Abstract
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. Clostridium perfringens type A is a Gram-positive bacterium that causes gas gangrene characterized by severe myonecrosis. It was previously demonstrated that C. perfringens θ-toxin is a TLR4 agonist, but the role of TLR4 in C. perfringens infection is unclear. Here, TLR4-defective C3H/HeJ mice infected with C. perfringens 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 C. perfringens. Remarkable increases in levels of inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF), were observed in C. perfringens-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 C. perfringens-infected C3H/HeN mice compared with non-infected mice, while the increase was lower in C. perfringens-infected C3H/HeJ mice. Furthermore, DNA microarray analysis revealed that the mutation in TLR4 partially affects host gene expression during C. perfringens infection. Together, our results illustrate that TLR4 is crucial for the innate ability to eliminate C. perfringens.
Highlights
Clostridium perfringens type A is a spore-forming Gram-positive anaerobic bacterium that causes gas gangrene in both humans and animals (Songer, 1996; Petit et al, 1999)
C3H/HeJ mice carry a missense mutation in the third exon of the Toll-like receptor 4 (TLR4) gene causing their hyporesponsiveness to LPS, and they have been widely used to examine the role of TLR4 signaling against bacterial infections (Poltorak et al, 1998)
Our results indicate that TLR4 signaling plays an important role in the regulation of granulocyte colonystimulating factor (G-CSF)-mediating granulopoiesis during C. perfringens infection, and this mechanism probably contributes to the replenishment of neutrophils and the elimination of bacteria (Figure 3C)
Summary
Clostridium perfringens type A is a spore-forming Gram-positive anaerobic bacterium that causes gas gangrene in both humans and animals (Songer, 1996; Petit et al, 1999). The disease is a lifethreatening necrotizing soft tissue infection that leads to myonecrosis, shock, multiple organ failure, and death of patients (Bryant, 2003; Titball, 2005). We previously reported that a-toxin inhibits neutrophil production by interfering with differentiation in the bone marrow, leading to the impairment of innate host immunity (Takehara et al, 2016a; Takehara et al, 2016b). These results indicate that a-toxin is involved in avoiding host immune clearance. Q-toxin enhances intravascular cell aggregation, leading to vascular occlusion (Bryant et al, 1993; Hickey et al, 2008). The infection process and virulence factors have become increasingly clear, but our understanding remains limited regarding the host immune exclusion mechanism after C. perfringens infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
