{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:35:23Z","timestamp":1785418523954,"version":"3.56.0"},"reference-count":97,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH 5R01AI090142"],"award-info":[{"award-number":["NIH 5R01AI090142"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["NIH 5R01AI090142"],"award-info":[{"award-number":["NIH 5R01AI090142"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>C. burnetii (Cb) is an obligate intracellular bacterial pathogen that replicates within alveolar macrophages following aerosol infection. Unlike most intracellular bacteria, Cb establishes a lysosome-derived replicative niche (Coxiella-containing vacuole or CCV) through the action of its Type IVB secretion system (T4BSS). This system translocates a large repertoire of effector proteins into the host cytoplasm after phagosome acidification. These effectors interfere with diverse signaling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, promoting pathogen survival without triggering robust proinflammatory signaling or host cell death pathways. This effector-triggered immune silencing is particularly unique given the central role of macrophages as innate immune sentinels. In this review, we examine Cb T4BSS effectors that have been characterized as central determinants of innate immunity modulation. We discuss innate immune sensing pathways potentially engaged during infection, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors, inflammasomes, and interferon signaling pathways, and highlight evidence indicating that these pathways are actively suppressed. Emphasis is placed on effector-mediated regulation of NF-\u03baB signaling, type I interferon responses, and inflammasome activation. Finally, we address unresolved questions related to effector-triggered immunity, redundancy in immune suppression, and discrepancies between in vitro and in vivo infection models.<\/jats:p>","DOI":"10.3390\/pathogens15040444","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T12:01:22Z","timestamp":1776686482000},"page":"444","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Subverting Host Defense from Within: Innate Immune Modulation by Coxiella burnetii"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0782-063X","authenticated-orcid":false,"given":"Anna O.","family":"Busbee","sequence":"first","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryashree","family":"Arunima","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3896-8581","authenticated-orcid":false,"given":"James E.","family":"Samuel","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin J.","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e02484-21","DOI":"10.1128\/spectrum.02484-21","article-title":"Primary Murine Macrophages as a Tool for Virulence Factor Discovery in Coxiella burnetii","volume":"10","author":"Mahapatra","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/imr.12223","article-title":"Macrophage heterogeneity in tissues: Phenotypic diversity and functions","volume":"262","author":"Gordon","year":"2014","journal-title":"Immunol. 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