U01AI168390

T Cell Immunity to CMV in Utero and in Early Childhood - Abstract:

CMV infection in utero leads to prolonged viremia and often devastating clinical sequelae. In adults, it is established that the T cell response to CMV is required for containment of viremia. However, the immunologic determinants of viral control and clinical sequelae following congenital CMV infection are not known.

In this project, we will study the immune response to CMV as a window into immune ontogeny and the age-related maturation of antiviral T cell function. We will leverage a large cohort of mother-infant pairs with samples banked longitudinally for immunologic studies. This cohort, which includes a large number of infants infected with CMV in utero and others infected during early childhood, affords a unique opportunity to examine the relationship between the age-related maturation of the immune system and control of CMV viremia.

Prior studies have shown that two populations of cytotoxic T lymphocytes, CD8 T and GD T cells, expand and differentiate upon CMV infection in utero. We hypothesize that T cells generated during fetal development (including both CD8 and GD T cells) are intrinsically biased toward rapid differentiation into terminal effector cells. We further hypothesize that this effector-biased programming limits the ability of infant CD8 T cells to generate the long-lived memory sub-populations that are required for sustained control of a chronic viral infection. This hypothesis is supported by data from experimental murine models but has not been fully examined in human infants in the context of a natural pathogen.

While the CD8 response continues to mature postnatally, GD T cells develop earlier in gestation and exhibit many innate-like qualities that could enable them to act as important antiviral effectors in utero. Remarkably, GD T cells that express CMV-reactive GD TCRs and pre-programmed effector functions are already present in the fetal thymus at mid-gestation. These fetal GD T cells can be rapidly activated to produce IFNG and granzymes upon stimulation. Hence, we hypothesize that fetal GD T cells play an important role in mediating anti-CMV effector functions in utero, while the adaptive AB T cell response matures.

In the first two aims, we will compare GD and CD8 T cell responses in congenitally CMV-infected newborns to those of children who acquire primary CMV infection during the second year of life, in order to identify critical pathways of immune maturation. CD8 and GD T cells will be assessed by high-parameter cytometry, functional assays, and paired transcriptional and TCRSEQ profiling of individual cells in order to identify differences in the response to CMV based on the developmental window during which infection occurred.

In Aim 3, we will relate these immunologic parameters to clinical sequelae and the resolution of viremia during infancy in order to identify immune correlates of viral containment. Understanding how variability in the infant immune response to CMV relates to clinical and virologic outcomes, and how age-related differences in this immune response enable the gradual resolution of viremia postnatally, could lend great insight into antiviral T cell function in early life.

San Francisco Regents Of The University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

Immune Development in Early Life (IDEaL) (U01 Clinical Trial Not Allowed) (RFA-AI-20-077)

Amendment Since initial award the total obligations have increased 294% from $797,946 to $3,141,235.