Interferon gamma increases survival in urine experimental cryptococcosis

Bava, Amadeo Javier; Afeltra, Javier; Negroni, Ricardo; Díez, Roberto A.

doi:10.1590/s0036-46651995000500003

Cited by 10 publications

(6 citation statements)

References 14 publications

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“…However, there seem to be differences in IFN-␥-related signaling in mice and humans. IFN-␥ has clearly been demonstrated to have a protective role in mouse model systems of cryptococcosis (5,24) and to increase fungicidal activity of murine macrophages (19). However, among human cells, IFN-␥ treatment reduces the capacity of human alveolar macrophages (44) and human monocyte-derived macrophages (30) to inhibit cryptococcal growth, a finding that is supported by our data.…”

Section: Discussionmentioning

confidence: 99%

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism byCryptococcus neoformans

2009

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The pathogenic yeast Cryptococcus neoformans and C. gattii commonly cause severe infections of the central nervous system in patients with impaired immunity but also increasingly in immunocompetent individuals. Cryptococcus is phagocytosed by macrophages but can then survive and proliferate within the phagosomes of these infected host cells. Moreover, Cryptococcus is able to escape into the extracellular environment via a recently discovered nonlytic mechanism (termed expulsion or extrusion). Although it is well established that the host's cytokine profile dramatically affects the outcome of cryptococcal disease, the molecular basis for this effect is unclear. Here, we report a systematic analysis of the influence of Th1, Th2, and Th17 cytokines on the outcome of the interaction between macrophages and cryptococci. We show that Th1 and Th17 cytokines activate, whereas Th2 cytokines inhibit, anticryptococcal functions. Intracellular yeast proliferation and cryptococcal expulsion rates were significantly lower after treatment with the Th1 cytokines gamma interferon and tumor necrosis factor alpha and the Th17 cytokine interleukin-17 (IL-17). Interestingly, however, the Th2 cytokines IL-4 and IL-13 significantly increased intracellular yeast proliferation while reducing the occurrence of pathogen expulsion. These results help explain the observed poor prognosis associated with the Th2 cytokine profile (e.g., in human immunodeficiency virus-infected patients).

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Section: Discussionmentioning

confidence: 99%

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism byCryptococcus neoformans

2009

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“…IFN-␥ is able to cross the BBB and persist in the brain at very low concentrations (42), and the biological effects of IFN-␥ are largely restrained by immunosuppressive factors in the brain such as TGF-␤ and IL-10 (54). IFN-␥ as single regimen has shown a limited therapeutic effect on cryptococcosis (55,56), and the amount of IFN-␥ given systemically is limited by the severe toxicity observed (57). The benefit of anti-CD40/IL-2 treatment was to stimulate immune cells to produce IFN-␥ at a physiologically effective level without this toxicity.…”

Section: Discussionmentioning

confidence: 99%

Protection from Direct Cerebral Cryptococcus Infection by Interferon-γ-Dependent Activation of Microglial Cells

Zhou

Gault

Kozel

et al. 2007

The Journal of Immunology

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The brain represents a significant barrier for protective immune responses in both infectious disease and cancer. We have recently demonstrated that immunotherapy with anti-CD40 and IL-2 can protect mice against disseminated Cryptococcus infection. We now applied this immunotherapy using a direct cerebral cryptococcosis model to study direct effects in the brain. Administration of anti-CD40 and IL-2 significantly prolonged the survival time of mice infected intracerebrally with Cryptococcus neoformans. The protection was correlated with activation of microglial cells indicated by the up-regulation of MHC II expression on brain CD45lowCD11b+ cells. CD4+ T cells were not required for either the microglial cell activation or anticryptococcal efficacy induced by this immunotherapy. Experiments with IFN-γ knockout mice and IFN-γR knockout mice demonstrated that IFN-γ was critical for both microglial cell activation and the anticryptococcal efficacy induced by anti-CD40/IL-2. Interestingly, while peripheral IFN-γ production and microglial cell activation were observed early after treatment, negligible IFN-γ was detected locally in the brain. These studies indicate that immunotherapy using anti-CD40 and IL-2 can augment host immunity directly in the brain against C. neoformans infection and that IFN-γ is essential for this effect.

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“…Lysates were then treated with collagenase A (1 mg/ml; Boehringer Mannheim, Chicago, IL) in digestion buffer (RPMI medium, 10% fetal calf serum) and incubated for 1 h at 37°C with occasional shaking. Cells were centrifuged and suspended in 0.17 M NH 4 Cl to lyse erythrocytes for 10 min at 4°C. A 10-fold excess of RPMI solution was then added to make the solution isotonic, and the cells were collected by centrifugation and suspended in staining buffer (PBS, 1% fetal bovine serum).…”

Section: Yeast Strain and Preparation Of Inocula For Infectionmentioning

confidence: 99%

“…Lavage fluids were pooled, and cells were collected by centrifugation. Red blood cells were lysed by incubation in 0.17 M NH 4 Cl at 4°C for 10 min. Cells were washed with PBS and suspended in Dulbecco's modified Eagle's medium (Invitrogen Life Technologies, Carlsbad, CA) with 10% heat-inactivated fetal calf serum (Gemini Bioproducts, Woodland, CA), 10% NCTC-109 medium (Gibco, Carlsbad, CA), and 1% nonessential amino acids (Mediatech Cellgro, Washington, DC).…”

Section: Yeast Strain and Preparation Of Inocula For Infectionmentioning

confidence: 99%

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The Relative Susceptibility of Mouse Strains to PulmonaryCryptococcus neoformansInfection Is Associated with Pleiotropic Differences in the Immune Response

Zaragoza¹,

Alvarez²,

Telzak³

et al. 2007

Infect Immun

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CBA/J mice were highly susceptible to intratracheal (i.t.) Cryptococcus neoformans infection relative to BALB/c mice, while both strains were equally susceptible to intravenous (i.v.) infection. Increased susceptibility in i.t. infection was associated with higher brain CFU, lower serum immunoglobulin M (IgM) and IgG responses to glucuronoxylomannan (GXM), lack of IgE regulation during infection, and alveolar macrophage permissiveness to intracellular replication in vitro. In contrast, for BALB/c mice, relative resistance was associated with increased interleukin-12 (IL-12) and decreased IL-10 pulmonary levels. In CBA/J mice, relative susceptibility was associated with a decreased proportion of CD4 ؉ and CD8 ؉ T cells and an increase in macrophage percentage in pulmonary infiltrates. In contrast, no significant differences in these cytokines or cell recruitment were observed in the i.v. model, consistent with no differences in the survival rate. Passive antibody (Ab) protection experiments revealed a prozone effect in the BALB/c mice with i.v. infection, such that Ab efficacy decreased at higher doses. In the i.t. model using CBA/J mice, low Ab doses were disease enhancing and protection was observed only at high doses. Our results show (i) that differences in mouse strain susceptibility are a function of the infection model, (ii) that susceptibility to pulmonary infection was associated with macrophage permissiveness for intracellular replication, and (iii) that the efficacy of passive Ab in pulmonary infection is a function of dose and mouse strain. The results highlight significant differences in the pathogenesis of cryptococcal infection among inbred mice and associate their relative susceptibility with differences in numerous components of the innate and adaptive immune responses.Cryptococcus neoformans is a fungal pathogen for individuals with late-stage human immunodeficiency virus infection. The initial infection is usually controlled and either cleared or contained by immunocompetent hosts into a latent asymptomatic state, and there is evidence that persistent infection might be associated with reactive airway disease (24). However, in immunocompromised individuals dissemination and/or reactivation of latent infection can lead to a life-threatening meningoencephalitis (for a review, see reference 9).C. neoformans has several well-characterized virulence factors, including a polysaccharide capsule, melanin production, phospholipase, urease, and the alpha mating factor, among others (for reviews, see references 9, 42, and 55). A recent study analyzing the relative contribution of each virulence factor showed that the capsular polysaccharide makes the largest contribution to C. neoformans virulence (41). The polysaccharide capsule is composed primarily of glucuronoxylomannan (GXM). The capsule participates in virulence through pleitropic effects on the immune system (9, 71, 72). Furthermore, C. neoformans strains that differ in virulence elicit different immune responses in the host (5, 14).

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Interferon gamma increases survival in urine experimental cryptococcosis

Cited by 10 publications

References 14 publications

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism byCryptococcus neoformans

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism byCryptococcus neoformans

Protection from Direct Cerebral Cryptococcus Infection by Interferon-γ-Dependent Activation of Microglial Cells

The Relative Susceptibility of Mouse Strains to PulmonaryCryptococcus neoformansInfection Is Associated with Pleiotropic Differences in the Immune Response

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