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This review explores how cellular variability\u2014both within clonal bacterial populations and among genetically identical host cells\u2014gives 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\n                      <jats:italic toggle=\"yes\">Listeria monocytogenes<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Salmonella enterica,<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      , 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01804-25","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:01:06Z","timestamp":1774962066000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Heterogeneity of bacterial host-pathogen interactions across biological scales"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-9848","authenticated-orcid":false,"given":"Juan Alfonso","family":"Redondo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03fs4aq04","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Fundamental Technological Research, Polish Academy of Sciences","place":["Warsaw, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3780-2866","authenticated-orcid":false,"given":"Niharika","family":"Purkait","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03fs4aq04","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Fundamental Technological Research, Polish Academy of Sciences","place":["Warsaw, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0363-0716","authenticated-orcid":true,"given":"Pawel","family":"Paszek","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03fs4aq04","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Fundamental Technological Research, Polish Academy of Sciences","place":["Warsaw, Poland"]},{"id":[{"id":"https:\/\/ror.org\/027m9bs27","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Manchester, The Lydia Becker Institute of Immunology and Inflammation","place":["Manchester, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/027m9bs27","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.12.006"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-111523-102459"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01846-z"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1244705"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006734"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.10.021"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat7148"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1235675"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2024.02.009"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a117542"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.12.020"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001928"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.027"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.02.008"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00348"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002597"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1374293"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40560"},{"key":"e_1_3_3_20_2","first-page":"355","article-title":"AI-assisted microscopy for infection biology:advances in high-content imagingof host-pathogen interactions","volume":"32","author":"Redondo JA","year":"2025","unstructured":"RedondoJA, Paszek P. 2025. 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