Abstract
Dermatophytosis is a superficial fungal infection mostly restricted to keratinized tissues such as skin, hair, and nails but with potential to cause invasive or even systemic disease in immunocompromised patients. Trichophyton rubrum is the main etiologic agent, accounting for approximately 80% of the cases. Mononuclear phagocytes respond to pathogens through phagocytosis followed by production of several antimicrobial molecules, such as reactive oxygen and nitrogen species, and failure in doing so may contribute to development of chronic fungal infections. Toll-like receptors (TLRs) located on the surface of phagocytic cells bind either directly to target particles or through opsonizing ligands and trigger an actin-mediated ingestion. Even though the mechanisms involved in TLR-mediated cytokine responses are well established, the contribution of TLR in the recognition of T. rubrum by adherent monocytes remains unclear. Here, we report that phagocytosis of T. rubrum conidia by adherent monocytes is mediated by TLR2. Blockade of TLR2 by neutralizing antibodies impaired the fungicidal activity of monocytes as well their secretion of tumor necrosis factor (TNF)-α, but neither nitric oxide (NO) production nor interleukin (IL)-10 secretion was disturbed. So far, our data suggest that TLR2 is required for efficient conidial phagocytosis, and the absence of TLR2 signaling in human monocytes may impair the subsequent inflammatory response. These findings expand our understanding of phagocyte modulation by this important fungal pathogen and may represent a potential target for interventions aiming at enhancing antifungal immune responses.
Highlights
Dermatophytosis is a superficial fungal infection that is usually limited to the keratinized layer of the epidermis, hair, and nails, and whose main etiologic agent is Trichophyton rubrum, accounting for approximately 80% of the cases (Svejgaard and Nilsson, 2004; Romano et al, 2005; Godoy-Martinez et al, 2009; Lee et al, 2015)
We first investigated whether TLR2 can be involved in the phagocytosis of T. rubrum conidia by human monocytes by determining the phagocytosis index (PI) after 3 h of interaction between phagocytes and fungal particles
Consistent with this, the fungicidal activity of monocytes (852.8 ± 97.6) was impaired when this receptor was blocked (405.5 ± 68.9; Figure 2A). These results indicate that TLR2 may be involved in the uptake and killing of T. rubrum by monocytes
Summary
Dermatophytosis is a superficial fungal infection that is usually limited to the keratinized layer of the epidermis, hair, and nails, and whose main etiologic agent is Trichophyton rubrum, accounting for approximately 80% of the cases (Svejgaard and Nilsson, 2004; Romano et al, 2005; Godoy-Martinez et al, 2009; Lee et al, 2015). Yoshikawa et al (2016), for example, using a murine model of deep dermatophytosis, demonstrated that the absence of the CLRs Dectin-1 and Dectin-2 promoted an inefficient proinflammatory response against T. rubrum infection characterized by lower production of TNF-α and IL-1β by spleen cells, impairing disease resolution (Yoshikawa et al, 2016). Other in vitro systems demonstrated that whole T. rubrum conidia could diminish TLR2 expression in a keratinocyte cell line (Huang et al, 2015). It is still unknown if and how TLR2 participates in the immunity to T. rubrum, in the human context. We investigated the role of TLR2 in the interaction of human monocytes with T. rubrum by examining the capacity of TLR2 to recognize T. rubrum conidia and to develop an inflammatory response following the fungal challenge
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