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Principal Investigator: SEBASTIAN JOYCE
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
The overarching goal of my research program is to understand tissue specific immunity with focus on the lungs.
Immune cells continuously surveil the lungs to respond quickly to infections. Mycobacterium tuberculosis (Mtb)
causes chronic tuberculosis (TB) and Francisella tularensis causes acute tularemia—two bacteria that cause
respiratory infectious diseases. I have developed two large-scale T cell epitope discovery programs that leverage
our strengths and my forte: the Merit supports the Mtb program; and AI137982 “Molecular Basis of CD1D and
Natural Killer T Cell Function”, awarded in August 2019, after the RCS began, supports F. tularensis research.
New support has been sought via a response to an RFA BAA-NIAID-DAIT-75N93022R00023: “FUNCTIONAL
IMMUNOPEPTIDOMICS: Large-Scale F tularensis-derived Epitope Discovery & Correlates of T Cell Immunity”.
Our Mtb work addresses a critical unmet need for an effective vaccine against TB that will significantly
improve the quality of life of our Veterans. Mtb lives and multiplies within the host immune cell called
macrophages, which are voracious eaters of bacteria and other foreign substances. Mtb has evolved ways to
prevent macrophages from doing so, making life within infected cells possible. To get rid of the infection, the
host needs to engage the killer cells of the immune system, one such killer cell is called CD8+ T cell. CD8+ T
cells are equipped to find infected cells in very specific manner when antigens are presented in association with
the hosts’ Human Leukocyte Antigen (HLA)-I molecule. HLA-I are different between individuals making T cell
vaccine development difficult. Fortunately, HLA-I can be grouped into nine supertypes—B7 is one such
supertype expressed by 40—45% of the human population. Once specific antigen recognition occurs, these
effector cells deploy killing mechanisms to destroy the infected cells, leaving no place for the bacteria to live.
Hence, the overarching goal of the Merit research is to develop a vaccine platform against TB that harnesses
CD8+ T cell functions. This program leverages 30+ years of my experience in the field of antigen processing and
presentation to T cells. Thus, in a systematic approach to vaccine design, our work involves pre-clinical studies
that aims to identify MTb-derived antigens expressed only by infected macrophages so that CD8+ T cells can
recognize such antigens, kill infected cells, and, thereby, confer protection to the host. In addition to vaccine
design, our research will develop platforms for the delivery of next generation TB vaccines directly to the site of
Mtb infection which is the lungs. We have made great strides toward both these goals: To facilitate the antigen
discovery goal, we have developed new HLA-I transgenic humanized mouse lines. Then in a high-throughput
antigen presentation assay that leverages a novel ultrahigh-density peptide arrays, we discovered 100s of
peptide antigens that are presented by four common human MHC molecules. By bioinformatics approach we
have winnowed down to 35 most likely MTb antigens recognized by CD8+ T cells, of which several are
immunogenic Mtb-derived peptides and presented by members of the B7 supertype. Candidate antigens in these
novel humanized mouse models are at the centre of the current investigations. Toward the development of
platforms for vaccine delivery to the lungs—we have designed and validated nanoparticle platforms adjuvanted
with three different chemicals that activate the innate immune system. The unique feature of these platforms is
the ability to target the nanoparticle to the cytosol of a host immune cell called dendritic cell (DC), which are
critical for antigen presentation to CD8+ T cells. We will harness this delivery platform to deliver the antigen/s
discovered in the discovery phase of the project summarized above, tether the nanoparticle with an adjuvant to
activate DCs, for delivery to the lungs. In summary, this pre-clinical, translational project is on an upward
trajectory and will validate the ‘discover & deliver’ platform for a vaccine against TB. Success with this project
brings with it the promise of delivering better health care to our Veterans, especially the downtrodden amongst
them and, hence, the most burdened by the scourge of tuberculosis.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><A fumigatus><A. fumigatus><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Adjuvant><Adult><Adult Human><Aerosols><Airway mucosa><Animal Model><Animal Models and Related Studies><Antibodies><Antigen Presentation><Antigen Presentation Pathway><Antigen Processing and Presentation><Antigenic Determinants><Antigens><Aspergillus fumigatus><Assay><Award><Bacteria><Binding Determinants><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Body Tissues><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19 virus><COVID19 virus><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Chemicals><Chronic><CoV-2><CoV2><Communicable Diseases><Contracting Opportunities><Contracts><Cytolytic T-Cell><Cytosol><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Dendritic Cells><Development><Disease><Disorder><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><ECTV><Ectromelia virus><Effector Cell><Epitopes><F tularensis><F tularensis infection><F. tularensis><F. tularensis infection><Francisella infection><Francisella tularensis><Francisella tularensis infection><General Population><General Public><Goals><HCV infection><HIV><HL-A Antigens><HLA Antigens><Health><Healthcare><Hepatitis B><Hepatitis C><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Homelessness><Human><Human Immunodeficiency Viruses><Human Leukocyte Antigens><Immune><Immune Surveillance><Immune system><Immunes><Immunity><Immunobiology><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunophysiology><Immunosurveillance><Incidence><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Innate Immune System><Investigation><K Cells><Killer Cells><LAV-HTLV-III><LYT3><Leukocyte Antigens><Life><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><M tb><M tuberculosis><M tuberculosis antigen><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis antigen><M. tuberculosis infection><M.tb antigen><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Macrophage><Memory><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Monitor><Monkey Pox Virus><Monkeypox virus><Monkeypoxvirus><Morbidity><Morbidity - disease rate><Mouse Pox Virus><Mousepox virus><Mtb antigen><Mtb drug resistance><Mucosa><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Mycobacterial Infection><Mycobacterium Infections><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Mφ><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Orthomyxovirus Type A><Outcome><Pasteurella tularensis><Peptides><Phase><Phenotype><Population><Poxviridae><Poxvirus muris><Poxvirus officinale><Poxviruses><Predisposition><Proteomics><Public Health><QOC><QOL><Quality of Care><Quality of life><Research><Research Support><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Respiratory Mucosa><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientist><Scourge><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Site><Smallpox><Subcellular Process><Susceptibility><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><TB infection><TB vaccine><Testing><Tissues><Transgenic Organisms><Transmission><Tuberculosis><Tuberculosis Vaccines><Tularemia><Type A Influenza><United States National Institutes of Health><Vaccinated><Vaccination><Vaccine Design><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Vaccinia virus><Variola><Veiled Cells><Veterans><Viral Diseases><Viral Hepatitis B><Virus><Virus Diseases><Virus-HIV><Work><Wuhan coronavirus><adulthood><anti-TB vaccine><base><bases><career><cell biology><co-infection><coinfection><coronavirus disease 2019 virus><coronavirus disease-19 virus><deliver vaccines><density><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disseminated TB><disseminated tuberculosis><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistant M.tb><experience><fungus><hCoV19><health care><hep C><hepatitis non A non B><high risk><homeless><humanized mice><humanized mouse><immunogen><immunogenic><improved><infected with F tularensis><infected with F. tularensis><infected with Francisella tularensis><infection by hepatitis c virus><infection due to Mycobacterium tuberculosis><insight><killer T cell><member><model of animal><molecular profile><molecular signature><mortality><mouse model><mpox virus><mpxv><mtb><multi-drug resistant><multidrug resistant><murine model><nCoV2><nano><nano particle><nano-sized particle><nanoparticle><nanosized particle><new vaccines><next generation><next generation vaccines><non A, non B hepatitis><non-A, non-B hepatitis><novel><novel vaccines><pathogen><pox virus><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><programs><pulmonary><recombinant vaccinia virus><respiratory><response><serum hepatitis><small pox><success><thymus derived lymphocyte><transgenic><transmission process><treatment adherence><treatment compliance><tuberculosis infection><tuberculous spondyloarthropathy><unhoused><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine candidates against tuberculosis><vaccine delivery><vaccine development><vaccine platform><vaccine strategy><variola major><viral infection><virus infection><virus-induced disease>