The bacterium Haemophilus influenzae inhabits the human nasopharynx and conjunctiva, and can disseminate to cause pneumonia, otitis media, or meningitis. The current vaccine against the capsule of type b strains is not effective against clinically relevant strains that lack the capsule, termed nontypeable H. influenzae (NTHi). After infection by influenza A virus (IAV), NTHi is associated with secondary pneumonia, a major cause of mortality in IAV infections. The lipooligosaccharide (LOS) of NTHi contributes to virulence in models of bacteremia and otitis media yet its function in the lung is not well understood. We have identified roles in the lung for several LOS structural genes involved in evasion of the complement (C) pathway, which targets NTHi for destruction by phagocytes. We have also found metabolic pathways critical for NTHi survival in the lung and depletion of neutrophils alleviates NTHi's requirement for these pathways. Understanding NTHi pathogenesis in the lung has been limited, in part because normal mice rapidly clear the bacterium and do not develop persistent pneumonia with NTHi alone. However, our preliminary data demonstrate extensive multiplication and rapid lethality of NTHi in mice infected with IAV. Therefore, the IAV/NTHi co-infection model provides an opportunity to examine previously uncharacterized pathogenic mechanisms of clinically relevant NTHi strains in the context of pulmonary disease. We hypothesize that immune evasion and physiological adaptations by NTHi within the respiratory tract allow this bacterium to exploit weakened host defenses in predisposing conditions such as IAV co-infection, thereby potentiating disease. We propose to use IAV co-infection as a model system to characterize the molecular basis by which bacteria exploit host vulnerability in the lung. To perform the first comprehensive examination of the roles of the diverse colonization factors of H. influenzae in promoting pulmonary disease we will: Comprehensively compare bacterial adaptations and immune evasion factors required for growth and survival of NTHi in IAV co- infection versus those required in infection with NTHi alone; Characterize roles in immune evasion of NTHi LOS structures and antioxidant defenses that are differentially involved in IAV co-infection; and Determine mechanisms of NTHi pathogenesis in the context of altered host response and in IAV co-infection. Relevance: The proposed work will generate insight into the roles of bacterial genes of immune evasion and physiological adaptation required to survive anti-bacterial defenses modeled in vitro, and how these genes contribute to bacterial survival and colonization in lungs of both normal versus virally infected mice. The results will provide unique insight into strategies used by H. influenza and potentially other respiratory pathogens to resist defenses in the lung and exploit conditions in individuals with underlying disease. Moreover, understanding this bacterium's interactions with molecular components of its environment in normal and virally infected hosts will be valuable for the selection of appropriate targets for preventative or therapeutic strategies specifically designed to combat bacteria in viral co-infections and potentially other conditions that predispose individuals to bacterial lung infection.

Public Health Relevance

Haemophilus influenzae is a bacterial pathogen that persistently infects the human nasal passages and causes disease by invading and multiplying in the bloodstream, lungs, or middle ear. The proposed studies will comprehensively investigate adaptations this pathogen uses to evade host immune responses in the both the normal lung and in the context of co-infection with Influenza virus, an infection which predisposes individuals to lethal secondary bacterial pneumonia. These studies will provide information needed to devise more effective preventative and therapeutic measures against infections by H. influenzae and other bacteria that use similar pathogenic strategies in the respiratory tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095740-04
Application #
8820880
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Lu, Kristina
Project Start
2012-02-01
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
4
Fiscal Year
2015
Total Cost
$379,020
Indirect Cost
$86,401
Name
University of Mississippi Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Li, Wenchao; Zhang, Xinyun; Yang, Ying et al. (2018) Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection. Proc Natl Acad Sci U S A 115:E7149-E7157
Wang, Y; Jiang, B; Guo, Y et al. (2017) Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. Mucosal Immunol 10:250-259
Wong, Sandy M; Shaughnessy, Jutamas; Ram, Sanjay et al. (2016) Defining the Binding Region in Factor H to Develop a Therapeutic Factor H-Fc Fusion Protein against Non-Typeable Haemophilus influenzae. Front Cell Infect Microbiol 6:40
Yang, Cheng; Khanniche, Asma; DiSpirito, Joanna R et al. (2016) Transcriptome Signatures Reveal Rapid Induction of Immune-Responsive Genes in Human Memory CD8(+) T Cells. Sci Rep 6:27005
Akerley, Brian J (2016) No-Go Zones for Mariner Transposition. MBio 7:
Rosadini, Charles V; Ram, Sanjay; Akerley, Brian J (2014) Outer membrane protein P5 is required for resistance of nontypeable Haemophilus influenzae to both the classical and alternative complement pathways. Infect Immun 82:640-9
Han, Daehee; Walsh, Matthew C; Cejas, Pedro J et al. (2013) Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity 38:1211-22
Wong, Sandy M; Bernui, Mariana; Shen, Hao et al. (2013) Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung. Proc Natl Acad Sci U S A 110:15413-8