Cell-autonomous immunity, the ability of a host cell to eliminate an invasive infectious agent, is a first line of host defence against microbial pathogens (Lopez-Jimenez and Mostowy, Nat Commun 2021). Recent studies of host-pathogen interactions have shown that components of the host cell cytoskeleton are important for cell-autonomous immunity, yet the structural processes and proteins involved are only beginning to emerge. We discovered that host cells can prevent the actin-based motility of Shigella (a Gram-negative enteroinvasive bacterial pathogen) by compartmentalizing bacteria targeted to autophagy inside ‘septin cages’, a novel mechanism of host defence that restricts bacterial dissemination (Van Ngo and Mostowy, J Cell Sci 2019; Robertin and Mostowy, Cell Microbiol 2020). We showed that septins, poorly characterized cytoskeleton components are recruited with autophagy proteins to cytosolic bacteria and counteract actin tail formation. A comprehensive understanding of autophagy-cytoskeleton interactions will have important consequences for the understanding of both bacterial pathophysiology and its control, as well as normal cell physiology. We recently pioneered a ‘bottom up’ cellular microbiology approach to study cell-autonomous immunity and discovered a fundamental link between bacterial cell biology and the assembly of septin cages around Shigella (Lobato-Marquez et al, Nat Commun 2021). This has been a transformative approach to studying cell-autonomous immunity and represents a milestone in the development of septin-mediated therapies.
Shigella causes ~160 million illness episodes per year. To explore the innate immune response to Shigella, several infection models have been useful, helping to discover key roles for NOD-like receptors (NLRs), neutrophil extracellular traps (NETs), bacterial autophagy, guanylate binding proteins (GBPs) and inflammasomes in host defence. However, mammalian models remain poorly suited to image the cell biology of Shigella infection in vivo. By contrast, the natural translucency of zebrafish (Danio rerio) larvae enables non-invasive in vivo imaging of individual cells and microbe-leukocyte interactions at high resolution throughout the organism (Gomes and Mostowy, Trends Microbiol 2020). Remarkably, the major pathogenic events that lead to shigellosis in humans (macrophage cell death, invasion and multiplication within epithelial cells, cell-to-cell spread, inflammatory destruction of the host epithelium) are faithfully reproduced in our zebrafish model of Shigella infection. We can exploit these results to examine the biogenesis, architecture, coordination and resolution of the innate immune response to Shigella spatio-temporally in vivo. Significantly, we were first to use zebrafish infection to explore the evolution and pathogenesis of Shigella species in vivo (Torraca et al, PLOS Pathog 2019; Torraca et al, Trends Microbiol 2020). We have also innovated new zebrafish infection models to visualise bacterial cell biology in vivo (Mickiewicz et al, Nat Commun 2019), investigate Toxoplasma – leukocyte interactions in vivo (Yoshida et al, Dis Model Mech 2019; Yakimovich et al, mSphere 2020), study interbacterial competition mediated by the Type 7 Secretion System (T7SS) (Ulhuq et al, PNAS 2020) and interrogate mycobacterial infection in vivo using confocal Raman spectroscopic imaging (Høgset et al, Nat Commun 2020).
