Genetics and Infectious Disease: Richard Bucala
Rick Bucala, MD, PhD, is Professor of Medicine, Pathology, and Epidemiology and Public Health. His research focuses on the role of immunity in the host-pathogen interaction and the clinical expression of different infectious diseases. Both experimental and genetic epidemiology studies are underway with a central interest in the innate cytokine, MIF (macrophage migration inhibitory factor), which is expressed in different allelic forms among different populations around the world.
Investigations by the Bucala group encompass the biochemical, biological, and genetic characterization of MIF, and remain focused on understanding MIF's role in physiology and pathology. They have uncovered a unique action for MIF in sustaining MAP kinase activation, a pathway that impacts on the proliferation and survival of many cell types. Studies support an important role for MIF in inhibiting p53-dependent growth arrest, which is an action that maintains the pro-inflammatory phenotype of monocytes/macrophages. Functionally important polymorphisms in the promoter for human MIF have been found to be associated with the severity of inflammatory and immunologic diseases such as rheumatoid arthritis, asthma, and SLE, and to play a role in the inflammatory pathogenesis of prostate cancer.
Studies of MIF's role in severe malaria, leishmaniasis, and tuberculosis also are underway. Malarial anemia is the proximate cause of death in almost half of the approximately 1 million deaths that occur annually from this disease. Bone marrow progenitor cells become resistant to the action of erythropoietin during malaria infection, and the lab has uncovered a molecular pathway by which MIF interferes with erythropoietin signal transduction. Clinical studies at the Macha Mission Hospital in Zambia are examining the frequency of different MIF genetic polymorphisms in an effort to understand why severe malaria develops in some children but not in others.
Dr. Bucala also has developed low-cost, biosensor chips that enable the genetic analyses DNA samples in rural field settings. Further research is being conducted in Colombia and Sudan (leishmaniasis), and in South Africa, Ghana, and Uganda (tuberculosis).
Thuma PE, van Dijk J, Bucala R, Debebe Z, Nekhai S, Kuddo T, Nouraie GW and Gordeuk VR. 2011. Distinct Clinical and Immunologic Profiles in Severe Malarial Anemia and Cerebral Malaria in Zambia. J Inf Dis. 203:211-219.
Awandare GA, Martinson JJ, Were T, Ouma C, Davenport GC, Ong'echa JM, Wang W, Leng L, Ferrell RE, Bucala R, Perkins DJ. 2009. MIF Promoter Polymorphisms and Susceptibility to Severe Malarial Anemia. J Infect Dis. 15: 629-637.
Yende S, Angus DC, Kong L, Kellum JA, Weissfeld L, Ferrell R, Finegold D, Carter M, Leng L, Peng ZY, Bucala R. 2009. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. FASEB J. 23, 2403-2411.
Griffith JW, Sun T, McIntosh MT, Bucala R. 2009. Pure Hemozoin Is Inflammatory In Vivo and Activates the NALP3 Inflammasome via Release of Uric Acid. J Immunol 183, 5208-5220.
Bucala R, Donnelly SC. 2007. Macrophage Migration Inhibitory Factor: A Probable Link between Inflammation and Cancer. Immunity 26, 281-285.
Arjona A, Foellmer HG, Town T, Leng L, McDonald C, Wang T, Wong SJ, Montgomery RR, Fikrig E, Bucala R. 2007. Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 117, 3059-3066.
McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R. 2006. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med. 203: 1185-1196.
Zhong XB, Leng L, Beitin A, Chen R, McDonald C, Hsiao B, Jenison RD, Kang I, Park SH, Lee A, Gregersen P, Thuma P, Bray-Ward P, Ward DC, Bucala R. 2005. Simultaneous detection of microsatellite repeats and SNPs in the macrophage migration inhibitory factor (MIF) gene by thin-film biosensor chips and application to rural field studies. Nucleic Acids Res. 33, 121-129.
McDevitt MA, Xie J, Gordeuk V, Bucala R. 2004. The anemia of malaria infection: role of inflammatory cytokines. Curr Hematol Rep. 3:97-106.