I have long-standing interests in understanding the innate immune responses that are critical in controlling various inflammatory, infectious and metabolic diseases and cancer. Host cells are equipped with pattern recognition receptors which are germ-lined encoded innate immune sensors that detect pathogen associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs). Some of these receptors assemble multiprotein complex called inflammasome which is critical for the processing of IL-1β and IL-18. Some receptors are important for production of type I interferons. The signaling pathways activated by these receptors lead to production of anti-microbial molecules. Beside production of cytokines, the activation of these receptors leads to programmed cell death. We use cutting-edge technology to study the mechanisms by which host sensors recognize pathogens, and how these sensors shape the overall immune response and maintain homeostasis.


Research Interests:


1) Host defense against infectious disease:

Inflammasome activation and cell death are very important for clearing pathogens such as bacteria, fungi and viruses. These innate immune sensors exhibit remarkable pathogen-selectivity. For example, AIM2 responds only to a small subset of pathogens, such as the bacterium Francisella, the virus mouse cytomegalovirus, and herpes simplex virus and the fungus Aspergillus fumigatus. We found that concerted activation of AIM2 and NLRP3 inflammasomes provides host defense against Aspergillus infection (Karki et al; Cell Host Microbe, 2015). Interferon inducible GTPase, including the guanylate-binding proteins (GBPs) and immunity-related GTPases (IRGs), can contribute to inflammasome responses. IRGB10 licenses AIM2 and NLRP3 inflammasome activation in response to E. coli, Citrobacter and Francisella (Man and Karki et al; Cell 2016). Interferon regulatory factor 8 (IRF8) regulates NAIP/NLRC4 inflammasome activation to provide host defense against Salmonella infection (Karki and Lee et al; Cell, 2018). Since these pathogens are emerging and re-emerging, it is critical to uncover how host cells recognize and respond to intracellular pathogens and danger signals.


2) Cytokine storm and pathogenesis:

Dysregulated inflammasome activation and cell death lead to overproduction of inflammatory cytokines, which in turn act on bystander cells to induce robust inflammatory cell death called PANoptosis, which leads to pathogenesis in various diseses (Karki et al, Trends in Immunology, 2021, 2023). Several pro-inflammatory cytokines are produced during infectious and inflammatory diseases. Particularly, synergism of TNF and IFN-γ drives PANoptosis to induce cytokine storm in COVID-19 (Karki et al; Cell, 2021). Moreover, ZBP1 mediated PANoptosis interferes the efficacy of IFN therapy in treatment of COVID-19 (Karki et al; Science Immunology, 2022). Since cytokine storm is involved in various disease settings such as infectious diseases, immunotherapies and so on, it is critical to unravel the molecular mechanisms of cytokine storm and subsequent pathogenesis of the diseases.


3) Cell death, metabolic diseases and cancer:

Inflammation drives various metabolic diseases and cancer (Karki et al, Nature Reviews Cancer, 2019). The cytosolic sensor NLRC3 regulates mTOR activity to control proliferation and inflammation, providing the resistance against the progression of colorectal cancer (Karki et al; Nature, 2016). In addition, cancer cells develop resistance against apoptosis induced by chemotherapeutics. However, inducing other cell death or engaging multiple cell death pathways can be an option in the treatment of cancer (Karki et al; Cell Reports, 2021). Therefore, identifying the molecules which suppresses inflammation or identifying the drugs that induces PANoptosis is critical for treatment of cancer.