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Host protein recruitment to pathogens is often refractory to accurate automated assessment due to its heterogeneous nature. An intuitive intelligent image analysis program to assess host protein recruitment within general cellular pathogen defense is lacking. We present HRMAn (Host Response to Microbe Analysis), an open-source image analysis platform based on machine learning algorithms and deep learning. We show that HRMAn has the capacity to learn phenotypes from the data, without relying on researcher-based assumptions. Using Toxoplasma gondii and Salmonella enterica Typhimurium we demonstrate HRMAn\u2019s capacity to recognize, classify and quantify pathogen killing, replication and cellular defense responses. HRMAn thus presents the only intelligent solution operating at human capacity suitable for both single image and high content image analysis.<\/jats:p>\n                  <jats:p>Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (&lt;xref ref-type=\"decision-letter\" rid=\"SA1\"&gt;see decision letter&lt;\/xref&gt;).<\/jats:p>","DOI":"10.7554\/elife.40560","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T19:00:22Z","timestamp":1549911622000},"source":"Crossref","is-referenced-by-count":87,"title":["Defining host\u2013pathogen interactions employing an artificial intelligence workflow"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-0367","authenticated-orcid":true,"given":"Daniel","family":"Fisch","sequence":"first","affiliation":[{"name":"Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-4904","authenticated-orcid":true,"given":"Artur","family":"Yakimovich","sequence":"additional","affiliation":[{"name":"MRC-Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3235-6170","authenticated-orcid":true,"given":"Barbara","family":"Clough","sequence":"additional","affiliation":[{"name":"Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Wright","sequence":"additional","affiliation":[{"name":"Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Bunyan","sequence":"additional","affiliation":[{"name":"Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Howell","sequence":"additional","affiliation":[{"name":"HTS, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-9541","authenticated-orcid":true,"given":"Jason","family":"Mercer","sequence":"additional","affiliation":[{"name":"MRC-Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-3442","authenticated-orcid":true,"given":"Eva","family":"Frickel","sequence":"additional","affiliation":[{"name":"Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2019,2,12]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1002\/cyto.a.22885","article-title":"Contribution of high-content imaging technologies to the development of anti-infective drugs","volume":"89","author":"Ang","year":"2016","journal-title":"Cytometry Part A"},{"key":"bib2","first-page":"319","volume-title":"Studies in Classification, Data Analysis, and Knowledge Organization","author":"Berthold","year":"2008"},{"key":"bib3","volume-title":"Pattern Recognition and Machine Learning","author":"Bishop","year":"2006"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.chom.2013.03.002","article-title":"Host cell subversion by toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression","volume":"13","author":"Bougdour","year":"2013","journal-title":"Cell Host & Microbe"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1084\/jem.20130103","article-title":"A toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation","volume":"210","author":"Braun","year":"2013","journal-title":"The Journal of Experimental Medicine"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.cbpa.2011.05.023","article-title":"High-content screening in infectious diseases","volume":"15","author":"Brodin","year":"2011","journal-title":"Current Opinion in Chemical Biology"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-10-r100","article-title":"CellProfiler: image analysis software for identifying and quantifying cell phenotypes","volume":"7","author":"Carpenter","year":"2006","journal-title":"Genome Biology"},{"key":"bib8","article-title":"Keras","author":"Chollet","year":"2015","unstructured":"Chollet F. 2015. 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