARCO scavenger receptor by alveolar macrophages, suppressed clearance of unopsonized pneumococci, and increased animal mortality. These inhibitory effects do not occur in IFN-3-/- mice and can be prevented by inoculation of anti-IFN-3 mAb following viral infection. Studies in this proposal are now designed to fully understand the functional changes in phagocytic cells that are induced by influenza virus infection and the mechanisms responsible for inhibition of pulmonary bacterial clearance. The hypothesis is that induction of an adaptive immune response against an intracellular pathogen in the lung (influenza virus) results in significant impairment of innate alveolar macrophage-mediated protection against extracellular pathogens (S. pneumoniae). To test these concepts, the functional properties of phagocytic cells derived from mice recovering from influenza infection will be examined with a focus on determining whether shifts in alveolar macrophage scavenger receptor and TLR function occur that are detrimental for innate immunity. Possible effects on other phagocytic cell populations will also be assessed. The mechanisms responsible for IFN-3 activity in the lung will be determined, including direct influences on alveolar macrophages and possible intermediary roles for T and epithelial cells, as well as a potential role for TGF-2. The effector cell(s) responsible for alveolar macrophage inhibition by influenza infection will be investigated using adoptive cell transfers and mice lacking specific cell subsets. Finally, we will examine in detail the potential for mucosal vaccination strategies, including use of the approved cold-adapted FluMist(R) vaccine, to mimic viral infection and induce enhanced susceptibility to respiratory bacterial infections. Our ultimate goal is to understand the immunological processes responsible for virus-bacteria synergy and to exploit the information obtained in order to design novel therapeutic approaches for prevention of enhanced susceptibility of humans to these pathogens.
This study focuses on understanding the mechanisms responsible for secondary bacterial infections that often follow influenza virus infection and which represent a significant cause of morbidity and mortality in humans. The results obtained from this study will provide a comprehensive model for understanding microbial interactions in the pulmonary tract and thus provide important insight into the development of effective therapeutics for human use.
|Sun, Keer; Yajjala, Vijaya Kumar; Bauer, Christopher et al. (2016) Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia. J Exp Med 213:1851-64|
|Metzger, Dennis W; Furuya, Yoichi; Salmon, Sharon L et al. (2015) Limited Efficacy of Antibacterial Vaccination Against Secondary Serotype 3 Pneumococcal Pneumonia Following Influenza Infection. J Infect Dis 212:445-52|
|Furuya, Yoichi; Furuya, Andrea K M; Roberts, Sean et al. (2015) Prevention of Influenza Virus-Induced Immunopathology by TGF-Î² Produced during Allergic Asthma. PLoS Pathog 11:e1005180|
|Sun, Keer; Salmon, Sharon; Yajjala, Vijaya Kumar et al. (2014) Expression of suppressor of cytokine signaling 1 (SOCS1) impairs viral clearance and exacerbates lung injury during influenza infection. PLoS Pathog 10:e1004560|
|Furuya, Yoichi; Roberts, Sean; Hurteau, Gregory J et al. (2014) Asthma increases susceptibility to heterologous but not homologous secondary influenza. J Virol 88:9166-81|
|Sun, Keer; Metzger, Dennis W (2014) Influenza infection suppresses NADPH oxidase-dependent phagocytic bacterial clearance and enhances susceptibility to secondary methicillin-resistant Staphylococcus aureus infection. J Immunol 192:3301-7|
|Metzger, Dennis W; Sun, Keer (2013) Immune dysfunction and bacterial coinfections following influenza. J Immunol 191:2047-52|
|Sun, Keer; Ye, Jianqiang; Perez, Daniel R et al. (2011) Seasonal FluMist vaccination induces cross-reactive T cell immunity against H1N1 (2009) influenza and secondary bacterial infections. J Immunol 186:987-93|
|Sun, Keer; Gan, Yan; Metzger, Dennis W (2011) Analysis of murine genetic predisposition to pneumococcal infection reveals a critical role of alveolar macrophages in maintaining the sterility of the lower respiratory tract. Infect Immun 79:1842-7|
|Pangule, Ravindra C; Brooks, Sarah J; Dinu, Cerasela Zoica et al. (2010) Antistaphylococcal nanocomposite films based on enzyme-nanotube conjugates. ACS Nano 4:3993-4000|
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