{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T16:39:54Z","timestamp":1777567194707,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases","award":["R21 AI156536-01"],"award-info":[{"award-number":["R21 AI156536-01"]}]},{"name":"National Institute of Allergy and Infectious Diseases","award":["R01 AI132674"],"award-info":[{"award-number":["R01 AI132674"]}]},{"name":"National Institute of Allergy and Infectious Diseases","award":["T32 AI007526-20"],"award-info":[{"award-number":["T32 AI007526-20"]}]},{"name":"National Institute of Allergy and Infectious Diseases","award":["AI078878"],"award-info":[{"award-number":["AI078878"]}]},{"name":"UTMB Center for Biodefense and Emerging Infectious Diseases Pilot","award":["R21 AI156536-01"],"award-info":[{"award-number":["R21 AI156536-01"]}]},{"name":"UTMB Center for Biodefense and Emerging Infectious Diseases Pilot","award":["R01 AI132674"],"award-info":[{"award-number":["R01 AI132674"]}]},{"name":"UTMB Center for Biodefense and Emerging Infectious Diseases Pilot","award":["T32 AI007526-20"],"award-info":[{"award-number":["T32 AI007526-20"]}]},{"name":"UTMB Center for Biodefense and Emerging Infectious Diseases Pilot","award":["AI078878"],"award-info":[{"award-number":["AI078878"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Orientia tsutsugamushi is an obligately intracellular bacterium and an etiological agent of scrub typhus. Human studies and animal models of scrub typhus have shown robust type 1-skewed proinflammatory responses during severe infection. Macrophages (M\u03a6) play a critical role in initiating such responses, yet mechanisms of innate recognition for O. tsutsugamushi remain unclear. In this study, we investigated whether Syk-dependent C-type lectin receptors (CLRs) contribute to innate immune recognition and the generation of proinflammatory responses. To validate the role of CLRs in scrub typhus, we infected murine bone marrow-derived M\u03a6 with O. tsutsugamushi in the presence of selective Syk inhibitors and analyzed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that Mincle\/Clec4a and Clec5a transcription was significantly abrogated upon Syk inhibition at 6 h of infection. The effect of Syk inhibition on Mincle protein expression was validated via Western blot. Syk-inhibited M\u03a6 had diminished expression of type 1 cytokines\/chemokines (Il12p40, Tnf, Il27p28, Cxcl1) during infection. Additionally, expression of innate immune cytosolic sensors (Mx1 and Oas1-3) was highly induced in the brain of lethally infected mice. We established that Mx1 and Oas1 expression was reduced in Syk-inhibited M\u03a6, while Oas2, Oas3, and MerTK were not sensitive to Syk inhibition. This study reveals that Syk-dependent CLRs contribute to inflammatory responses against O. tsutsugamushi. It also provides the first evidence for Syk-dependent activation of intracellular defenses during infection, suggesting a role of pattern recognition receptor crosstalk in orchestrating macrophage-mediated responses to this poorly studied bacterium.<\/jats:p>","DOI":"10.3390\/pathogens12010053","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T02:56:50Z","timestamp":1672282610000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Orientia tsutsugamushi Infection Stimulates Syk-Dependent Responses and Innate Cytosolic Defenses in Macrophages"],"prefix":"10.3390","volume":"12","author":[{"given":"James","family":"Fisher","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"},{"name":"School of Medicine, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Chroust","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9557-1847","authenticated-orcid":false,"given":"Yuejin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3370-3434","authenticated-orcid":false,"given":"Lynn","family":"Soong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"},{"name":"Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xu, G., Walker, D.H., Jupiter, D., Melby, P.C., and Arcari, C.M. 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