GSBS Dissertations and Theses
ORCID ID
0000-0001-8364-8088
Publication Date
2020-08-31
Document Type
Doctoral Dissertation
Academic Program
MD/PhD
Department
Microbiology and Physiological Systems
First Thesis Advisor
Christopher Sassetti
Keywords
interferon, IFNg, interferon-gamma, CRISPR, macrophage, tuberculosis, respiration, OXPHOS, complex I, Med16, Gsk3b, CRISPR screen
Abstract
The breadth of genetic diversity in the mammalian immune response stands out amongst the ubiquity of variation seen in the genome, evidence that microbial infections have been a major driver of evolution. As technology has facilitated an understanding of the etiology of immunological diversity, so too has it enabled the assessment of its varied functions. Functional genomics, with its ability to assess both cause and effect, has revolutionized our understanding of fundamental biological phenomena and recalibrated our hypotheses. We build upon the model of host immunity established by rare genetic variants that are causative of immunodeficiencies, but that incompletely consider the complexities of the genome. To expand our understanding, we performed a series of forward genetic screens to identify regulators of distinct functions of the innate immune system. Our studies discovered genes with novel functions in antigen presentation and immunoregulation, including several involved in central metabolism. Studies in macrophages and dendritic cells identified mitochondrial respiration as a positive regulator of the interferon-gamma response, and cells incapable of respiration failed to activate T cells. Notably, human mutations in several of these genes are responsible for immune dysfunction. In summary, this work uses new methods in genetic engineering to systematically assess the regulation of innate immunity. Our results suggest that variation in these regulatory pathways is likely to alter immunity in states of health and disease. Thus, our work validates a new approach to identify candidate genes relevant to immune dysfunction.
Repository Citation
Kiritsy MC. (2020). Functional Genomics of Mammalian Innate Immunity. GSBS Dissertations and Theses. https://doi.org/10.13028/1g8s-8p20. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/1102
DOI
10.13028/1g8s-8p20
Rights and Permissions
Copyright is held by the author, with all rights reserved.
Included in
Bacterial Infections and Mycoses Commons, Genomics Commons, Immune System Diseases Commons, Immunity Commons