Role of TLR2 and TLR4 on human neutrophil functions against Paracoccidioides brasiliensis

Abstract

Paracoccidioides brasiliensis (Pb) is the aetiological agent of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. The infection can be acquired by inhalation of airborne conidia that reach the lung alveoli, where they transform into yeast cells, the infective form [1]. Many people are exposed to the fungus, but only a small number develop clinical symptoms, suggesting that both innate and adaptive mechanisms are important in fungus clearance [2–5]. The host innate immune response against fungus has been well characterized, and several studies have clearly shown the role of phagocytic cells. In this context, in last years, various studies have focused on the role of neutrophils [6]. Some in vitro studies suggest that Pb-infected macrophages induce the onset of extravascular neutrophilia by releasing chemotactic peptides [7]. Heavy neutrophil infiltration in the lungs of Pb-infected mice at early acute infection was correlated with the release of keratinocytederived chemokine (KC) and macrophage inflammatory protein-1a (MIP-1a), two important neutrophil chemoattractants [8]. In consequence of these chemotactic processes, massive neutrophil infiltration is found in infected tissues from patients with paracoccidioidomycosis [9] and in the early lesions of experimentally infected animals [10, 11]. Neutrophils from infected individuals can kill Pb [12]. However, experiments using more sensitive methods showed that despite their phagocytic capacity, these neutrophils are unable to digest Pb in vitro, indicating that a defect of neutrophil function may represent a susceptibility factor [13]. Further, studies in mice strongly suggest that lack of fungicidal activity correlates with defect in neutrophil activation because only those neutrophils from P. brasiliensis-sensitized mice exhibited efficient fungicidal *Department of Microbiology and Immunology, Biosciences Institute, Sao Paulo State University, Botucatu, S.P., Brazil; and Botucatu Blood Center, School of Medicine, Sao Paulo State University, Botucatu, S.P., Brazil