Power struggle between Shigella bacterium and its human victims involves tails and cages
Considering the rise of antibiotic-resistant strains, the World Health Organization has listed Shigella as one of the most important bacterial pathogens for which the development of new antimicrobials is urgently required.
Human defence – entrap the intruder in a cage for wrapping in membranes
First in the line of the patient’s defence is a highly conserved process called autophagy. Breaking down unwanted material, autophagy recycles cellular ‘trash’ inside double-membrane vesicles known as autophagosomes. A few rounds of evolution have turned this process into a battle between the bacterium avoiding autophagy to survive and the sick patient dealing with the infection. To avoid autophagy, the bacterium hijacks the host cell actin cytoskeleton to form an ‘actin tail’. The now-mobile microbe can propel itself from cell-to-cell, increasing the scope of the infection. To counteract actin tail formation and its dire consequences, septins (a component of the host cell cytoskeleton) entrap the actin-polymerising Shigella in cage-like structures as a target for autophagy. “It is now recognised that septin cages are important for cell-autonomous immunity, yet the molecular determinants of cage assembly and its antimicrobial activity are mostly unknown,” Serge Mostowy, project coordinator and Professor of Cellular Microbiology at the London School of Hygiene & Tropical Medicine (LSHTM)(opens in new window) points out.
‘Cagey’ secrets unveiled
“In-depth investigation of the Shigella-septin cage can reveal new roles for the cytoskeleton in cell-autonomous immunity,” explains Damián Lobato Márquez, the Marie Skłodowska-Curie fellow. Key results discovered that septins recognise the membrane curvature and lipid composition of dividing bacterial cells for cage entrapment. Cardiolipin, a lipid, interacts with septins on the bacterial poles. “Using purified proteins and high-resolution microscopy techniques, we demonstrated that bacteria without cardiolipin are poorly recognised by the host cell septin cytoskeleton,” Lobato Márquez informs us. Using fluorescent reporters and time-lapse microscopy, Lobato Márquez observed the grim fate of the septin-caged Shigella: “Bacteria in cages fail to replicate because they are targeted for autophagy and degradation by lysosomes.”
Septin surprises for further investigation with scope for future therapies
Lobato Márquez continues with more details of the exciting revelations: “Depletion of septins from the host cell had a negative impact on bacterial replication, a surprise considering that septins are widely recognised for their antibacterial role during Shigella infection.” Metabolic measurements also revealed a new link between the cytoskeleton and host cell glycolysis. In vitro reconstitution assays the team used are a cell-free system to study bacterial and host cell factors that can restrict or promote septin cage entrapment. “These might be suitable for high-throughput testing to screen for pharma compounds that impact cage assembly,” Mostowy points out. As to his research future, Lobato Márquez is optimistic: “To achieve my goal of becoming group leader in the field of infection biology, the Marie Curie fellowship-funded INCAGE project has enabled me to train under Serge Mostowy in internationally recognised research institutes in microbiology expertise – the Medical Research Council (MRC) Center for Molecular Bacteriology and Infection (CMBI) at Imperial College London, and the London School of Hygiene & Tropical Medicine (LSHTM).” In recognition of the work of Marie Skłodowska-Curie, LSHTM and Lobato Márquez have made a promotional video(opens in new window).
