Microbial manipulation of eukaryotic membranes

The National Institute of General Medical Sciences awarded Massachusetts Institute of Technology $438,788 in project grant funding on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support research on microbial manipulation of eukaryotic membranes.

The research examines how bacteria including Listeria monocytogenes and Rickettsia parkeri manipulate host cell membranes to disseminate through tissues and cross cellular compartments. The study focuses on micron-scale membrane trafficking and interactions, including how Listeria mobilizes the host actin cytoskeleton for intracellular motility and cell-to-cell spread via double-membrane protrusions, and how Rickettsia forms stable contacts with the endoplasmic reticulum and invades the nuclear envelope. The work aims to identify cellular factors required for cargo transportation across double-membrane barriers and clarify organelle uptake and interorganelle contact mechanisms that remain poorly understood due to lack of suitable experimental models.

Performance takes place in Cambridge, Massachusetts. The period of performance runs from July 1, 2026, through June 30, 2031. This is a Project Grant, an assistance type supporting investigator-initiated biomedical research that NIGMS uses to fund meritorious discoveries advancing understanding of human health and disease.

Abstract

The cellular membranes delineating eukaryotic cells and subcellular compartments serve varied and dynamic functions. These membranes permit selective cargo transport, enable communication of biochemical and mechanical signals, and provide platforms for key interactions. Much of our focus has been on nanometer-scale membrane cargo or interactions, but these membranes also control larger-scale functions. Indeed, membranes can support organelle uptake into neighboring cells or subcellular compartments, and they drive close interorganelle contacts to synergize unique functions. Despite their importance, some of these processes have received far less attention due to a lack of suitable models to dissect the molecular mechanisms. This proposal seeks to elucidate the regulatory mechanisms that control micron-scale membrane trafficking and interactions by studying how they are manipulated when under microbial control. The bacterium listeria monocytogenes disseminates through human tissues using cell-to-cell spread, a vesicular-mediated form of intercellular exchange that mimics host trans-endocytosis. Listeria spreads from cell to cell by mobilizing the host's actin cytoskeleton for intracellular motility and transport to the cell-cell junction. Once at the junction, IT pushes against the membrane and forms a double-membrane protrusion that is engulfed by a neighboring cell. We also found that the bacterium rickettsia parkeri uses a similar process to cross the nuclear envelope and invade human nuclei. Not all rickettsia are motile, though, and some can form extensive, stable contacts with the endoplasmic reticulum by mimicking contacts formed by mitochondria. Studying these distinctive transport and interaction processes will allow US to examine several outstanding cell biological questions. First, which cellular factors are needed to promote micron-scale cargo transportation across double-membrane barriers? Second, how and why does the ER stably wrap directly around microbes in the cytosol? To answer these questions, this program will combine molecular studies, advanced imaging, and hypothesis-generating screens to identify the core pathways that drive micron-scale membrane functions. Ultimately, our proposed studies will improve our fundamental understanding of basic cell biology and may uncover how these processes are altered in human disease.