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Here, we developed a zebrafish model to dissect the innate immune response to<jats:italic>Legionella pneumophila<\/jats:italic>during infection. We show that<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>cause zebrafish larvae death in a dose dependent manner. Additionally, we show that macrophages are the first line of defence and cooperate with neutrophils to clear the infection. Immunocompromised humans have an increased propensity to develop pneumonia, similarly, when either macrophages or neutrophils are depleted, these \u201cimmunocompromised\u201d larvae become lethally sensitive to<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>. Also, as observed in human infections, the adaptor signalling molecule Myd88 is not required to control disease in the larvae. Furthermore, proinflammatory cytokine genes<jats:italic>il1\u03b2<\/jats:italic>and<jats:italic>tnf-\u03b1<\/jats:italic>were upregulated during infection, recapitulating key immune responses seen in human infection. Strikingly, we uncovered a previously undescribed infection phenotype in zebrafish larvae, whereby bloodborne, wild type<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>invade and grow in the larval yolk region, a phenotype not observed with a type IV secretion system deficient mutant that cannot translocate effectors into its host cell. Thus, zebrafish larva represents an innovative<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>infection model that mimics important aspects of the human immune response to<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>infection and will allow the elucidation of mechanisms by which type IV secretion effectors allow<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>to cross host cell membranes and obtain nutrients from nutrient rich environments.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011375","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T18:33:15Z","timestamp":1683570795000},"page":"e1011375","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hiding in the yolk: A unique feature of Legionella pneumophila infection of zebrafish"],"prefix":"10.1371","volume":"19","author":[{"given":"Fl\u00e1via","family":"Viana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Boucontet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Laghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Schator","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Ibranosyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Jarraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Colucci-Guyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-9190","authenticated-orcid":true,"given":"Carmen","family":"Buchrieser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"issue":"2","key":"ppat.1011375.ref001","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/BF00185888","article-title":"Ecology 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Boamah","year":"2017","journal-title":"Frontiers in cellular and infection microbiology"},{"issue":"4","key":"ppat.1011375.ref005","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1128\/AEM.72.4.2885-2895.2006","article-title":"Planktonic replication is essential for biofilm formation by Legionella pneumophila in a complex medium under static and dynamic flow conditions","volume":"72","author":"J Mampel","year":"2006","journal-title":"Appl Environ Microbiol"},{"issue":"22","key":"ppat.1011375.ref006","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1056\/NEJM197712012972202","article-title":"Legionnaires\u2019 disease: isolation of a bacterium and demonstration of its role in other respiratory disease","volume":"297","author":"JE McDade","year":"1977","journal-title":"N Engl J Med"},{"issue":"1","key":"ppat.1011375.ref007","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.idc.2016.10.014","article-title":"Legionnaire\u2019s Disease in Compromised 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