A. Phillip West, PhD
Education and Post-Graduate Training
Yale School of Medicine, 2011-2015
Postdoctoral Fellowship, Pathology
Yale University, 2004-2011
North Carolina State University, 1997-2001
Bachelor of Science, Biological Sciences
Bachelor of Science, Science Education
- Mitochondrial regulation of innate immunity
- Mitochondrial stress responses in cancer
Mitochondria are complex and dynamic organelles integral to many processes including energy generation, programmed cell death, signal transduction, and immunity. Research in my laboratory centers on understanding how mitochondria regulate innate immunity and inflammatory processes to influence human health and disease.
Mitochondrial Signaling in the Innate Immune System
The mammalian innate immune system constitutes the first line of defense against pathogens, triggering inflammation, promoting the expression of antimicrobial products, and properly licensing the adaptive immune response. Mounting evidence suggests that mitochondria are critical participants in innate immunity. Mitochondria serve as antiviral signaling hubs and facilitate antibacterial immunity by generating reactive oxygen species (see West et al. Nature 2011), but can also activate inflammatory cascades following cell and tissue damage (see West et al. Nat. Rev. Immunol. 2011). The intersection of mitochondria and immunity constitutes a research area of increasing significance with broad-ranging implications for infectious diseases, autoimmune and inflammatory disorders, and cancer.
We have recently uncovered a novel pathway by which mitochondria trigger cytosolic innate immune signaling to enhance antiviral immunity (see West et al. Nature 2015). Mechanistically, we found that mitochondrial DNA (mtDNA) stress engages the cGAS-STING axis to augment type I interferon responses and antiviral gene expression, thereby boosting viral resistance. We are currently exploring the signaling pathways linking mitochondrial stress to innate immunity, and we aim to characterize how these pathways modulate host responses to pathogens and influence the pathobiology of mitochondrial disorders and inflammatory diseases.
Mitochondrial Stress Signaling in Cancer
Alterations in mitochondrial function and cellular metabolism have long been recognized as hallmarks of cancer. However, more recent studies suggest that metabolic reprogramming is just one mechanism by which mitochondria influence cancer. For example, mitochondrial genome instability and copy number alterations have been observed many aggressive cancers including melanoma, and recent reports indicate that mitochondrial DNA (mtDNA) dysfunction can engage stress signaling responses to enhance tumor growth and invasion. We are currently utilizing a physiologically relevant model of metastatic melanoma and patient-derived melanoma cell lines to explore how mtDNA instability and mitochondrial stress influence the development and progression of this cancer. We are actively investigating how mitochondrial stress alters pro-growth signaling in melanoma cells and are characterizing how mtDNA instability augments the invasive properties of melanoma cells. In addition, we are examining how mitochondrial genome instability modulates innate and adaptive immunity in the melanoma microenvironment to shape anti-tumor immune responses.
- Kerur N, Fukuda S, Banerjee D, Kim Y, Fu D, Apicella I, Varshney A, Yasuma R, Fowler BJ, Baghdasaryan E, Marion KM, Huang X, Yasuma T, Hirano Y, Serbulea V, Ambati M, Ambati VL, Kajiwara Y, Ambati K, Hirahara S, Bastos-Carvalho A, Ogura Y, Terasaki H, Oshika T, Kim KB, Hinton DR, Leitinger N, Cambier JC, Buxbaum JD, Kenney MC, Jazwinski SM, Nagai H, Hara I, West AP, Fitzgerald KA, Sadda SR, Gelfand BD, Ambati J. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med. 2017 Nov 27. doi: 10.1038/nm.4450. [Epub ahead of print] PubMed PMID: 29176737.
- West AP. Mitochondrial dysfunction as a trigger of innate immune responses and inflammation. Toxicology. 2017 Nov 1;391:54-63. doi: 10.1016/j.tox.2017.07.016. Epub 2017 Jul 29. Review. PubMed PMID: 28765055.
- West AP*, Shadel GS*. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 2017 Jun;17(6):363–375. doi:10.1038/nri.2017.21. PubMed PMID: 28393922. *, co-corresponding authors.
- West A.P., Khoury-Hanold W., Staron M., Tal M.C., Pineda C.M., Lang S.M., Bestwick M., Duguay B.A., Raimundo N., MacDuff D.A., Kaech S.M., Smiley J.R., Means R.E., Iwasaki A., Shadel G.S. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 2015, 520(7548): 553–557. PMCID: PMC4409480
- Rongvaux A., Jackson R., Harman C., Li T., West A.P., de Zoete M.R., Wu Y., Yordy B., Lakhani S.A., Kuan C-Y., Taniguchi T., Shadel G.S., Chen Z.J., Iwasaki A., Flavell R.A. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 2014, 159:1563-77. PMCID: PMC4272443.
- West A.P., Shadel G.S., Ghosh S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011, 11:389-402. PMCID: PMC4281487.
- West A.P., Brodsky I.E., Rahner C., Woo D.K., Erdjument-Bromage H., Tempst P., Walsh M.C., Choi, Y., Shadel G.S., and Ghosh S. TLR signaling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011, 472:476-480. PMCID: PMC3460538.
- Rao P., Hayden MS, Long M., Scott M.L., West A.P., Zhang D., Oeckinghaus A., Lynch C., Hoffmann A., Baltimore D., Ghosh S. IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. Nature 2010, 466:1115-9. PMCID: PMC2946371.
- Hayden MS, West A.P., Ghosh S. SnapShot: NF-kappaB signaling pathways. Cell 2006, 127:1289-7.
- West A.P., Koblansky A.A., Ghosh S. Recognition and signaling by Toll-like receptors. Annu. Rev. Cell Dev. Bio. 2006, 22:409-37.
- West A.P., Dancho B.A., Mizel S.B. Gangliosides inhibit flagellin signaling in the absence of an effect on flagellin binding to Toll-like receptor 5. J. Biol. Chem. 2005, 280:9482-8.