Research: Robert Modlin Laboratory at UCLA
Infectious disease poses a major health problem worldwide. Essential to control of these diseases is the elucidation of mechanisms by which the innate and adaptive immune systems defend against microbial pathogens. We have investigated human immune responses in the context of two major human infectious diseases, leprosy and tuberculosis.
Our studies provided new paradigms for human innate immune responses including the first evidence that toll-like receptors recognize microbial lipoproteins and can activate macrophages to kill intracellular pathogens. Our work revealed that:
- Humans and mice have evolved distinct antimicrobial pathways in their innate immune systems
- We demonstrated a novel vitamin D-dependent pathway in human macrophages that generates antimicrobial peptides, for example, cathelicidin, that kill intracellular pathogens, including M. tuberculosis.
- We have shown that macrophage antimicrobial and phagocytic programs are differentially programmed by the innate system via IL-15 and IL-10 respectively, which impact the outcome of microbial infection.
Our lab has also described new paradigms for human-acquired immunity by demonstrating:
- Distinct Th1 and Th2 cytokine patterns in disease lesions of different clinical forms of human leprosy
- Similar utilization of the common vitamin D-dependent and antimicrobial peptide pathway
- Differential regulation of this activity by different cytokines
Since vitamin D is synthesized in response to UV light, these studies have provided novel insights into the known differential susceptibility to microbial pathogens of humans of African and Asian descent and suggested new approaches to translational intervention to enhance immunity.
These discoveries were made through study of human leprosy and tuberculosis, ancient diseases caused by intracellular pathogens that still pose major health and economic burdens to developing countries.