Resistance to Paracoccidioides brasiliensis Infection Is Linked to a Preferential Th1 Immune Response, Whereas Susceptibility Is Associated with Absence of IFN-gamma Production

Abstract

The secretion of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-5, and IL-10 by antigen-stimulated lymph node cells, eosinophil maturation, and the antibody isotypes produced were examined during intraperitoneal infection of susceptible (B10.A) and resistant (A/Sn) mice with Paracoccidioides brasiliensis. Lymph node cells from resistant mice produced early and sustained levels of IFN-gamma and IL-2, whereas susceptible animals secreted low to undetectable amounts of these type 1 cytokines. Both mouse strains presented late and transient production of IL-4, whereas IL-10 was produced constantly throughout the course of disease. Resistant animals produced increasing levels of IL-5 in the chronic phase of the infection (from the eighth week on), whereas susceptible mice showed two peaks of IL-5 production, at the first and twelfth weeks after infection. Only the susceptible strain presented medullary and splenic eosinophilia concomitant with the raised IL-5 production. In resistant mice, the levels of IgG2a antibodies were significantly higher than those observed in susceptible mice, which preferentially secreted IgG2b and IgA isotypes. Taken together, these results demonstrate that a sustained production of IFN-gamma and IL-2 and a predominant secretion of IgG2a antibodies are associated with resistance to P. brasiliensis. In contrast, the production of low levels of IFN-gamma, early secretion of high levels of IL-5 and IL-10, eosinophilia, and a preferential secretion of IgG2b and IgA isotypes characterize the progressive disease in susceptible animals.

Alveolar macrophages from susceptible mice are more competent than those of resistant mice to control initialParacoccidioides brasiliensisinfection

“…When described, it was demonstrated that during the first weeks of infection, the lung of susceptible mice presented lower fungal loads than that of resistant animals [6]. This pattern was lately reverted when A/J mice develop positive DTH reactions, their lymph node cells secrete IL-2 and IFN-␥, and pulmonary macrophages acquire fungicidal ability [6,8,9]. In susceptible mice, the early control of fungal growth was, however, followed by anergy in DTH reaction, unrestrained increase of yeasts multiplication in the lungs and further dissemination to liver and spleen.…”

“…brasiliensis Pb18, a highly virulent isolate [19], was used throughout this investigation. To ensure the maintenance of its virulence, the isolate was used after three animal passages [8]. Pb18 yeast cells were then maintained by weekly subcultivation in semisolid Fava Netto's culture medium [20] at 35°C and used on day 7 after culture.…”

“…On the contrary, A/J mice presented a regressive disease with well-organized lesions containing a low number of yeasts, positive cellular immunity, and macrophage activation, resembling the benign forms of PCM [6]. Studies on pulmonary cytokines demonstrated that both mouse strains are able to secrete proinflammatory and anti-inflammatory cytokines, but higher levels of IFN-␥, IL-5, and IL-10 were present in the lungs of susceptible mice [7,8]. Using gene knockout or cytokine-depleted mice, protective immunity to Pb infection was shown to be mediated by IFN-␥, IL-12, and TNF-␣ [9 -12], all macrophage-activating cytokines.…”

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

“…Resistance to P. brasiliensis infection is linked preferentially to a Th1 immune response, whereas susceptibility is associated with absence of IFN-gamma production [130]. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4, and in the pulmonary infection, IL-4, IL-5 and IL-10 were preferentially detected in lung cells' washings of susceptible animals [62].…”

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

“…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).…”