Heterogeneity of bacterial host-pathogen interactions across biological scales

Recent advances in single-cell technologies have revealed the dynamic and heterogeneous nature of host-pathogen interactions at the single-cell level. This review explores how cellular variability-both within clonal bacterial populations and among genetically identical host cells-gives rise to distinct infection outcomes, from pathogen clearance to persistence across multiple biological scales, from single cells to tissues and the whole organism. We highlight the conceptual and technological progress that has enabled the dissection of these interactions at single-cell resolution, including microscopy, single-cell transcriptomics, proteomics, and emerging dual RNA-seq and spatial approaches. Drawing on examples from well-characterized bacterial pathogens like Listeria monocytogenes, Salmonella enterica, and Mycobacterium tuberculosis, we discuss how stochastic gene expression, intrinsic and extrinsic factors, as well as tissue context shape the variable activation of the immune responses and ultimately determine the outcomes of host-pathogen interactions. We argue that the outcome of single-cell interactions is shaped by a combination of host states, bacterial-intrinsic features, and the local microenvironment. We further discuss how computational and mathematical modeling can integrate these heterogeneous single-cell events across spatial scales, linking intracellular variability with tissue-level pathogenesis and progression of infection. Gaining insight into and controlling these layers of variability holds promise for the development of more precise, context-dependent antimicrobial strategies.