Biophysical Society Thematic Meeting | Ascona 2026

Mechanobiology of Infection

Monday Speaker Abstracts

BREAKING AND ENTERING: HOW RICKETTSIA FORCES ITS WAY ACROSS CELLULAR BARRIERS Hannah Margolis; Rebecca Lamason Massachusetts Institute of Technology, Cambridge, MA, USA Eukaryotic membranes form formidable barriers that compartmentalize cellular processes, yet some pathogens have evolved mechanisms to breach them and access highly protected intracellular spaces. Here, we investigate the obligate intracellular pathogen Rickettsia parkeri, which undergoes a complex and dynamic intracellular lifecycle unlike that of many human pathogens. A particularly striking feature of this lifecycle is its unusually frequent invasion of human nuclei. Using live-cell and fixed-cell microscopy, we found that R. parkeri harnesses actin-based motility to drive into the nuclear envelope and generate extensive protrusions that support both nuclear entry and exit without causing overt damage to the host cell. To identify factors that mediate this process, we applied a proteomic labeling approach and discovered novel secreted effectors, including one that specifically localizes to sites of nuclear invasion and egress. Loss of this effector reduced successful nuclear invasion while increasing caspase activation and subsequent host cell death. Together, these findings reveal an unexpected capacity of R. parkeri to forcibly access intracellular spaces typically considered inaccessible and underscore the need to understand how this remarkable adaptation evolved.

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