Thomas C. Mitchell, Ph.D.

 

Research
‘QUIET PRIMING’ BY NEXT GENERATION VACCINE ADJUVANTS

Dr. Mitchell is dedicated to discovering how the immune system can be safely stimulated to fight disease.  His work is most relevant to development of vaccine adjuvants, which are used in modern vaccines to boost their effectiveness without causing harm or unnecessary discomfort.

Modern immunology is guided by the paradigm that innate immunity against microbes is necessary for adaptive immunity to be generated in individuals for long term protection against re-infection. Dr. Mitchell’s research to advance safe  immunostimulation is based on the idea that partial signaling through receptors of the innate immune system can achieve sufficient priming of the adaptive immune response so as to be protective while minimizing counterproductive effector responses by innate immune cells such as neutrophils and macrophages. TLR4-MD2, the innate receptor for bacterial LPS, is currently a focus of research for the Mitchell lab because it is targeted by a clinically successful vaccine adjuvant, monophosphoryl lipid A (MPL).

TLR4 participates in recognition of microbial structures, as well substances generated by ‘damaged self’. As such it is a pattern recognition receptor for both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR4 is also the only member of the Toll-like receptor family to signal via i) the endocytic TRIF pathway, and ii) the plasma membrane MyD88 pathway. Studies with mice rendered genetically deficient for either signaling adapter and various agonists of TLR4-MD2 have shown a trend toward a separation of functions of the two signaling pathways. With TLR4, TRIF-dependent signaling outcomes (also called MyD88-independent outcomes) are more necessary for adaptive immune priming, particularly of short-term CD4+ T cells and thus ‘help’ for B cells to generate improved antibody responses against an antigen. MyD88-dependent outcomes are linked more often to pro-inflammatory effects, such as production of the powerful cytokines IL-1β and IL-6.

Dr. Mitchell and members of his research group study the mechanisms by which TLR4-MD2 can be shifted to favor TRIF-dependent signaling outcomes necessary for adequate immune responses to occur. Work on this topic includes study of the vaccine adjuvant MPL and structurally similar compounds from naturally occurring sources as well as those that are manufactured synthetically.


Selected Publications

  1. Mitchell, TC and Casella, CR. No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines. Current Opinion in Immunology 2017, 47:17–25.
  2. SenGupta S, Hittle LE, Ernst RK, Uriarte SM and Mitchell TC. A Pseudomonas aeruginosa hepta-acylated lipid A variant associated with cystic fibrosis selectively activates human neutrophils.J Leukoc Biol. 2016 Nov;100(5):1047-1059. 
  3. Kolb JP, Casella CR, SenGupta, S, Chilton PM and Mitchell TC. Type I interferon signaling contributes to the bias that Toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF. Sci Signal. 2014 Nov 11;7(351):ra108
  4. Chilton PM, Hadel DM, To TT, Mitchell TC and Darveau RP. Adjuvant activity of naturally occurring monophosphoryl lipopolysaccharide preparations from mucosa-associated bacteria. Infect Immun. 2013 Sep;81(9):3317-25.
  5. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, and Mitchell TC.The Vaccine Adjuvant Monophosphoryl Lipid A as a Trif-biased Agonist of TLR4. Science, 2007; 316(5831):1628-1632. Perspective on this paper published in Science, 2007; 316(5831):1574-1576.