On a global scale, infectious agents as a group are the leading cause of mortality in infants, children, and adults. With its focus on disease prevention, vaccination is one of the most efficacious and cost effective means for infectious disease control. However in order to design safe and effective vaccines, a better understanding of how adaptive immune responses are generated and the specific immunological conditions during antigen exposure that will confer long-lived protection is needed. In addition to their role in triggering innate immune responses, the Toll-like receptor (TLR) family of molecules is believed to play essential roles in controlling the adaptive immune response by facilitating the generation of antigen-specific Thl-(IFN-yproducing) CD4 T cells. In the absence of TLRs or the downstream signaling molecule, MyD88, most infections or immunizations trigger an exclusive Th2-(no IFN-y produced, and IL-4 and IL-13 produced instead) immune response. Listeria monocytogenes (Lm) is a major pathogen in the neonate and in other immune-compromised hosts; and in the absence of TLR/MyD88, Lm infection retains the ability to generate IFN-y producing CD4 and CDS T cells. An analysis of the mechanistic basis for TLR/MyD88-independent generation of Thl immunity will be important for designing vaccines that aim to trigger this type of immune response, and will require me to become proficient with cellular immunology techniques that I yet do not have. We hypothesize (1) that entry into the cell cytoplasm and induction of type I-IFNs distinguish Lm from other infection and immunization models and allow Lm to induce Thl-immunity in the absence of TLR/MyD88 and (2) that regulatory T cells (normally inhibited by TLR-dependent pathways) can also be inhibited during Lm infection despite the lack of TLR-mediated cell activation. To test the role of Lm cytoplasmic entry and induction of type I-IFNs, we will examine the immune response following infection with Lm mutants that cannot gain access to the cell cytoplasm, and in mice with targeted disruption of type IIFN receptor. To test the role of regulatory T cells, we will isolate these cells during Lm infection and examine their function both in vitro and following adoptive transfer in vivo. The studies proposed will begin to characterize the mechanistic details of a TLR-independent pathway by which Thl-adaptive immune responses can be generated, and serve as the preliminary experiments for my transition into an independent investigator in the fields of immunology and infectious disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD051584-02
Application #
7213367
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Coulombe, James N
Project Start
2006-04-01
Project End
2007-05-01
Budget Start
2007-04-01
Budget End
2007-05-01
Support Year
2
Fiscal Year
2007
Total Cost
$10,563
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Johanns, Tanner M; Ertelt, James M; Rowe, Jared H et al. (2010) Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection. PLoS Pathog 6:e1001043
Ertelt, James M; Johanns, Tanner M; Rowe, Jared H et al. (2010) Interleukin (IL)-21-independent pathogen-specific CD8+ T-cell expansion, and IL-21-dependent suppression of CD4+ T-cell IL-17 production. Immunology 131:183-91
Curtis, Meredith M; Rowell, Emily; Shafiani, Shahin et al. (2010) Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle. Cell Host Microbe 8:163-73
Johanns, Tanner M; Ertelt, James M; Lai, Joseph C et al. (2010) Naturally occurring altered peptide ligands control Salmonella-specific CD4+ T cell proliferation, IFN-gamma production, and protective potency. J Immunol 184:869-76
Rowe, Jared H; Johanns, Tanner M; Ertelt, James M et al. (2009) Cytotoxic T-lymphocyte antigen 4 blockade augments the T-cell response primed by attenuated Listeria monocytogenes resulting in more rapid clearance of virulent bacterial challenge. Immunology 128:e471-8
Curtis, Meredith M; Way, Sing Sing; Wilson, Christopher B (2009) IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. J Immunol 183:381-7
Ertelt, James M; Rowe, Jared H; Johanns, Tanner M et al. (2009) Selective priming and expansion of antigen-specific Foxp3- CD4+ T cells during Listeria monocytogenes infection. J Immunol 182:3032-8
Curtis, Meredith M; Way, Sing Sing (2009) Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 126:177-85
Muller, William J; Orgun, Nural N; Dong, Lichun et al. (2008) Recombinant Listeria monocytogenes expressing an immunodominant peptide fails to protect after intravaginal challenge with herpes simplex virus-2. Arch Virol 153:1165-9
Orgun, Nural N; Way, Sing Sing (2008) A critical role for phospholipase C in protective immunity conferred by listeriolysin O-deficient Listeria monocytogenes. Microb Pathog 44:159-63

Showing the most recent 10 out of 16 publications