Streptococcus pneumoniae (Spn) is a major respiratory bacterial pathogen, asymptomatically carried (colonization) in the nasopharynx, by a significant proportion of the human population (children and adults). Colonization is a precursor to Spn disease (pneumonia, sinusitis, otitis media, sepsis, meningitis) which accounts for a significant disease burden in humans. Despite a decline in the overall Spn disease burden caused by currently available vaccines, Spn diseases continue to occur and remain a significant medical problem. Nasopharyngeal colonization is a precursor for Spn diseases, and co-infection with an influenza virus is a significant risk factor for the development of Spn disease. The influenza virus promotes damaging inflammation in the nasopharynx, which leads to bacterial outgrowth and dissemination of Spn bacteria to sterile tissues (lungs, blood) to establish disease. However, the mechanisms implicated in the damaging inflammation and consequent transition of Spn colonization into the disease, remain poorly understood. We developed an Spn-Influenza A Virus (IAV) co-infection model of Spn disease, by introducing IAV in Spn colonized mice. Our nasopharyngeal co-infection model mimics the natural pathogenesis of Spn involving the transition of Spn colonization to disease. Our preliminary data shows that the infection of Spn (serotype 6A) colonized mice with IAV elicits a robust IL-17A response that promotes hyper-inflammation in the NP, which leads to bacterial dissemination (lungs/blood) and the development of Spn disease. An antibody-mediated neutralization of IL-17A mitigated inflammation in the nasopharynx, results in a reduced Spn burden in the NP and blood with improved survival. Additionally, we show that innate lymphoid cells 3 (ILC3s) are a potential source of the pathogenic IL-17 response in our co-infection model of Spn disease. This data highlights the previously unrecognized role of the IL-17 response as a contributor to nasopharyngeal hyper-inflammation and the promotion of Spn disease in a co-infection setting with influenza virus. Based on our presented preliminary data, this 5-year research proposal hypothesizes that ?influenza-induced IL- 17 response leads to the development of a pro-inflammatory immune phenotype, epithelial inflammation, and compromised barrier response in the NP, resulting in the dissemination/invasion of Spn bacteria from the NP into the lungs/bloodstream to establish Spn disease?. This hypothesis will be tested in three structured aims that will describe the mechanisms operating at multiple levels from the generation of the pathogenic IL-17 response and the role of IL-17 receptor signaling in epithelial inflammation and airway-barrier integrity, leading to the development of Spn disease. The findings will be central to designing interventions for translational utility, in the future.

Public Health Relevance

The proposal seeks to investigate the role of the influenza-induced pathogenic IL-17 response in the nasopharynx, leading to the transition of colonizing Streptococcus pneumoniae (Spn) into a pathogen. We hypothesize that the nasopharyngeal IL-17 response contributes to influenza-mediated hyper-inflammation and dysregulated barrier integrity in the nasopharynx, which allows colonizing Spn to outgrow and disseminate/invade to sterile tissues, establishing disease. The proposed research plan will lead to the development of an IL-17-based, novel interventional approach to mitigate inflammation and Spn pathogenesis during a co-infection with influenza virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI143741-02
Application #
10064127
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Lu, Kristina
Project Start
2019-12-03
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of North Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202