Roles of Cytosolic Nucleic Acid Sensors in Cancer and Infection

<p>Pattern recognition receptors are innate immune sensors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) with crucial roles in host defense against microbial infection, autoimmune diseases and cancer. Cytosolic nucleic acids including DNA and RNA originate from pathogens or self-cells, which form major groups of PAMPs and DAMPs. A range of nucleic acid sensors have evolved to sense various types of nucleic acids. How different DNA-sensing pathways regulate microbial infection and cancer is the focus of this dissertation.</p> <p>Stimulator of IFN genes (STING) is a cytosolic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. A physiological role for STING in cancer was previously unknown. We showed that STING-deficient mice were highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibited significant intestinal damage and overt proliferation with increased levels of pro-inflammatory cytokines during early stages of tumorigenesis, uncovering an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.</p> <p>Absent in melanoma 2 (AIM2) forms an inflammasome with ASC and caspase-1 upon recognition of double-stranded DNA (dsDNA) in the cytosol leading to caspase-1 activation and caspase-1-dependent pyroptosis and release of cytokines IL-1 and IL-18. Mutations in AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. We found that AIM2-deficient mice were hypersusceptible to colonic tumor development. While production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in AIM2-deficient mice, intestinal stem cells lacking AIM2 were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2 driving the tumor development in AIM2-deficient mice. In addition to its role in cancer, AIM2 recognizes bacteria including <em>Francisella tularensis </em>subspecies <em>novicida </em>(<em>F. novicida</em>) and induces inflammasome responses. Type I interferon (IFN) signaling drives activation of AIM2 inflammasome in <em>F. novicida</em>-infected macrophages; however, the relative contribution of IFNs and inflammasome responses in host defense against <em>F. novicida </em>infection is less understood. We found intact AIM2 inflammasome responses in mice lacking type I IFN signaling during infection with <em>F. novicida</em>. Lack of type I IFN signaling conferred protection to <em>F. novicida </em>infection in contrast to the increased susceptibility in AIM2-deficient mice. Interestingly, mice lacking both AIM2 and IFNAR2 were protected against the infection indicating a dominant role for type I IFNs in mediating detrimental responses despite the protective AIM2 inflammasome responses. Gasdermin D (GSDMD) is activated by caspase-1 to generate pores on the plasma membrane to induce pyroptosis downstream of the AIM2 inflammasome. We also demonstrated that mice lacking GSDMD were highly susceptible to <em>F. novicida </em>infection. Interestingly, GSDMD is required for optimal caspase-1 activation during <em>F. novicida </em>infection, providing protection to the host during the infection.</p> <p>In addition, we identified differential mechanisms regulating expression of inflammasome-associated cytokines IL-1β and IL-18. IL-1β is only induced in response to inflammatory stimuli and its expression is not sustained during chronic treatment, while IL-18 is constitutively expressed and further induced after the stimulation in a type I IFN signaling-dependent manner.</p> <p>Overall, this dissertation addresses protective roles for cytosolic nucleic acid-sensing molecules, STING and AIM2, in colon cancer, uncovers an interplay between the AIM2 inflammasome and type IFN signaling during <em>F. novicida </em>infection, and demonstrates a novel function for GSDMD in regulating AIM2 inflammasome. The dissertation finally describes distinctive mechanisms governing inflammasome-associated cytokines IL-1β and IL-18.</p> <h5> </h5>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2018

Author dc:creator

• Zhu, Qifan

Contributors dc:contributor

• Thirumala-Devi Kanneganti, Ph.D.

• Cancer
• Immunology
• Infection
• Inflammasome
• Innate immunity
• Pattern recognition receptors
• Biological Phenomena, Cell Phenomena, and Immunity
• Medical Cell Biology
• Medical Immunology
• Medical Sciences
• Medicine and Health Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/477

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1469