{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:15:11Z","timestamp":1790792111703,"version":"4.1.0"},"reference-count":108,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01 DE028536"],"award-info":[{"award-number":["R01 DE028536"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2025,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Periodontitis (PD) is a polymicrobial dysbiotic immuno-inflammatory disease. Toll-like receptors (TLRs) are present on gingival epithelial cells and recognize pathogen-associated molecular patterns on pathogenic bacteria, inducing the secretion of proinflammatory cytokines and initiating innate and adaptive antigen-specific immune responses to eradicate the invading microbes. Since PD is a chronic inflammatory disease, TLR2\/TLR4 play a vital role in disease pathogenesis and in maintaining the periodontium during health. Many factors modulate the TLR-mediated signaling pathway, including specific microRNAs (miRNAs). The present study was designed to characterize the function of TLR2\/4 signaling in the miRNA profile after polybacterial infection with\n                      <jats:italic toggle=\"yes\">Streptococcus gordonii, Fusobacterium nucleatum, Porphyromonas gingivalis, Treponema denticola,<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Tannerella forsythia<\/jats:italic>\n                      in C57BL6\/J wild-type, global knockout strains of TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      , and TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 16\/group) using RT-qPCR. The selection of 15 dominant miRNAs for RT-qPCR analysis was based on prior NanoString global miRNA expression profiling in response to polymicrobial and monobacterial infection. Polybacterial infections established gingival colonization in wild-type, TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      , and TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice with the induction of bacterial-specific IgG. A significant reduction in alveolar bone resorption and gingival inflammation was observed in the mandibles of TLR2\/4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice compared to C57BL6\/J wild-type mice (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.0001). Periodontal bacteria disseminated from gingival tissue to multiple organs in wild-type and TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice (heart, lungs, brain, and kidneys) and were limited to the heart (\n                      <jats:italic toggle=\"yes\">F. nucleatum<\/jats:italic>\n                      ), lungs (\n                      <jats:italic toggle=\"yes\">P. gingivalis<\/jats:italic>\n                      ), and kidneys (\n                      <jats:italic toggle=\"yes\">T. forsythia<\/jats:italic>\n                      ) in TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. The diagnostic potential of miRNAs was assessed by receiver operating characteristic curves. Among the 15 miRNAs, three were upregulated in C57BL6\/J wild-type mice, two in TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      , and seven in TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Notably, the anti-inflammatory miR-146a-5p was consistently upregulated in wild-type and TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice but not in TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Additionally, miR-15a-5p was upregulated in wild-type and TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. let-7c-5p was upregulated in TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice and downregulated in wild-type mice. The upregulated miRNAs (miR-146a, miR-15a-5p, and let-7c-5p) and downregulated miRNAs could be candidate biomarkers for oral bacteria and TLRs-mediated induction of periodontitis if they are confirmed in large-scale human studies. Multi-species oral bacterial infection alters the TLR2\/4 signaling pathways by modulating the expression of several potential biomarker miRNAs in the periodontium.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Periodontitis is the most prevalent chronic immuno-infectious multispecies dysbiotic disease of the oral cavity. The Toll-like receptors (TLRs) provide the first line of defense, one of the best-characterized pathogen detection systems, and play a vital role in recognizing multiple microbial products. Multispecies infection with periodontal bacteria\n                      <jats:italic toggle=\"yes\">Streptococcus gordonii<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Fusobacterium nucleatum<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Porphyromonas gingivalis<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Treponema denticola<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Tannerella forsythia<\/jats:italic>\n                      induced gingival inflammation, alveolar bone resorption (ABR), and microRNA (miRNA) expression in the C57BL6\/J wild-type mice, whereas infection did not significantly increase ABR in the TLR2\/4 deficient mice. Among the 15 miRNAs investigated, miR-146a-5p and miR-15a-5p were upregulated in wild-type and TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice, and miR-146a-5p, miR-30c-5p, and let-7c-5p were upregulated in the TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice compared to sham-infected controls. Notably, the inflammatory miRNA miR-146a-5p was uniquely upregulated among the wild-type and TLR2\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice but not in the TLR4\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. The upregulated miRNAs (miR-146a, miR-15-a-5p, let-7c-5p) and downregulated miRNAs could be candidate biomarkers for oral bacteria and TLRs-mediated induction of periodontitis if they are confirmed in large-scale human studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00160-25","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T13:02:01Z","timestamp":1755176521000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Altered microRNA expression correlates with reduced TLR2\/4-dependent periodontal inflammation and bone resorption induced by polymicrobial infection"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2769-8619","authenticated-orcid":false,"given":"Syam","family":"Jeepipalli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvathi","family":"Gurusamy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Rafaela Luz","family":"Martins","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Colella","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya R.","family":"Nadakuditi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Desaraju","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashitha","family":"Yada","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Onime","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Periodontology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"William","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oral Biology, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indraneel","family":"Bhattacharyya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida","place":["Gainesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward K. 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