Influenza A H1N1 represents a major cause of morbidity and mortality in the United States. In addition, Influenza A poses a significant risk of pandemic outbreak as evidenced in the past two years. A large proportion of severe cases of Influenza A pneumonia are associated with secondary bacterial infection, most commonly caused by Staphylococcus aureus or Streptococcus pneumoniae. Incidence and severity of S. aureus pneumonia is increasing worldwide due to the emergence of methicillin-resistant (MRSA) strains. For these reasons, understanding the molecular mechanisms that promote bacterial host defense in the lung is of critical importance. Little is known about the cell-mediated immune response to S. aureus infection. Using a mouse model of Influenza A infection (Influenza A PR/8/34) coupled with S. aureus challenge our group has found that Influenza A exacerbates secondary bacterial pneumonia. We have shown that the mechanism is likely mediated by type I Interferon suppression of IL-23 production and subsequent TH17 immune activation. In this proposal we will further investigate the Influenza A, S. aureus co-infection model in three specific aims. First, we will examine the role of type I interferon in mediating Influenza A exacerbation of secondary bacterial infection. Second, we will examine the mechanism by which IL-23 promotes immunity against S. aureus. Finally, we will investigate the mechanism by which the TH17 pathway promotes S. aureus killing via the airway epithelium. These studies will involve numerous TH17 pathway gene altered mouse studies and in vitro studies with both mouse and human airway epithelial cells. The goal of the study is to elucidate the molecular mechanisms involved in S. aureus host defense and to identify interventions that can restore TH17 immunity following Influenza A infection and improve the host response against secondary bacterial pneumonia. These data may be directly applicable to the hospital setting and may reveal novel therapeutic strategies that would decrease morbidity and mortality, and improve patient outcome.

Public Health Relevance

The Influenza A virus infects millions nationally each year compounded with thousands of severe pneumonia cases associated with bacterial superinfection which often results in severe illness and/or death. This study addresses the mechanisms by which Influenza A makes the lung more susceptible to later bacterial infection. This proposal defines the molecular pathways by which Influenza A leads to suppressed bacterial host defense and attempts to identify novel therapeutic targets to improve patient outcomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL107380-01A1
Application #
8233846
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$372,570
Indirect Cost
$122,570
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Eddens, Taylor; Campfield, Brian T; Serody, Katelin et al. (2016) A Novel CD4(+) T Cell-Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology. Am J Respir Crit Care Med 194:807-820
Manni, Michelle L; Mandalapu, Sivanarayana; McHugh, Kevin J et al. (2016) Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation. J Immunol 196:963-77
Alcorn, John F; Sarkar, Saumendra N (2015) What is the oligoadenylate synthetases-like protein and does it have therapeutic potential for influenza? Expert Rev Respir Med 9:1-3
Rynda-Apple, Agnieszka; Robinson, Keven M; Alcorn, John F (2015) Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease. Infect Immun 83:3764-70
Alcorn, John F; Kolls, Jay K (2015) Physiology. Killer fat. Science 347:26-7
Robinson, Keven M; Kolls, Jay K; Alcorn, John F (2015) The immunology of influenza virus-associated bacterial pneumonia. Curr Opin Immunol 34:59-67
Lee, Benjamin; Robinson, Keven M; McHugh, Kevin J et al. (2015) Influenza-induced type I interferon enhances susceptibility to gram-negative and gram-positive bacterial pneumonia in mice. Am J Physiol Lung Cell Mol Physiol 309:L158-67
Travanty, Emily; Zhou, Bin; Zhang, Hongbo et al. (2015) Differential Susceptibilities of Human Lung Primary Cells to H1N1 Influenza Viruses. J Virol 89:11935-44
Robinson, Keven M; Lee, Benjamin; Scheller, Erich V et al. (2015) The role of IL-27 in susceptibility to post-influenza Staphylococcus aureus pneumonia. Respir Res 16:10
Robinson, Keven M; McHugh, Kevin J; Mandalapu, Sivanarayana et al. (2014) Influenza A virus exacerbates Staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production. J Infect Dis 209:865-75

Showing the most recent 10 out of 19 publications