Rickettsia pathogenesis and host response: new approaches for investigating tick-borne pathogens:

Tick-borne Rickettsia cause serious human disease in the United States and worldwide, including spotted fever. These bacteria obligately reside in the host cell cytosol where they parasitize over 50 nutrients from the host. We hypothesize that this obligate lifestyle has led Rickettsia to evolve distinctive strategies to manipulate innate immunity.

We use bacterial and host genetic approaches paired with super-resolution microscopy to decipher how virulence genes enable Rickettsia to avoid inflammasomes, ubiquitylation, and interferon-stimulated genes. We also use a variety of mouse models to determine how Rickettsia evade innate immunity in vivo. We recently discovered a mouse model that recapitulates key manifestations of human disease. This facilitates our ability to ask new questions about Rickettsia pathogenesis in vivo, including studies on improved therapeutics and vaccines.

Mouse vs human innate immunity: revealing the molecular basis of arthropod-borne disease:

Many arthropod-borne viral and bacterial pathogens cause severe disease in humans, yet no disease in certain animals. This includes SARS-CoV2 (which causes COVID-19), Dengue virus, Rickettsia, and many other mosquito- and tick-borne pathogens. Rickettsia infection in mice is a valuable model system to study this phenomenon, as Rickettsia use rodents for their propagation and horizontal transmission in the wild. We are pursuing the hypothesis that animals including mice evolved inhibitory innate immune responses that have been lost in humans. Uncovering human susceptibility versus mouse resistance phenomena will lead us to improved animal models, improved therapeutic strategies, and an understanding of the animals that serve as reservoirs for arthropod-borne pathogens in nature.

Targeting innate immunity for cancer immunotherapy:

Bacterial pathogens preferentially target and reside in tumors, making them engineerable drug delivery vehicles. We are investigating molecular mechanisms by which microbial cancer therapies elicit anti-tumor responses, and engineering bacteria for cancer immunotherapy.

As pathogens are detected by multiple innate immune receptors, we are investigating how combinations of small molecules can mimic bacteria to elicit synergistic anti-tumor responses. This work has uncovered a potent strategy to unleash innate immunity against cancer in mouse tumors with combinations of small molecules (see Figure). In collaboration with Dr. Vy Dong at UCI, we are synthesizing novel anti-cancer drugs that target multiple arms of innate immunity.