The fundamental premise of our application is to provide unbiased, non-hypothesis driven, analysis of immune signatures (IMS) associated with human disease. We will elucidate whether specific IMS are associated with preferential expansion/contraction of certain defined subsets which are already physiologically and homeostatically present within the individual's T cell pool, and which largely maintain their characteristic IMS. We will also consider the alternative, and not mutually exclusive, possibility that changes in IMS reflect generation of distinct T cell subsets with differentiation / activation states uniquely associated with infection, disease and vaccination. Addressing these issues in different human pathogen systems and in different geographical locations, it will be possible to establish to what extent the results obtained are generally applicable. Accordingly, we propose to characterize CD4 and CD8 memory T cell IMS associated with Mycobacterium tuberculosis (MTB) and dengue virus (DENV) in the context of 1) natural immunity and/or control of infection, 2) active and severe disease and 3) administration of licensed or experimental vaccines. Our group has studied MTB and DENV for several years for the following reasons. 1.They are both current global health problems. 2. For these diseases memory T cells are fundamentally associated with protective immunity. 3. Antigen-specific T cell responses are detected in sufficient numbers ex vivo, allowing omics study without the need for in vitro expansion or stimulation. 4. Human specimens associated with natural infection/immunity and severe diseases are easily accessible in large numbers. As a result, we have developed a critical mass that is extensively leveraged herein, based on: 1) an established team of experienced LJI investigators, 2) established clinical collaborations with leaders in the field, ensuring that the goal of recruitment of large numbers of suitably characterized individuals will be met (in fact, hundreds of samples are already available), 3) hundreds of epitopes restricted by a variety different HLA class I and II molecules to allow an analysis of memory T cells of unprecedented precision 4) existing data identifying specific T cell subsets as key players in immunity and 5) established and well validated micro- scaled omics assays for generating IMC related to MTB and DENV. The HIPC format is ideally suited to accomplish the proposed mission. Each project and core is critically dependent on other elements of the program. Only in the context of HIPC will we be able to realize the synergies, benefit from an economy of scale and operation, and bring different groups of investigators with different expertise together in a well and organized plan.

Public Health Relevance

Our goal is the characterization of immune signatures (IMS) of T cell subsets associated with protection vs. susceptibility to severe disease following infection with Dengue virus (DENV) and Mycobacterium tuberculosis (MTB) and IMS associated with vaccination with DENV and MTB vaccines. To accomplish this goal we will analyze CD4 and CD8 memory T cells in the context of natural endemic exposure, disease, and vaccination. Our studies will address whether specific IMS are associated with expansion/contraction of certain memory T cells already present within the individual's T cell pool. We will also consider the possibility that changes may not be due to the number of T cells belonging to different types of T cells but rather the IMS of the specific T cell in response to the perturbation introduced by DENV and MTB infection, disease and vaccination. Project-001: Human immune signatures of natural immunity to DENV infection, severe disease, and vaccination with attenuated live vaccine Project Leader (PL): Alessandro Sette DESCRIPTION (as provided by applicant): Our goal is to characterize immune signatures (IMS) of T cell subsets associated with protection vs. susceptibility to severe disease following infection with dengue virus, and IMS associated with administration of DENV experimental vaccines. To accomplish this goal we will analyze CD4+ and CD8+ memory T cells in the context of natural endemic exposure to DENV, DENV disease and vaccination. To ensure generality of the findings, samples from two rather distinct endemic areas (Nicaragua and Sri Lanka) will be analyzed. In Aim 1 we will compare the IMS of total CD4+ and CD8+ memory T cell populations in infected/immune individuals to those of non-infected individuals from the same population. These IMS will be compared with those obtained from specific subsets of CD4+ and CD8+ T cells, identified on the basis of memory markers and chemokine receptors, and implicated in protection from severe disease. We will further compare these IMS with those of DENV antigen specific T cells derived from the same phenotypic subsets, and restricted by HLA class I and class II molecules associated with decreased or increased susceptibility to severe disease. In Aim 2 we will study T cell responses associated with severe disease, defined by T cell phenotypes observed in longitudinal sampling of PBMCs from DENV infected individuals associated with differential disease severity, from early infection time points into convalescence. Finally, in Aim 3 the phenotypes defined above will be compared with experimental DENV live-attenuated vaccines (DLAV) and those observed following vaccination against another flavivirus (yellow fever; YF). The IMS associated with specific T cell subsets will be compared with IMS associated with DENV-specific T cells, isolated on the basis of tetramer staining techniques. We will utilize a variety of complementary approaches including: cytometry analysis of a large panel of phenotypic markers, RNA-Seq profiling and single cell analysis, mesoscale assays of cytokine production and proteomic analysis of specific memory T cell subsets. These results will be further correlated with tertiary outcome measurements such as viral titers, antibody titers, virus neutralization assays, clinical outcomes, HLA type and other individual donor-related characteristics. Our results will be compared with those obtained by Project 2, which studies a chronic bacterial disease (Tuberculosis) in the context of natural exposure, disease and vaccination. These results will also be the basis of initial validation for additional RNAi and epigenetic profiling performed in Project 3.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LGR-I (M1))
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Kelly, Halonna R
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La Jolla Institute
La Jolla
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