{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T12:12:07Z","timestamp":1774959127159,"version":"3.50.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Toll-like receptor 4 (TLR4) has been reported to protect against Gram-negative bacteria by acting as a pathogen recognition receptor that senses mainly lipopolysaccharide (LPS) from Gram-negative bacteria. However, the role of TLR4 in Gram-positive bacterial infection is less well understood. <jats:italic>Clostridium perfringens<\/jats:italic> type A is a Gram-positive bacterium that causes gas gangrene characterized by severe myonecrosis. It was previously demonstrated that <jats:italic>C. perfringens<\/jats:italic> \u03b8-toxin is a TLR4 agonist, but the role of TLR4 in <jats:italic>C. perfringens<\/jats:italic> infection is unclear. Here, TLR4-defective C3H\/HeJ mice infected with <jats:italic>C. perfringens<\/jats:italic> showed a remarkable decrease in survival rate, an increase in viable bacterial counts, and accelerated destruction of myofibrils at the infection site compared with wild-type C3H\/HeN mice. These results demonstrate that TLR4 plays an important role in the elimination of <jats:italic>C. perfringens<\/jats:italic>. Remarkable increases in levels of inflammatory cytokines, such as interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), and granulocyte colony-stimulating\u00a0factor\u00a0(G-CSF), were observed in <jats:italic>C. perfringens<\/jats:italic>-infected C3H\/HeN mice, whereas the increases were limited in C3H\/HeJ mice. Generally, increased G-CSF accelerates granulopoiesis in the bone marrow and the spleen to exacerbate neutrophil production, resulting in elimination of bacteria. The number of neutrophils in the spleen was increased in <jats:italic>C. perfringens<\/jats:italic>-infected C3H\/HeN mice compared with non-infected mice, while the increase was lower in <jats:italic>C. perfringens<\/jats:italic>-infected C3H\/HeJ mice. Furthermore, DNA microarray analysis revealed that the mutation in TLR4 partially affects host gene expression during <jats:italic>C. perfringens<\/jats:italic> infection. Together, our results illustrate that TLR4 is crucial for the innate ability to eliminate <jats:italic>C. perfringens<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fcimb.2021.633440","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T06:02:30Z","timestamp":1615183350000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Toll-Like Receptor 4 Protects Against Clostridium perfringens Infection in Mice"],"prefix":"10.3389","volume":"11","author":[{"given":"Masaya","family":"Takehara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Nagahama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1146\/annurev-immunol-020711-074942","article-title":"Neutrophil function: from mechanisms to disease","volume":"30","author":"Amulic","year":"2012","journal-title":"Annu. 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