Principal Investigator: Adrian Gombart, Ph.D.
Our research is focused on understanding the importance of the regulation of antimicrobial peptide expression by the vitamin D pathway. When immune cells called macrophages encounter a pathogen and become activated, the vitamin D pathway is turned on, leading to the induction of the cathelicidin antimicrobial peptide if serum levels of vitamin D are sufficient. We have shown that this mechanism is conserved in humans and primates but not in other mammals. Therefore, we developed a transgenic mouse that carries the human cathelicidin gene, which is properly expressed and responds to vitamin D. Using this model, we are testing the ability of vitamin D to protect against infection by influenza, Salmonella and Mycobacterium tuberculosis—the pathogen that causes tuberculosis. Vitamin D has been used to treat tuberculosis, and its deficiency is associated with increased risk of tuberculosis. This model will allow us to test the role of vitamin D and cathelicidin during initial infection, latency, and reactivation.
Another focus of our research is to identify additional nutritional compounds and small molecules that regulate the expression of the cathelicidin gene. In addition to vitamin D, the cathelicidin gene is induced by sodium butyrate and lithocholic acid. Lithocholic acid functions through the vitamin D receptor. Nutrients that bind the vitamin D receptor may modulate the immune system by inducing the cathelicidin gene. We discovered that curcumin, a compound found in curry, modestly induces expression of the cathelicidin gene. This could enhance protection of the gut from infection in those individuals that consume curry on a regular basis. In collaboration with colleagues at Cedars-Sinai Medical Center in Los Angeles, we discovered that vitamin B3 (niacin) boosts killing of methicillin-resistant Staphylococcus aureus (MRSA) by white blood cells, in part, by increasing cathelicidin levels. A small molecule library is being screened for regulators of the cathelicidin gene. The identification of new regulatory compounds may give clues as to how the gene is regulated in vivo and lead to the identification of other nutrients that can be used to boost the immune system.
Finally, we are interested in determining the impact that vitamin D insufficiency or deficiency has on the function of the innate immune system in the elderly, who are often vitamin D deficient. Aging is accompanied by a low-grade, chronic, systemic up-regulation of inflammation, and vitamin D has important anti-inflammatory properties. We hypothesize that this excess inflammation may be due, in part, to vitamin D deficiency. We are interested in determining if restoration of sufficient levels of vitamin D will reduce the inflammatory phenotype. We also want to determine if reversing severe deficiency will raise cathelicidin protein levels in the blood. Our research has shown that high levels of the cathelicidin protein in the blood of kidney dialysis patients and sepsis patients may be protective against poor outcomes from infection or sepsis. Both of these conditions predominantly afflict the elderly.
