H.A. Eskandarian
Harvard Medical School,
United States
Keywords: LTTL-AFM, mycobacteria, mechanical adaptation, microbiology, host-pathogen interactions, persistence, infection, pathogenesis, virulence, antibiotic resistance, anti-infectives discovery
Summary:
It is critical to understand why bacterial pathogens phenotypically resist killing despite harboring genetic sensitivities to host immunity and cidal antibiotics. The fundamental principles and molecular mechanisms underlying phenotypic refraction to killing remain largely unknown. This is particularly problematic in the case of mycobacterial pathogens, which are the etiological agents of a wide variety of infectious diseases. We developed Long-Term Time-Lapse Atomic Force Microscopy (LTTL-AFM) as a discovery-based, hypothesis-generating technique. LTTL-AFM expands the breadth of phenotypes by which we understand how and why fundamentally microbes manifest and interact in a physical world. I will provide an overview of how we have used LTTL-AFM to discover biophysical and biomechanical properties driving fundamental cell processes, for which no molecular mechanisms are known. Thus, we are laying a new foundation for expanding microbiological study. Our findings have culminated in the discovery of previously unknown processes, such as cell mechanical adaptation in mycobacteria, which represents a critical virulence mechanism during host infection. Our studies provide new perspectives for how we may treat and prevent bacterial pathogenesis in humans.