Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Antibody inducing Influenza A virus (IAV) vaccines are available, however protection is suboptimal and requires annual reformulation of the vaccine. IAV can escape neutralization by preexisting antibodies due to the high rate of mutation in the primary targets of neutralization (hemagglutinin, HA and neuraminidase, NA) and due to its capacity to recombine in non-human hosts. In the absence of neutralizing antibodies, memory CD8 T-cell specific for epitopes located in conserved regions of IAV proteins like the internal components nucleoprotein (NP), polymerase A and matrix protein can confer protection. Recent human challenge studies and longitudinal analyses during the 2009 H1N1 IAV pandemic support the notion that cross-reactive memory CD8 T cells are capable of ameliorating disease when pre-existing antibodies are absent. As most humans carry a small number of these broadly protective memory CD8 T-cells, increasing the number of these cells through boosting is an attractive strategy to bolster their protective capacity. However, memory CD8 T-cells constitute a very heterogeneous population and little is known about how boosting or multiple antigen exposures effects CD8 T-cell mediated protection against IAV, For instance, we have recently reported that the type of booster agent significantly affects the localization and protective capacity of the resulting memory CD8 T-cell population (Sl?tter et al, 2013). Therefore, our long-term goal is to determine optimal memory CD8 T-cell characteristics for protection against IAV and to understand how such memory populations can be generated. In turn, these studies will provide crucial information to optimize broadly protective vaccines for IAV.
Specific Aim 1. Determine the molecular mechanisms regulating CXCR3 expression in memory CD8 T cells to enhance airway localization.
Specific Aim 2. Determine the impact of repetitive IAV infections on the generation of airway---surveilling, tissue resident and circulatin memory CD8 T cells and their relative contribution in protection from IAV.

Public Health Relevance

Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Due to the ability of influenza to mutate and reassert, protection antibody inducting vaccines has limitations. Here, we will identify properties of memory CD8 T cells with the capacity to induce subtype transcending protection, information that will be crucial for the design of broadly protective vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114543-03
Application #
9172644
Study Section
Immunity and Host Defense (IHD)
Program Officer
Hauguel, Teresa M
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Cabrera-Perez, Javier; Badovinac, Vladimir P; Griffith, Thomas S (2016) Enteric immunity, the gut microbiome, and sepsis: Rethinking the germ theory of disease. Exp Biol Med (Maywood) :
Cabrera-Perez, Javier; Babcock, Jeffrey C; Dileepan, Thamotharampillai et al. (2016) Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis. J Immunol 197:1692-8
Strother, Robert K; Danahy, Derek B; Kotov, Dmitri I et al. (2016) Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo. J Immunol 197:4301-4311
Martin, Matthew D; Badovinac, Vladimir P (2015) Antigen-dependent and -independent contributions to primary memory CD8 T cell activation and protection following infection. Sci Rep 5:18022
Martin, Matthew D; Kim, Marie T; Shan, Qiang et al. (2015) Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection. PLoS Pathog 11:e1005219
Khan, Shaniya H; Martin, Matthew D; Starbeck-Miller, Gabriel R et al. (2015) The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses. PLoS Pathog 11:e1005199
Cabrera-Perez, Javier; Condotta, Stephanie A; James, Britnie R et al. (2015) Alterations in antigen-specific naive CD4 T cell precursors after sepsis impairs their responsiveness to pathogen challenge. J Immunol 194:1609-20
Khan, Shaniya H; Badovinac, Vladimir P (2015) Listeria monocytogenes: a model pathogen to study antigen-specific memory CD8 T cell responses. Semin Immunopathol 37:301-10
Condotta, Stephanie A; Khan, Shaniya H; Rai, Deepa et al. (2015) Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion. J Immunol 195:116-25
Markwart, Robby; Condotta, Stephanie A; Requardt, Robert P et al. (2014) Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function. PLoS One 9:e115094