Cellular and humoral immune responses during intrathoracic paracoccidioidomycosis in BALB/c mice (original) (raw)
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FEMS Immunology & Medical Microbiology, 2011
The important role of interferon-gamma (IFN-c) in protective immunity in mycosis is well established, except for its participation in fungal granulomas. Herein, we employ immunohistochemical reactions to describe the in situ localization of IFN-c in granulomas of susceptible (B10.A) and resistant (A/J) mice to infection with Paracoccidioides brasiliensis (Pb). After infection with the highly virulent Pb18, IFN-c-positive lymphomononuclear cells were localized mainly at the periphery of granulomas in both mouse strains. The numbers of positive cells found in compact granulomas of A/J mice increased significantly from 15 to 120 days postinfection. At this time, significantly more positive cells were detected in the compact granulomas of resistant mice than in the loose, multifocal lesions of the susceptible ones. In infection with the slightly virulent Pb265, the same pattern of IFN-c localization was found as in Pb18 infection, but there was decreased staining at 120 days due to the presence of only residual lesions in both mouse strains. The marked IFN-c staining observed in the granulomas of resistant mice at the later stage of Pb infection confirms its importance in fungal dissemination control, and suggests a contribution to the development of paracoccidioidal granuloma.
Brazilian Journal of Medical and Biological Research, 1998
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-α and TGF-ß) and type-1 (IL-2 and IFN-γ) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected ip with P. brasiliensis produced early and sustained levels of IFN-γ 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-γ 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-ß and low levels of TNF-α. In contrast, macrophages from A/Sn animals released high levels of TNF-α associated with a small production of TGF-ß. The in vivo depletion of IFN-γ 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-α and IFN-γ followed by a sustained secretion of IL-2 and IFN-γ plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-α and IFN-γ associated with production of IL-5, IL-10 and TGF-ß characterizes the progressive disease of susceptible animals.
Human Immunology, 2001
Paracoccidioides brasiliensis causes a chronic granulomatous mycosis prevalent in South America, and cell-mediated immunity represents the main mode of protection against this fungal infection. We investigated in vitro the response of peripheral blood mononuclear cells (PBMC) from paracoccidioidomycosis (PCM) patients presenting different clinical forms to antigenic fractions from P. brasiliensis yeast cell lysate (PbAg). These fractions designated F0 to FV were obtained using anion-exchange chromatography on a FPLC system. Our studies showed variation in the cellular responses induced by different antigenic fractions. The fraction F0 caused significant decrease in cellular proliferation, granuloma formation, accompanied by significant elevation in the production of IL-10. The fractions FII and FIII increased in vitro gran-uloma formation associated with high production of TNF-␣. Besides that, FII and FIII evoked decrease in NO production but not F0 that induced very high levels, among patients with PCM from acute form. The findings suggest that P. brasiliensis antigenic components participate in the modulation or activation of PBMC response in PCM, and IL-10 and NO could be important in the regulation of in vitro granuloma formation. Human Immunology 62, 799 -808 (2001).
Clinical and Experimental Immunology, 2008
The dissemination of Paracoccidioides brasiliensis cells to the heart, omentum/pancreas, spleen, liver and lungs, assessed by colony forming unit (CFU) counts, the levels of specific antibodies to this fungal agent (by ELISA), and the specific DTH reaction were studied in susceptible (B10.A) and resistant (A/Sn) mice. The animals were infected intraperitoneally with P. brasiliensis yeast cells and were evaluated 2, 4, 12 and 16 weeks later. The mosl remarkable differences between the two mouse strains were observed 16 weeks after infection, when B10.A mice displayed high numbers ofCFU in all examined organs, except the heart, high antibody titres, and depressed DTH response. At this point. A/Sn mice presented low or absent CFU in all organs, low antibody litres and expressive DTH response. The CFU counts were shown to be a reliable parameter to discriminate susceptible from resistant animals. The fungal load in the most affected organs correlated wilh the antibody litres and was inversely correlated with the intensity of the DTH reaction. The patterns of immune response in this model mimic human paracoccidioidomycosis, in which high specific antibody levels and depressed DTH reactions are found in multifocal and severe forms of the disease.
The American journal of tropical medicine and hygiene
The specific recognition pattern of antibodies produced by susceptible and resistant mice infected with the low virulence Paracoccidioides brasiliensis isolate (Pb265) was examined by an immunoblotting procedure and compared with that of antibodies produced by highly virulent isolate (Pb18) in infected mice. Both mouse strains produced IgG antibodies to 13 of the 16 major antigen bands, and showed a recognition pattern similar to sera from mice infected with the virulent isolate. Nevertheless, the reaction to components interposed among major bands (intermediate antigen bands of 75, 73, 68, 64, 33, 23, 22, and 12.5 kD) were detected exclusively with antibodies raised in response to the virulent P. brasiliensis isolate independent of the resistance pattern of the host. It was also demonstrated here that the most diversified repertoire of specific IgA was produced when the susceptible host and virulent fungus were associated.
Medical Mycology, 2003
Pro-inflammatory cytokines play an important role in both recruitment and activation of leukocytes migrating into tissues in response to invading pathogens. In this study the production of pro-inflammatory cytokines, determined by ELISA assays, and the recruitment of leukocytes into the lungs of BALBIc mice infected with Paracoccidioides brasiliensis conidia were evaluated during the early stages of infection. The results showed that infected mice had a significant increase in leukocytes in the lung during the first 4 days with a peak at day 2 post-challenge; infiltrates were composed mainly of polymorphonuclear neutrophils (PMN). Proinflammatory cytokines such as tumour necrosis factor alpha (TNF-a), interleukin (IL) 6, IL-1P and macrophage inflammatory protein (MIP) 2 were produced at elevated levels during the first 4 days post-challenge, but only in pulmonary samples and not in sera. Additionally, during the early stages of infection, overall weight loss was recorded in infected mice. These results suggest that proinflammatory cytokines could be responsible for the recruitment of leukocytes into the lung during the early stages of 19 brasiliensis infection. In addition, both pro-inflammatory cytokine production and leukocyte recruitment may participate in the control of infection by influencing the organization of the immune response in the host exposed to P brasiliensis conidia.
Infection and Immunity, 2008
The protective role of specific antibodies against Paracoccidioides brasiliensis is controversial. In the present study, we analyzed the effects of monoclonal antibodies on the major diagnostic antigen (gp43) using in vitro and in vivo P. brasiliensis infection models. The passive administration of some monoclonal antibodies (MAbs) before and after intratracheal or intravenous infections led to a reduced fungal burden and decreased pulmonary inflammation. The protection mediated by MAb 3E, the most efficient MAb in the reduction of fungal burden, was associated with the enhanced phagocytosis of P. brasiliensis yeast cells by J774.16, MH-S, or primary macrophages. The ingestion of opsonized yeast cells led to an increase in NO production by macrophages. Passive immunization with MAb 3E induced enhanced levels of gamma interferon in the lungs of infected mice. The reactivity of MAb 3E against a panel of gp43-derived peptides suggested that the sequence NHVRIPIGWAV contains the binding epitope. The present work shows that some but not all MAbs against gp43 can reduce the fungal burden and identifies a new peptide candidate for vaccine development.
Medical Mycology, 1989
A suppression of the IgE antibody response to ovalbumin was obtained in susceptible mice infected with Paracoccidioides brasiliensis yeast cells a few days prior to immunization with the former antigen plus adjuvant. A direct relationship between the number of injected fungi and the suppressive effect was established. When infection with a pathogenic isolate of P. brasiliensis (Pbl8) was compared to a non-pathogenic isolate (IVIC Pb267), the IgE antiovalbumin response was reduced by both. A similar effect was observed if mice were injected with dead yeast cells prior to immunization. Two strains of mice with completely opposite susceptibilities to infection with Pbl8 cells (B10.A--susceptible and A/SN--resistant) both showed suppressed IgE anti-ovalbumin antibody production when infected 3 days prior to immunization. Injection of both strains of mice with P. brasiliensis antigen on the same day as immunization also had the same suppressive effect. These results suggest that the suppression of IgE response to an unrelated antigen in experimental murine paracoccidioidomycosis could be due to antigenic competition or to a suppressive component present in P. brasiliensis cells.