Selective Protection against Conidia by Mononuclear and against Mycelia by Polymorphonuclear Phagocytes in Resistance to Aspergillus

Schaffner, Andreas; Douglas, Herndon; Braude, Abraham I.

doi:10.1172/jci110489

Cited by 579 publications

(436 citation statements)

References 28 publications

(30 reference statements)

Supporting

Mentioning

412

Contrasting

Unclassified

Order By: Relevance

“…Six clinical isolates of Aspergillus fumigatus, all from immunocompromised patients with invasive disease and all isolated at the University Hospital of Zurich, and a strain each of Aspergillus flavus and Aspergillus niger isolated from patients at the University Hospital in San Diego were propagated, and suspensions of single spores were prepared as previously described [10]. Figure 1.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

177

View full text Add to dashboard Cite

The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus f/avus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to >2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P < . (01) or not (P < .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinicalimportance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

show abstract

Section: Methodsmentioning

confidence: 99%

“…To abolish the conidiacidal activity of macrophages, mice were given a single dose of 5 mg of cortisone acetate (gift from Merck Sharp & Dohme, West Point, Pa) sc [10]. Antimycelial defense was ablated by bone marrow suppression with nitrogen mustard (Merck Sharp & Dohme) [10].…”

Section: Methodsmentioning

confidence: 99%

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

177

View full text Add to dashboard Cite

show abstract

“…In these cases the exact pathophysiology of IPA manifestation and the way in which it disseminates to local and distant sites are not completely understood. Although the release of fungal metabolites with immunosuppressive activity may contribute to the pathogenesis of aspergillosis (12), local cellular defects in the innate and adaptive immune effector mechanisms are major predisposing factors of the host to IPA (13)(14)(15)(16). Resident alveolar macrophages ingest and kill resting conidia, largely through nonoxidative mechanisms, while neutrophils use oxygen-dependent mechanisms to attack hyphae germinating from conidia that escape macrophage surveillance (13,14).…”

Section: T Cell Vaccination In Mice Withmentioning

confidence: 99%

“…Although the release of fungal metabolites with immunosuppressive activity may contribute to the pathogenesis of aspergillosis (12), local cellular defects in the innate and adaptive immune effector mechanisms are major predisposing factors of the host to IPA (13)(14)(15)(16). Resident alveolar macrophages ingest and kill resting conidia, largely through nonoxidative mechanisms, while neutrophils use oxygen-dependent mechanisms to attack hyphae germinating from conidia that escape macrophage surveillance (13,14). The effectiveness of this system is evident from the observation that challenge with even large numbers of conidia fails to cause disease in immunocompetent animals (17), and recognized major risk factors in humans are defects in phagocyte functions, such as those occurring in chronic granulomatous disease (18,19), cortisone-induced suppression of macrophage conidiocidal activity (20,21), and chemotherapy-induced neutropenia (22).…”

Section: T Cell Vaccination In Mice Withmentioning

confidence: 99%

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Cenci

Mencacci

Bacci

et al. 2000

The Journal of Immunology

204

166

View full text Add to dashboard Cite

Aspergillus fumigatus, an opportunistic fungal pathogen, is responsible for multiple airway diseases of an allergic and a nonallergic nature. In a murine model of invasive pulmonary aspergillosis, resistance is associated with a decreased lung inflammatory pathology and the occurrence of an IL-12-dependent Th1-type reactivity that are both impaired by IL-4. In the present study we assess the ability of Aspergillus crude culture filtrate Ags and the recombinant allergen Asp f 2 to induce protective antifungal responses in mice with invasive pulmonary aspergillosis. Similar to what occurred upon nasal exposure to viable A. fumigatus conidia, treatment of immunocompetent mice with Aspergillus crude culture filtrate Ags resulted in the development of local and peripheral protective Th1 memory responses, mediated by Ag-specific CD4+ T cells producing IFN-γ and IL-2 capable of conferring protection upon adoptive transfer to naive recipients. Protective Th1 responses could not be observed in mice deficient of IFN-γ or IL-12 and did not occur in response to Asp f 2, which, on the contrary, elicited high level production of inhibitory IL-4. The results show that Ags of Aspergillus exist with the ability to induce both Th1- and Th2-type reactivity during infection, a finding that suggests a possible mechanism through which potentially protective immune responses are inhibited in mice with the infection. However, the occurrence of Th1-mediated resistance upon vaccination with Aspergillus crude culture filtrate Ags, suggests the existence of fungal Ags useful as a candidate vaccine against invasive pulmonary aspergillosis.

show abstract

“…The role of neutrophils in the innate host defense against Aspergillus species has been well documented in both in vitro (9,10) and in vivo (11,12) experiments. Other immune cells also play a role in host defense against Aspergillus species, however.…”

Section: Macrophage Inflammatory Protein-1␣ Is a Critical Mediator Ofmentioning

confidence: 99%

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

Mehrad

Moore

Standiford

2000

The Journal of Immunology

View full text Add to dashboard Cite

Invasive pulmonary aspergillosis is a devastating complication of immunosuppression that usually occurs in neutropenic patients. In this setting, augmentation of the antifungal activity of available immune cells may improve the outcome of the infection. Macrophage inflammatory protein-1α (MIP-1α) is a CC chemokine with potent chemotactic activity for various subsets of mononuclear leukocytes. We therefore tested the hypothesis that the influx of mononuclear cells into the lung in invasive pulmonary aspergillosis is in part mediated by MIP-1α, and the manipulation of this ligand alters the outcome of the infection. We found that in both immunocompetent and neutropenic mice, MIP-1α was induced in the lungs in response to intratracheal administration of Aspergillus fumigatus conidia. In neutrophil-depleted mice challenged with intratracheal conidia, there was evidence of invasive fungal pneumonia associated with a predominantly mononuclear leukocyte infiltrate. Ab-mediated depletion of MIP-1α resulted in a 6-fold increase in mortality in neutropenic mice, which was associated with a 12-fold increase in lung fungal burden. Studies of single-cell suspensions of whole lungs revealed a 36% decrease in total lung leukocyte infiltration as a result of MIP-1α neutralization. Flow cytometry on whole lung suspensions showed a 41% reduction in lung monocyte/macrophages as a result of MIP-1α neutralization, but no difference in other lung leukocyte subsets. These studies indicate that MIP-1α is a critical mediator of host defense against A. fumigatus in the setting of neutropenia and may be an important target in devising future therapeutic strategies against invasive aspergillosis.

show abstract

Selective Protection against Conidia by Mononuclear and against Mycelia by Polymorphonuclear Phagocytes in Resistance to Aspergillus

Cited by 579 publications

References 28 publications

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

Contact Info

Product

Resources

About