In Vivo Bronchoalveolar Macrophage Defense Against Rhizopus oryzae and Aspergillus fumigatus

Waldorf, Alayn R.; Levitz, Stuart M.; Diamond, Richard D.

doi:10.1093/infdis/150.5.752

Cited by 231 publications

(156 citation statements)

References 23 publications

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“…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%

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T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Cenci

Mencacci

Bacci

et al. 2000

The Journal of Immunology

207

166

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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.

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Section: T Cell Vaccination In Mice Withmentioning

confidence: 99%

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

207

166

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“…However, AmB is considered highly nephrotoxic (18) and has often been found inadequate for complete elimination of the infection in the immunosuppressed subjects. Because invasive aspergillosis is extremely rare in immunocompetent individuals, therapy aimed at strengthening the host's immune response to the organisms offers a promising new approach in the treatment of this disease.Host defense against Aspergillus infections is considered to be mediated by macrophages, neutrophils, and polymorphonuclear cells (PMNs) (6,16,23,24,25,28). The respiratory tract appears to be the portal of entry in most cases of IPA (3).…”

mentioning

confidence: 99%

“…Host defense against Aspergillus infections is considered to be mediated by macrophages, neutrophils, and polymorphonuclear cells (PMNs) (6,16,23,24,25,28). The respiratory tract appears to be the portal of entry in most cases of IPA (3).…”

mentioning

confidence: 99%

Protective Role of Lung Surfactant Protein D in a Murine Model of Invasive Pulmonary Aspergillosis

et al. 2001

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Aspergillus spp. are increasingly recognized as major fungal pathogens in immunocompromised or neutropenic patients, and Aspergillus fumigatus is responsible for nearly 90% of cases of invasive pulmonary aspergillosis (IPA) (7). As the incidence of AIDS, aplastic anemia, and organ transplantation increases and the use of chronic glucocorticoid treatment and aggressive antineoplastic chemotherapy regimes becomes more frequent, the number of patients susceptible to Aspergillus infection is rising. In immunocompromised or neutropenic patients, IPA, the most common form of the disease, is characterized by hyphal invasion and destruction of pulmonary tissue. Dissemination of Aspergillus infection to other organs occurs in approximately 20% of IPA cases (4). In spite of correct diagnosis and treatment, IPA results in patient mortality of greater than 80%. The mortality rate among bone marrow transplantation patients can be as high as 95% (26). Early empirical treatment with antifungal drugs, such as amphotericin B (AmB), reduces the mortality rate. However, AmB is considered highly nephrotoxic (18) and has often been found inadequate for complete elimination of the infection in the immunosuppressed subjects. Because invasive aspergillosis is extremely rare in immunocompetent individuals, therapy aimed at strengthening the host's immune response to the organisms offers a promising new approach in the treatment of this disease.Host defense against Aspergillus infections is considered to be mediated by macrophages, neutrophils, and polymorphonuclear cells (PMNs) (6,16,23,24,25,28). The respiratory tract appears to be the portal of entry in most cases of IPA (3). Therefore, there has been an extensive search for molecules in the lung which can selectively enhance the contribution of the innate immune mechanism of phagocytes against Aspergillus infection. Lung surfactant proteins SP-A and SP-D have potent chemotactic activity for various subsets of mononuclear leukocytes and have been shown to enhance phagocytosis and production of superoxide anion by macrophages and neutrophils (29). SP-A and SP-D, which belong to a family of proteins called collectins, are also known to interact with carbohydrate structures present on the surfaces of a wide range of pathogens, such as viruses, bacteria, and fungi, via their carbohydrate recognition domains (CRDs) and to enhance phagocytosis and killing by neutrophils and macrophages (22,29). Collectins are composed of subunits, each of which contains a collagen-like triple-helical region, followed by an ␣-helical, trimerizing neck region and three CRDs at its C-terminal end. Six of these trimeric subunits make up the overall structure of SP-A, while SP-D is composed of a cruciform structure with four arms of equal lengths (10). Mice deficient in SP-A were observed to be less effective in clearing Staphylococcus aureus and Pseudomonas aeruginosa and were more susceptible to lung inflammation and splenic dissemination of group B streptococci (13-15).We have previously shown that SP-A and S...

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“…Endogenous alveolar macrophages recognize, phagocytize, and kill fungal spores (10), and neutrophils can recognize and eliminate germinating hyphae (11). Immunotherapeutic strategies such as adoptive transfer of preselected CD4 + T-cell clones can help control Aspergillus infection indirectly by producing interferon-gamma (IFN-γ) (12).…”

mentioning

confidence: 99%

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Kumaresan

Manuri

Albert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

188

121

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Significance Patients with compromised T-cell function are at risk for opportunistic fungal infections. We have developed a novel approach to restore immunity by using a fungal pattern-recognition receptor Dectin-1 to redirect T-cell specificity to carbohydrate antigen in the fungal cell wall. We did so by genetically modifying T cells using the nonviral Sleeping Beauty gene-transfer system to enforce expression of a chimeric antigen receptor (CAR) that recapitulates the specificity of Dectin-1 (D-CAR). The D-CAR + T cells can be electroporated and propagated on artificial activating and propagating cells in a manner suitable for human application, enabling this immunology to be translated into immunotherapy. This approach has implications for genetically modifying T cells to express CARs with specificity for carbohydrate and thus broadening their application in the investigational treatment of pathogens and malignancies.

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In Vivo Bronchoalveolar Macrophage Defense Against Rhizopus oryzae and Aspergillus fumigatus

Cited by 231 publications

References 23 publications

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Protective Role of Lung Surfactant Protein D in a Murine Model of Invasive Pulmonary Aspergillosis

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

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