The mucosal surfaces are covered by a thin epithelium which is adapted for selective adsorption of essential nutrients, but is a weak physical barrier against the outside environment. Because this epithelium can be easily breached many infectious agents use the mucosal tissues as gateways into the body. These pathogens include several highly pathogenic respiratory viruses which pose a constant threat to human health. The fragile membranes ofthe alveoli make the lungs particulariy vulnerable to immune damage. We will use a heterosubtypic reinfection model to examine the mechanisms that help protect the lungs from these infections. Previous studies have shown that local populations of cytotoxic T lymphocytes (CTL) and IgA antibodies in the respiratory tract can provide immunity between different stains of influenza virus. Our data indicate that these mechanisms are facilitated by mild antigen-driven inflammation, which helps pathogen-specific CTL stay near the mucosal surface between repeated viral infections and augments local antibody production. The goals ofthe current study are to investigate how a tightly regulated cytokine response promotes enduring T and B cell mediated heterosubtypic immunity. We will focus on the cytokines that trigger innate immune activation, as well as long-term TGF-beta production which plays a pivotal role in immune regulation in the lungs.

Public Health Relevance

Influenza viruses are highly contagious pathogens that are in constant circulation in human populations. High death tolls make these infections a top priority for mass vaccination programs but accumulating data indicate that the current vaccination approaches are not optimized to generate enduring immunity. Our data indicate that T cell mediated immunity in the lungs can be prolonged by a mild inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI056172-08A1
Application #
8424008
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Project Start
2003-09-01
Project End
2018-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$399,249
Indirect Cost
$117,682
Name
University of Connecticut
Department
Type
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Benoun, Joseph M; Peres, Newton G; Wang, Nancy et al. (2018) Optimal protection against Salmonella infection requires noncirculating memory. Proc Natl Acad Sci U S A 115:10416-10421
Ménoret, Antoine; Buturla, James A; Xu, Maria M et al. (2018) T cell-directed IL-17 production by lung granular ?? T cells is coordinated by a novel IL-2 and IL-1? circuit. Mucosal Immunol 11:1398-1407
Svedova, Julia; Ménoret, Antoine; Mittal, Payal et al. (2017) Therapeutic blockade of CD54 attenuates pulmonary barrier damage in T cell-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 313:L177-L191
Shinde, Paurvi; Liu, Wenhai; Ménoret, Antoine et al. (2017) Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production. J Leukoc Biol 102:57-69
Liu, Wenhai; Menoret, Antoine; Vella, Anthony T (2017) Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2. Cell Mol Immunol 14:254-253
Lee, Seung-Joo; Benoun, Joseph; Sheridan, Brian S et al. (2017) Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells. J Immunol 199:1353-1361
Romagnoli, P A; Fu, H H; Qiu, Z et al. (2017) Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol 10:520-530
Pham, Oanh H; O'Donnell, Hope; Al-Shamkhani, Aymen et al. (2017) T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS Pathog 13:e1006566
Risso, Gabriela S; Carabajal, Marianela V; Bruno, Laura A et al. (2017) U-Omp19 fromBrucella abortusIs a Useful Adjuvant for Vaccine Formulations againstSalmonellaInfection in Mice. Front Immunol 8:171
Benoun, Joseph M; Labuda, Jasmine C; McSorley, Stephen J (2016) Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory. MBio 7:

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