Modulation of Biodefense Responses to Microbial Pathogens

University Of Connecticut Sch Of Med/Dnt, Farmington CT

Investigators

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Abstract

Revised ran Project 1: Protective immunity to typhoid, P.1. McSorley, S. immunity to typhoid, P.1. McSorley, S. Next-generation typhoid vaccines are urgently required since Salmonella are rapidly developing resistance to Salmonella are rapidly developing resistance to Next-generation typhoid vaccines antibiotics and current vaccines have safety concerns or are poorly immunogenic. Protective immunity induced of Salmonella, or following resolution of primary typhoid after antibiotic treatment, by live vaccine strains (LVS) of Salmonella, or following resolution of primary typhoid after antibiotic treatment, are very poorly understood. In this revised project, we propose to examine development of CD4 memory T poorly understood. revised project, we propose to examine development of CD4 memory T cells in these circumstances and define the critical requirements for protective immunity to secondary typhoid requirements protective secondary typhoid. cells This focus should allow for considerable synergy with Projects 1 and 4 where protective T cell and antibody considerable synergy with Projects I and 4 where protective T cell and antibody This focus should allow responses to List eriaand Influenza are being studied. The specific aims of this sub-project are: Aim 1. To responses to Listeria and Influenza are being studied. The specific aims of this sub-project are: Aim 1. determine the parameters of sustained antigen presentation that generate a robust Th1 memory response. Aim sustained antigen presentation that generate a robust Thi memory response. Aim 2. To define the critical parameters of aaprotective secondary response to typhoid. Our preliminary data 2. To define the critical parameters of protective secondary response to typhoid. Our preliminary data describe the development of state-of-the-art technology to track Salmonella-specific CD4 T cells in vivo, and technology Salmonella-specific cells in vivo, and describe the generation of a novel antibiotic-treatment model to study immunity to typhoid. Our hypothesis is that generation novel antibiotic-treatment model to study immunity to typhoid. Our hypothesis is that the effective CD4 Th1 memory requires sustained antigen presentation. It is further proposed that Salmonellaeffective CD4 Thi memory requires sustained antigen presentation. It is further proposed that Salmonellaspecific antibody responses can supplement a protective CD4 response during secondary typhoid challenge. response secondary challenge. specific antibody responses can This hypothesis will be tested in two specific aims using technology that allows detection of endogenous tested in two specific aims using technology that allows detection of endogenous This hypothesis will Salmonella-specific CD4 T cells and examination of acquired immunity to typhoid following antibiotic treatment antibiotic treatment. #11 CM'S ,-r 'O+ em. .CZ fl. rte. o0) (CD 33B. {p' Cep ro[unreadable][unreadable] _,' c}- -0+ -from C/) .A' cep Project 3: Antibody and T Cell Interactions During Influenza Virus Infection 3: Antibody and T Cell Interactions During Influenza Influenza is a category C pathogen that has the potential to cause massive loss of human life. Genetic potential to cause massive loss of human life. Genetic instability of the virus and large animal reservoirs ensure that new strains will continue to cause human that new strains will continue to cause human pandemics until efficient vaccination strategies can be developed. Antibodies and T cells are important be developed. and T cells are important mechanisms of viral clearance and therefore potential targets for vaccination, In an optimal situation, the for vaccination. In an optimal situation, the vaccine would boost both antibody and T cell responses simultaneously. However in a previously published simultaneously. However in a previously published study we found evidence that virus-specific antibodies in the respiratory tract induce a suppressive in respiratory tract induce a suppressive environment in the lungs which prevents reactivated memory COB T cells from accumulating at the site of the which prevents reactivated memory CD8 T cells from accumulating at the site of reinfection. In this application we will: 'q. chi Vii crop -[unreadable]. ,-r Project 2: Mechanisms of Staphylococcus aureus enterotoxin induced pathogenesis 2: Mechanisms of Staphylococcus The biodefense agent Staphylococcus aureus enterotoxin is regarded as a superantigen (SAg) because it is aureus is regarded as a superantigen (SAg) because it is an incredibly powerful T cell stimulant. Intentional aerosol not processed as conventional peptide and is an incredibly powerful T cell stimulant, Intentional aerosol exposure of S. aureus enterotoxin has the potential to incapacitate large groups of people in enclosed S. incapaCitate large groups of people in enclosed of attack leading severe respiratory illness in all individuals structures with the consequences of such an attack leading to severe respiratory illness in all individuals exposed. Notwithstanding, certain pulmonary diseases in human patients have recently been associated with in human patients have recently been associated with exposed. the presence of SAg, and stimulation of T cells with SAg in the respiratory tract drives an inflammatory of SAg in the respiratory tract drives an inflammatory cascade resulting in severe pathological outcomes in the lung. Although this pathogenic response is T cell resulting pathological outcomes in the lung Although this pathogenic response dependent, the individual contributions of CD4 or CD8 T cells is largely unknown. Aim 1 will uncover the of or COB cells is largely unknown. Aim 1 will uncover the is responsible for after S. aureus enterotoxin inhalation. Our pathogenic contribution that each T cell subset is responsible for after S. aureus enterotoxin inhalation. Our hypothesis is that T cell subsets play different roles in inducing and perhaps mitigating disease. An emerging in inducing and perhaps mitigating disease. An emerging aspect in this model is a role for key cytokines during the induction of lung injury and this idea will be tested in during induction of lung injury and this idea will be tested in Aim 2. We will model how S. aureus enterotoxin inhalation induces cytokines thought to be restricted to the cytokines thought to be restricted to the action of the inflammasome, a process mostly associated with innate immunity. We will begin to assess a role mostly with innate immunity. We will begin to assess a role for a T cell triggered inflammatory cascade that drives multiple pathways of inflammation resulting in different cell triggered cascade that drives multiple pathways of inflammation resulting in different aspects of pathogenesis. Our hypothesis is that the SAg T cell cytokine response will trigger pulmonary is SAg cell cytokine response will trigger pulmonary inflammation by swaying the balance of cytokines detected in the lung. In sum, this project of the UCONN of detected in the lung. In sum, this project of the UCONN medically relevant model by discovering the mechanisms Biodefense Program Project grant will explore a medically relevant model by discovering the mechanisms underlying SAg mediated pulmonary inflammation. chi t'1 ,., cep try 2)-00)) =U) --1 '.. CA' ,O, SS? {f} Crop C.0 S31 m_-0'-'t ,-[unreadable] .em SS} pro !S1 9D+ 0ro {CI CT} .-r 0)0 >.c 0-0 0 t07 a)-cm ..ro >,> [unreadable]w0 7s= (/) >,[unreadable] m-[unreadable]s Z'7 CC) c-0 0 1. Investigate why proliferating COB cells do not accumulate lungs of fully immune mice Aim 1. Investigate why proliferating CD8 T cells do not accumulate in the lungs of fully immune mice during heterosubtypic challenge. Aim 2. Characterize the APCs that participate in memory CD8 T cell reactivation during homotypic and 2. Characterize COB reactivation and heterosubtypic challenge. Until recently it was believed that memory CD8 T cells have minimal requirements memory COB T cells have minimal requirements challenge. during reactivation and are therefore independent of antigen presentation by for costimulatory signals during reactivation and are therefore independent of antigen presentation by [unreadable]0p ms's w=r 0 CD. (G3 .,_. Q-[unreadable]... -fit 0-00 Q.[unreadable]of .(0 C;) o'- '-GI) try C;) coy '*- Chi .f? o-[unreadable] +-' ,.. 0.0 cue a)' L71 .LM [unreadable]U. cum M:3 C.9 ''- +-. "C- cad a)0 r^. 42' recently changed when it became clear that DCs playa central role in the recall professional APC. This view recently changed when it became clear that DCs play a central role in the recall and others have also shown that specific signals were required for DC to response to influenza infection. We and others have also shown that specific signals were required for DC to COB celis. identify the APCs that participate in memory COB T cell reactivation reactivate memory CD8 T cells. We will identify the APCs that participate in memory CD8 T cell reactivation during homotypic and heterosubtypic challenge. (C) --'p Cat) c01)0 0.2 's.