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Pathogenic role of IL-17 response in Streptococcus pneumoniae nasopharyngeal pathogenesis during an influenza virus co-infection

Award Number: R01AI143741
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Pathogenic role of IL-17 response in Streptococcus pneumoniae nasopharyngeal pathogenesis during an influenza virus co-infection - ABSTRACT 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $381,056 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	6	5/16/2024	NON-COMPETING CONTINUATION	$38,104
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	6	11/3/2023	NON-COMPETING CONTINUATION	$342,952
														Subtotal = $381,056

Issue Date FY: 2023 ( Subtotal = $381,056 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	11/3/2022	NON-COMPETING CONTINUATION	$381,056
														Subtotal = $381,056

Issue Date FY: 2022 ( Subtotal = $390,046 )
2022	2022	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	001	3	4/7/2022	NON-COMPETING CONTINUATION	-$353,721
2022	2022	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	3	11/23/2021	NON-COMPETING CONTINUATION	$353,721
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	004	4	5/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,887
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	4	4/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,046
2022	2021	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	003	2	5/17/2022	NON-COMPETING CONTINUATION	-$29,887
														Subtotal = $390,046

Issue Date FY: 2021 ( Subtotal = $357,081 )
2021	2021	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$357,081
														Subtotal = $357,081

Issue Date FY: 2020 ( Subtotal = $360,589 )
2020	2020	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	1	12/2/2019	NEW	$360,589
														Subtotal = $360,589

Grand Total All Awards = $1,869,828

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Pathogenic role of IL-17 response in Streptococcus pneumoniae nasopharyngeal pathogenesis during an influenza virus co-infection

Award Number: R01AI143741

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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