Document text
Principal Investigator: SEBASTIAN JOYCE
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2020
Funding agency: Veterans Affairs
The overarching goal of my research program is to understand the molecular mechanisms of immune
surveillance mediated by tissue-resident memory T cells that patrol the mucosal barrier of the lungs to control
infectious diseases and cancers. My laboratory is best recognized for its contributions to the cell biology and
biochemistry of MHC and MHC-like CD1d molecules. These molecules play important roles in protein and
lipid antigen presentation and, thereby, control T cell and natural killer T (NKT) cell biology, respectively. In
recent years, our research focus has turned toward harnessing what we have learnt in basic immunology to
augment immune reaction through vaccine and adjuvant design to prevent or treat microbial infections and
cancer, deathly diseases that ail humankind: We recently reported a strategy for CD8+ T cell-targeted vaccine
design to identify targets that confer protective immunity against poxvirus disease (J. Clin. Invest. 123: 1976—
1987;; 2013). Using this model, we have elucidated the mechanisms of induction, maintenance and action of
tissue resident memory (Trm) CD8+ T cells and how Trm cells impart lung/pulmonary mucosal immunity (Cell
Rep 16: 1800;; 2016). New work supported by the Research Career Scientist and the VA Merit will refine the
above strategies to devise ways to identify, characterize and develop vaccine candidates against tuberculosis.
Aims of this project are, (a) to identify T cell epitopes that will protect against pulmonary M tuberculosis
infection in a preclinical humanized mouse model;; (b) to identify globally protective epitopes that cross MHC
restriction barriers;; and (c) to characterize nanoparticle-based delivery systems for intracellular STING-
targeted adjuvant and antigen delivery. Hence, as a Research Career Scientist, I hope to identify T cell
epitopes that will protect against tuberculosis and devise ways to enhance immunological memory at the lung
mucosal surfaces by vaccinating with subunit vaccines and intracellular adjuvants. This outcome will impact
clinical management of tuberculosis as well as other respiratory infectious diseases and cancers.
My research program was developed through numerous collaborations with investigators at the VA, the
University Affiliate, the NIH, and at national and international institutions. I have published over 120 articles,
several in top-tier journals. These works have been cited over 9,700 times, and have an h-index of 48 and an
i10-index of 93. Significantly, our research has been continuously supported by federal grants over the last
20+ years and by a VA Merit Award over the last four years. In sum, I am well-poised to serve our Veterans
as a Research Career Scientist. Through this appointment, I hope to enhance research in vaccines and
vaccine delivery mechanisms that will utilize T cell epitopes. The emerging vaccines and delivery mechanisms
will enhance immunological memory at the lung mucosal surfaces through vaccination with subunit vaccines
and intracellular adjuvants to mediate protective immunity against infectious diseases and cancers.
Our Veterans are exposed to deathly infectious diseases, such as tuberculosis and cancers. For example,
the wars in Afghanistan and Iraq as well as deployment in Korea and other South Eastern countries have
contributed to the tuberculosis incidence in the US Military. A recent study identified 113 Veterans in Western
US with confirmed tuberculosis diagnosis between 2010—2013. The incidence has since risen amongst our
Veterans. Another study noted that of the 42 Veterans diagnosed with latent TB, only ~43% had initiated
treatment and only ~31% had completed the drug regimen. This foretells a grim situation as the untreated
Veteran population, especially those with latent TB infection, are potential disease transmitters;; still worse,
those that do not complete the drug regimen can raise drug-resistant strains for transmission. Hence, our
research and its outcomes will directly impact clinical practice paradigms against tuberculosis and other
respiratory infectious diseases. Thus, our research will better the lives of Veterans.
Terms: <21+ years old><AAAS><Acute Disease><Address><Adjuvant><Adult><Adult Human><Aerosols><Afghanistan><Aging><American Association for the Advancement of Science><American Cancer Society><Antigen Presentation><Antigen Presentation Pathway><Antigen Processing and Presentation><Antigenic Determinants><Antigens><Appointment><Area><Armed Forces Personnel><Award><Basic Research><Basic Science><Binding Determinants><Biochemical><Biochemical Process><Biochemistry><Biological><Biological Chemistry><Biology><Body Tissues><Botanies><Botany><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancers><Cell Body><Cell Function><Cell Process><Cell physiology><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cessation of life><Chemistry><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Management><Collaborations><Communicable Diseases><Country><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Death><Dental Schools><Diagnosis><Disease><Disorder><Doctor of Philosophy><Drug Resistance Tuberculosis><Drug Resistant TB><Drug Resistant Tuberculosis><Drug resistance><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistance in tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><Drugs><Dysfunction><Effector Cell><Epitopes><Exposure to><Foundations><Functional disorder><Funding Agency><Funding Source><Generations><Genomic approach><Goals><Grant><Health><Immune><Immune Surveillance><Immune memory><Immune reaction><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Memory><Immunologic Surveillance><Immunologic Surveillances><Immunological><Immunological Memory><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically><Immunologics><Immunology><Immunosurveillance><Incidence><India><Infection><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Institution><International><Investigators><Iraq><Japan><Journals><Korea><Laboratories><Lipids><Lung><Lung Respiratory System><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Magazine><Maintenance><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Medicine><Memory><Mentors><Microbiology><Military><Military Personnel><Modeling><Molecular><Morbidity><Morbidity - disease rate><Mtb drug resistance><Mucosa><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIH><National Institutes of Health><Outcome><Pathology><Peer Review><Pennsylvania><Peptides><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiology><Physiopathology><Play><Population><Poxviridae><Poxviruses><Pre-Clinical Model><Preclinical Models><Privatization><Process><Proteins><Proteomics><Publications><Publishing><Regimen><Reporting><Research><Research Personnel><Research Support><Researchers><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Respiratory Infections><Respiratory Tract Infections><Role><Science><Scientific Publication><Scientist><Site><Subcellular Process><Subunit Vaccines><Sum><Surface><System><T memory cell><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><TB drug resistance><TB infection><Testing><Time><Tissues><Transmission><Tuberculosis><United States National Institutes of Health><Universities><Vaccinated><Vaccination><Vaccine Design><Vaccines><Veterans><Virginia><Visit><War><Work><Zoology><acute disease/disorder><acute disorder><adulthood><allergic/immunologic body system><allergic/immunologic organ system><anamnestic reaction><austin><base><career><cell biology><chronic disorder><clinical practice><college><collegiate><design><designing><disseminated TB><disseminated tuberculosis><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistant><drug resistant M.tb><drug resistant in tuberculosis><drug/agent><faculty research><genomic effort><genomic strategy><host response><humanized mice><humanized mouse><immunogen><immunoreaction><immunoresponse><indexing><infection due to Mycobacterium tuberculosis><infectious organism><insight><interdisciplinary approach><killer T cell><malignancy><memory T lymphocyte><microbial><microbial antigen><microbial pathogen><microorganism antigen><mortality><mouse model><mtb><multi-drug resistant><multidisciplinary approach><multidrug resistant><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><pathogen><pathogenic microbe><pathophysiology><pox virus><pre-clinical><preclinical><prevent><preventing><professor><programs><pulmonary><resistance strain><resistance to Drug><resistant strain><resistant to Drug><respiratory><seal><secondary immune response><social role><tenure process><tenure track><thymus derived lymphocyte><translational medicine><transmission process><tuberculosis infection><tuberculous spondyloarthropathy><vaccine candidate><vaccine delivery>