Cytokines produced by susceptible and resistant mice in the course of Paracoccidioides brasiliensis infection

Abstract

Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-alpha and TGF-beta) and type-1 (IL-2 and IFN-gamma) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected i.p. with P. brasiliensis produced early and sustained levels of IFN-gamma and IL-2; type-2 cytokines (IL-4 and IL-5) started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-gamma concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-beta and low levels of TNF-alpha. In contrast, macrophages from A/Sn animals released high levels of TNF-alpha associated with a small production of TGF-beta. The in vivo depletion of IFN-gamma not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-alpha and IFN-gamma followed by a sustained secretion of IL-2 and IFN-gamma plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-alpha and IFN-gamma associated with production of IL-5, IL-10 and TGF-beta characterizes the progressive disease of susceptible animals.

The low efficiency of dendritic cells and macrophages from mice susceptible to Paracoccidioides brasiliensis in inducing a Th1 response

“…In contrast, the secretion of low levels of IFN-g associated with the production of Th2 cytokines characterizes the progressive disease of susceptible animals (10).…”

“…On the other hand, susceptible mice (B10.A) activate Th2 with low levels of IFN-g and early secretion of high levels of IL-5 and IL-10, thus leading to progressive disease (10,11).…”

Pulmonary immune responses induced in BALB/c mice by Paracoccidioides brasiliensis conidia

“…It has also been shown that TNF-a is one of the cytokines produced during the first week of the experimental PCM infection [61]. Besides, in other studies, it has been shown that this pro-inflammatory cytokine plays a crucial role in resistance to P. brasiliensis yeast cells infection [52,62]. In vitro, other pro-inflammatory cytokines such as GM-CSF and IL-1b have also been shown capable of inducing fungicidal/fungistatic activity in both human and murine PMNs directed against P. brasiliensis yeast cells [63][64][65].…”

Capture enzyme-linked immunosorbent assay to detect specific immunoglobulin E in sera of patients with paracoccidioidomycosis.

“…[4][5][6] Experimental evidence strongly suggests that in humans, PCM resistance and susceptibility may be associated with a Th1 and Th2 pattern of cytokines, respectively. 7,8 Considering that the isotypes of the immunoglobulins are determined by the patterns of cytokines present in microenvironment where B cells are being activated, the detection of particular isotypes may be considered as indicators of the corresponding pattern of inductive cytokines. [9][10][11] The excellent correlation between IL-4 and help for IgE suggests that IgE production can be used as a good marker for the existence of a strong Th2-like response.…”