Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.
Early life and education
Kagan was born and raised in Farmingville on Long Island, New York, USA. He attended Sachem High School, where he was a standout wrestler. Kagan attended Bucknell University, where he wrestled for a nationally ranked Division I wrestling program and performed research in the laboratory of Dr. David Pearson. He received his Bachelor of Science degree from Bucknell and earned his Ph.D. in Microbial Pathogenesis from Yale University under Dr. Craig Roy. He then performed postdoctoral training with Ruslan Medzhitov at the Yale University School of Medicine.
Research
Kagan runs a research lab at Harvard Medical School and Boston Children's Hospital. His lab's primary interest is to understand the molecular and cellular basis of inflammation and protective immunity. He has researched inflammatory pathways stimulated by Toll-like Receptors, cGAS-STING, RIG-I like Receptors and inflammasomes. Kagan's studies have led to a map of the subcellular sites of innate immune signal transduction, which describes the initial triggers of infection-induced immunity.
Studies of bacterial pathogenesis
During his Ph.D. studies with Craig Roy, a protégé of Lasker Awardee Stanley Falkow, Kagan studied how virulent bacteria multiply within macrophages. Through his studies of Legionella pneumophila, the cause of a potentially lethal pneumonia, he discovered that Legionella uses a Type IV secretion system to intercept vesicular traffic from endoplasmic reticulum (ER) exit sites. He identified the GTPases ARF1 and Rab1 as the host factors that mediate ER association with Legionella phagosomes and that these proteins are required for bacterial intracellular replication. Subsequent to this work, several additional pathogens were found to manipulate similar membrane trafficking pathways to establish a replicative niche. Kagan's research focus shifted during his postdoctoral studies to questions of how immune cells detect infection, which was an area pioneered by Charles Janeway Jr and Ruslan Medzhitov.
Mapping the subcellular sites of innate immune signal transduction
Kagan is recognized for pioneering the cell biological analysis of innate immunity, which revealed a map of the subcellular sites of innate immune signal transduction. His work identified subdomains of the plasma membrane that permit Toll-like Receptor 4 (TLR4) signaling and identified endosomes as a key site from which TLR4 signaling occurs. These discoveries led to the identification of a novel means by which TLR4 is transported between the cell surface and endosomes via CD14 and MD-2, and in the process revealed endocytosis as a TLR4-independent cellular response to bacterial lipopolysaccharides (LPS). Subsequent studies by Vishva Dixit and Edward Miao demonstrated additional TLR4-independent cellular responses to LPS. Kagan's work with the fruit fly Drosophila melanogaster provided the first in vivo evidence for the importance of protein localization for the antibacterial functions of the Toll pathway.
Kagan's lab identified peroxisomes and confirmed mitochondria as organelles that initiate signaling by the RIG-I like Receptors (RLRs). These organelles were found to induce distinct classes of interferon (IFN) genes, with Type III IFNs being selectively induced from peroxisomes and Type I IFNs from mitochondria. Kagan's studies of the cGAS-STING pathway revealed mutant cGAS proteins that signal from within mitochondria to induce Type I IFNs, and the role of mitochondrial reactive oxygen species in potentiating inflammasome-mediated pyroptosis through oxidation of the pore forming protein gasdermin D.
Kagan's work with Dr. Randi Rotjan explored the limits of innate immune pattern recognition. They discovered that human and mouse cells were unable to detect bacteria from ecosystems that are not inhabited by mammals. Specifically, the LPS receptors CD14, MD-2, TLR4, caspase-4 and caspase-11 were unable to detect LPS from >80% of bacteria harvested from the deep central Pacific Ocean. These findings established that LPS receptors preferentially detect bacteria from sympatric habitats—suggesting that innate immunity is defined locally, not globally.