Absence of TLR2 influences survival of neutrophils after infection withCandida albicans

Abstract

Candida albicans is an opportunistic pathogen, which causes local and/or disseminated diseases in immunosuppressed humans. Phagocytic cells play a critical role in the immune response against C. albicans. Toll like receptors (TLR) are important in the identification of invading microorganisms and in the regulation of neutrophil survival. TLR2 has been shown to participate in the response against pathogenic yeasts and to increase the functional life span of neutrophils. In view of these observations, we studied the involvement of TLR2 in neutrophil function after C. albicans infection. The absence of TLR2 resulted in lower chemotaxis of neutrophils to the site of infection. This in turn was associated with lower levels of chemokines from neutrophils, facilitating the dissemination of the pathogen to the lymph nodes and spleen. A high frequency of apoptotic neutrophils and macrophages in the inflammatory exudates from TLR2(-/-) mice was found. In addition, the phagocytic activity of neutrophils and macrophages, nitric oxide production and myeloperoxidase activity were diminished in cells from TLR2(-/-) mice. Together, these data demonstrate the importance of TLR2 signals for neutrophils activation and survival after C. albicans infection.

The Role of TLR2 in Infection and Immunity

“…Studies with TLR2 knockout mice showed both resistance (Netea et al, 2004b) or susceptibility to primary or secondary systemic C. albicans infection (Gil et al, 2005; Hise et al, 2009), while TLR2 knockout macrophages showed impaired fungal clearance (Blasi et al, 2005), with both impairment or enhancement of pro-inflammatory cytokine production (especially TNF-α; Blasi et al, 2005; Gil and Gozalbo, 2006). The absence of TLR2 also decreased chemotaxis rate of murine neutrophils, together with decreased fungal killing mechanisms and survival of these cells (Tessarolli et al, 2009). TLR2 is probably not directly involved with humoral response after secondary C. albicans systemic infection, since this parameter was not altered in TLR2 knockout mice (Villamón et al, 2004).…”

Fungal pathogens—a sweet and sour treat for toll-like receptors

“…Notably, the lack of TLR2 impairs the early recruitment as well as killing capacity of neutrophils against A. fumigatus (Meier et al, 2003; Bellocchio et al, 2004a). Similarly, fewer neutrophil/monocytes are recruited in TLR2 −/− mice in comparison to wild-type animals at day 1 after post-peritoneal infection with live C. albicans (Tessarolli et al, 2010). Interestingly, upon intraperitoneal challenge with heat-killed C. albicans , TLR2 defficiency has no effect on early (4 h) phagocyte recruitment, but results in an enhanced macrophage recruitment in mutant versus control mice at day 3 after infection (Netea et al, 2004).…”

“…Additionally, the use of live versus heat-killed Candida cells may affect both kinetics and nature of recruited phagocytes. Phagocytes emerging at day 1 of post-peritoneal infection with live Candida exhibit impaired nitric-oxide release, myeloperoxidase activity, chemokine, and cytokine production, as well as neutrophil survival in the absence of TLR2 (Tessarolli et al, 2010). Thyoglycolate-elicited TLR2 −/− neutrophils and macrophages show reduced phagocytic activity toward C. albicans than their wild-type counterparts (Tessarolli et al, 2010).…”

“…Phagocytes emerging at day 1 of post-peritoneal infection with live Candida exhibit impaired nitric-oxide release, myeloperoxidase activity, chemokine, and cytokine production, as well as neutrophil survival in the absence of TLR2 (Tessarolli et al, 2010). Thyoglycolate-elicited TLR2 −/− neutrophils and macrophages show reduced phagocytic activity toward C. albicans than their wild-type counterparts (Tessarolli et al, 2010). Notably, no significant effects of TLR2 on phagocytosis by similar cells has also been reported (Netea et al, 2004), perhaps due to distinct experimental conditions used in the phagocyte preparations.…”

“…Upon intravenous Candida infection, absence of Tregs results in improved fungal clearance 7 days after infection and better survival of TLR2 −/− mice when compared to wild-type mice (Bellocchio et al, 2004a; Netea et al, 2004). By contrast, in an intraperitoneal model of candidiasis, clearance is impaired 1 day afterinfection in the absence of TLR2 (Tessarolli et al, 2010). TLR2-deficient mice infected with P. jirovecii display intenser severity in symptoms, as well as increased fungal burden and decreased TNFα and nitric oxide release in the lungs (Wang et al, 2008).…”