Following PhD training in medical microbiology and animal models of infectious diseases at the University of Wisconsin, and post-doctoral training in immunology at the Tulane University International Center for Medical Research in Cali, Colombia, I began my academic research career at the Texas A&M University College of Medicine in 1976. One major research focus has been the impact of vaccination and nutritional status on immune responses and infectious disease resistance in a highly relevant guinea pig model of low-dose pulmonary tuberculosis (TB). Protein-deprived guinea pigs exhibit many of the metabolic and clinical hallmarks of kwashiorkor in humans. In many papers published over the past 35 years, with continual funding from NIH, we have dissected the detrimental impact of diet on mechanisms of vaccine-induced resistance of guinea pigs to pulmonary TB.
In order to study macrophage-lymphocyte interactions, including cytokine cross-talk, in the guinea pig model of TB, we have sub-cloned and expressed several guinea pig cytokine and chemokine genes, and studied the immunological response to vaccination and virulent mycobacterial infection in various leukocyte populations ex vivo, and directly in pulmonary granulomas in situ. In addition, the development of both prokaryotic and eukaryotic expression systems have allowed us to produce sufficient quantities of recombinant protein to alter cellular functions in vivo and in vitro, and to raise neutralizing antibodies to block cytokine function in cell cultures and in the whole animal. These reagents are being used to assess the role of specific chemokines and cytokines in vaccine-induced immunity to pulmonary tuberculosis.
In addition to our NIH R01 grant-funded research program, we obtained several years of support under an NIH subcontract to Colorado State University to test more than 100 candidate TB vaccines for protective efficacy in guinea pigs against low-dose, pulmonary infection. In a second NIH sub-contract to Johns Hopkins University, we tested many putative virulence mutants of M tuberculosis to determine their phenotype in guinea pigs infected by the respiratory route.
A second major research focus has been a 20-year collaboration with Dr. Robb Chapkin on an NIH-and USDA-funded program to examine the mechanisms by which n-3 poly-unsaturated fatty acids (PUFA) suppress T cell activation and pro-inflammatory immune function in several mouse models. We have utilized various gene knock-out (e.g., IL-10 -/- ; PPARδ-/-), transgenic (e.g., D011.10; fat-1), and reporter (IL-17, IFNγ) mouse strains to delineate the functions of specific immune and metabolic mediators of the n-3 PUFA effects. We have applied mouse models of inflammatory bowel disease (IBD) to link basic immunological changes induced by n-3 PUFA to the pathogenesis of gut inflammation.
My extramural grants and contracts, principally from NIH, brought in more than $10 million in the past 35 years. One NIH R01 grant was funded continuously for 27 years. We have published more than 210 papers in peer-reviewed journals, and I have trained nearly 50 graduate students and post-doctoral fellows.