Influenzae A virus (IAV) is highly contagious and is responsible for outbreaks of seasonal flu. In humans, IAV infection is usually confined to the epithelia of nasopharynx, trachea and large bronchi. Only in some cases does the infection progress to a primary viral pneumonia. However, secondary bacterial pneumonia is a frequent and serious complication with high mortality. In addition to annual influenza epidemics, there is an ever-present threat of a global pandemic and several recent pandemics have inflicted widespread devastation. In the majority of cases, the high mortality associated with these influenza pandemics is not due to primary viral pneumonia, but is instead caused by secondary bacterial infections. Streptococcus pneumoniae (Sp) is a Gram-positive bacterium that is the leading cause of secondary bacterial pneumonia associated with both influenza epidemics and pandemics. The effect of IAV infection on host susceptibility to Sp has been studied extensively in the murine model. However, limited information is available on how Sp may affect the course of IAV infection, and consequently, disease outcome. Even less is known about how Sp co-infection may affect the generation of immunological memory and anti-flu immunity. Our recent results have shown that inflammation induced by a bacterial pathogen can have opposing effects on different phases of the adaptive immune response. These results have important implications that are particularly relevant to co-infection where inflammatory responses induced by one pathogen can have bystander effects on the other pathogen. As such, we hypothesize that inflammation induced by Sp could alter host resistance/susceptibility to IAV and influence the lAV-specific adaptive immune response. We will test our hypothesis by 1) determining the effect of Sp co-infection on host resistance/susceptibility to IAV infection, 2) studying the role of inflammatory responses in mediating protection or immunopathology during lAV/Sp coinfection, 3) determine the effect of Sp co-infection on CDS T cell responses to IAV and lAV-specific CDS T cell memory. At the end of this study, we hope to gain a better understanding of the complex host-virusbacterium interactions occuring during co-infection, with the goal of developing interventions that will shift the balance of the interaction to benefit the host.

Public Health Relevance

Second bacterial pneumonia is a serious complication during and shortly after influenza A infection. Understadning how a bacterial co-infection may affect host resistance to influenza virus will help us develop novel strategies to treat the severe diseases and prevent mortality caused by secondary bacterial pneumonia associated with flu infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Pennsylvania
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Kurachi, Makoto; Barnitz, R Anthony; Yosef, Nir et al. (2014) The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol 15:373-83
Schadler, Keri L; Crosby, Erika J; Zhou, Alice Yao et al. (2014) Immunosurveillance by antiangiogenesis: tumor growth arrest by T cell-derived thrombospondin-1. Cancer Res 74:2171-81
Wolf, Amaya I; Strauman, Maura C; Mozdzanowska, Krystyna et al. (2014) Pneumolysin expression by streptococcus pneumoniae protects colonized mice from influenza virus-induced disease. Virology 462-463:254-65
Richard, Aimee L; Siegel, Steven J; Erikson, Jan et al. (2014) TLR2 signaling decreases transmission of Streptococcus pneumoniae by limiting bacterial shedding in an infant mouse Influenza A co-infection model. PLoS Pathog 10:e1004339
Crawford, Alison; Angelosanto, Jill M; Kao, Charlly et al. (2014) Molecular and transcriptional basis of CD4? T cell dysfunction during chronic infection. Immunity 40:289-302
Wolf, Amaya I; Strauman, Maura C; Mozdzanowska, Krystyna et al. (2014) Coinfection with Streptococcus pneumoniae modulates the B cell response to influenza virus. J Virol 88:11995-2005
Farber, Donna L; Yudanin, Naomi A; Restifo, Nicholas P (2014) Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 14:24-35
Weissler, Katherine A; Caton, Andrew J (2014) The role of T-cell receptor recognition of peptide:MHC complexes in the formation and activity of Foxp3? regulatory T cells. Immunol Rev 259:11-22
Crosby, Erika J; Goldschmidt, Michael H; Wherry, E John et al. (2014) Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection. PLoS Pathog 10:e1003970
Turner, Damian L; Gordon, Claire L; Farber, Donna L (2014) Tissue-resident T cells, in situ immunity and transplantation. Immunol Rev 258:150-66

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