Patrick is a proud alumnus of Pitzer College. He received his Ph.D. from the University of Washington and the Fred Hutchinson Cancer Research Center under the mentorship of Dr. Harmit Malik and Dr. Michael Emerman studying the evolution of host-virus interactions. Patrick completed his postdoctoral training with Russell Vance at the University of California, Berkeley, where he studied pathogen (both viral and bacterial) detection by a class of host innate immune sensors called inflammasomes.
Research in the Mitchell lab is focused on understanding basic principles that govern host-pathogen interactions that influence host immunity and pathogenesis. We are particularly interested in molecular innovations born from host-pathogen evolutionary ‘arms races.’ We combine approaches from evolution, genetics, biochemistry, immunology and microbiology to decipher mechanisms that govern innate immune recognition and other host-pathogen interactions.
Some major focus areas of the Mitchell Lab are described briefly below:
Inflammasome-forming sensors of pathogen-specific activities:
We have great interest in the emerging concept that host cells can detect pathogens not only via the recognition of pathogen-associated molecular patterns (PAMPs) but also through the detection of pathogen-specific activities. One particular focus is the NLRP1 inflammasome. We recently determined that NLRP1 detects and responds to pathogens by sensing the activities of diverse pathogen-encoded enzymes (e.g., proteases and ubiquitin ligases). Building upon this discovery, we have multiple projects studying the mechanistic basis of how the activities of human pathogenic viruses and bacteria are sensed by NLRP1 and other inflammasome-forming sensors, and in turn, how pathogens evade host recognition.
Inflammasomes in epithelial cells as molecular barriers to pathogen invasion:
In intestinal epithelial cells inflammasomes mediate defense via coordinating cell death, pro-inflammatory cytokines and the expulsion of infected cells, which is essential for limiting tissue invasion and the maintenance of barrier integrity. This protection is robust. For example, the human pathogen Shigella fails to invade the intestinal epithelium and thus does not cause shigellosis (dysentery) in mice. However, mice that specifically lack the NAIP–NLRC4 inflammasome in intestinal epithelial cells are highly susceptible to Shigella. We are currently utilizing NAIP–NLRC4-deficient mice (the first mouse model of shigellosis!) to study Shigella replication and pathogenesis. We are also interested in exploiting this model to understand the pronounced susceptibility of humans (whom encode a functional NAIP–NLRC4 inflammasome) to Shigella. More generally, the lab is also studying how inflammasomes in the gut and other epithelial barriers provide defense against a variety of pathogens.
Recent Publications from PubMed
- Tsu BV, Beierschmitt C, Ryan AP, Agarwal R, Mitchell PS, Daugherty MDeLife. 2021 01; 10 :
- Mitchell PS, Roncaioli JL, Turcotte EA, Goers L, Chavez RA, Lee AY, Lesser CF, Rauch I, Vance REeLife. 2020 10; 9 :
- Daskalov A, Mitchell PS, Sandstrom A, Vance RE, Glass NLProceedings of the National Academy of Sciences of the United States of America. 2020 08; 117 31: 18600-18607
- Herlin T, Jørgensen SE, Høst C, Mitchell PS, Christensen MH, Laustsen M, Larsen DA, Schmidt FI, Christiansen M, Mogensen THRheumatology (Oxford, England). 2020 09; 59 9: 2334-2339
- Mitchell PS, Sandstrom A, Vance RECurrent opinion in immunology. 2019 10; 60 : 37-45