Yale and Cambridge scientists discover new immune pathway for detecting infection

Monday, June 22, 2020

Dr. John MacMicking, an HHMI investigator in the Yale Systems Biology Institute and Associate Professor of Immunobiology and Microbial Pathogenesis at Yale School of Medicine, has discovered a new way in which human cells recognize bacterial infections caused by food-borne pathogens such as Salmonella and Shigella.

Working with colleagues from the MRC Laboratory of Molecular Biology (LMB) in Cambridge, U.K., his team found a family of human immune defense proteins, called guanylate binding proteins (GBPs), assembled directly on the surface of these bacteria as part of an immune “coat” to liberate microbial cell-wall components called lipopolysaccharide (LPS). A new nanomachine built for antimicrobial defense

LPS is then recognized by another human protein called caspase-4 to trigger an immune cascade that alerts the host to the presence of Gram-negative bacteria and helps remove infected cells.

The work, published June 15 in Nature Immunology, opens up new paradigm for understanding how we sense and respond to bacterial infection.

Earlier Nobel-prize winning efforts discovered innate immune proteins called Toll-like receptors detect LPS at the host cell surface, however, the GBP sensory system instead operates in the host cytosol. It also elicits a different set of signaling outputs than the one recognized by the Nobel committee in 2011.

How the new GBP “coatomer” assembles at a structural level and whether it can be manipulated to help treat infections and Gram-negative sepsis are both major questions going forward, said Dr. MacMicking.

Septic shock is one of the most common causes of death in developed countries and is associated with a high rate of mortality, despite advances in critical care medicine.

Contact: jon.atherton@yale.edu