Resistance of MBL gene-knockout mice to experimental systemic aspergillosis

Clemons, Karl V.; Martinez, Marife; Tong, Ann-Jay; Stevens, David A.

doi:10.1016/j.imlet.2009.12.021

Cited by 22 publications

(16 citation statements)

References 33 publications

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“…The importance of C1q and the classical complement pathway is stressed in a nonimmunocompromised mouse infection model. C1q-deficient mice are more susceptible to A. fumigatus infection, while MBL-deficient mice are affected the same as wild-type mice [38,39]. …”

Section: Discussionmentioning

confidence: 99%

Effective Neutrophil Phagocytosis of Aspergillus fumigatus Is Mediated by Classical Pathway Complement Activation

et al. 2015

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Aspergillus fumigatus is an important airborne fungal pathogen and a major cause of invasive fungal infections. Susceptible individuals become infected via the inhalation of dormant conidia. If the immune system fails to clear these conidia, they will swell, germinate and grow into large hyphal structures. Neutrophils are essential effector cells for controlling A. fumigatus infection. In general, opsonization of microbial particles is crucial for efficient phagocytosis and killing by neutrophils. Although the antibodies present in human serum do bind to all fungal morphotypes, we observed no direct antibody-mediated phagocytosis of A. fumigatus. We show that opsonization, phagocytosis and killing by neutrophils of A. fumigatus is complement-dependent. Using human sera depleted of key complement components, we investigated the contribution of the different complement initiation pathways in complement activation on the fungal surface. We describe the classical complement pathway as the main initiator of complement activation on A. fumigatus swollen conidia and germ tubes. Antibodies play an important role in complement activation and efficient innate recognition, phagocytosis and killing of A. fumigatus by neutrophils.

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Section: Discussionmentioning

confidence: 99%

Effective Neutrophil Phagocytosis of Aspergillus fumigatus Is Mediated by Classical Pathway Complement Activation

et al. 2015

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“…To determine the possible relevance of MIF in host defense against A. fumigatus we have conducted experiments using a model of systemic aspergillosis (Cenci et al 1997;Clemons et al 2010;Mirkov et al 2011), induced in MIF-deficient mice generated on the relatively resistant C57BL/6 background (Cenci et al 1997;Mirkov et al 2010;Zaas et al 2008). We found that MIF −/− mice are more susceptible than WT mice to A. fumigatus infection, as evidenced by higher mortality at the dose of 10 7 conidia as well as a greater organ fungal burden after sublethal conidia inoculum.…”

Section: Discussionmentioning

confidence: 99%

“…In one short report (Nicolo et al 2006) antibody neutralization of MIF increased mortality in mice infected with C. albicans with a decrease of proinflammatory cytokines in the affected kidneys. Taking advantage of mice genetically deficient in MIF, and generated on the relatively resistant C57BL/6 background, here we analyzed for the first time a role for MIF in protective immunity against A. fumigatus using a well-established murine model of systemic aspergillosis in which fungal inoculum delivered by tail-vein injection progresses from the bloodstream to the spleen and deep-seated infection of major organs, such as the kidneys and lungs (Clemons et al 2010;Mirkov et al 2008Mirkov et al , 2010.…”

Section: Introductionmentioning

confidence: 99%

A role for macrophage migration inhibitory factor in protective immunity against Aspergillus fumigatus

et al. 2011

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“…In this context, it is important to mention another study showing that non-immunosuppressed MBL-knockout mice were less susceptible to systemic A. fumigatus infection compared to wild-type mice (24). It was suggested (not shown) by the authors that the wild types did not die due to A. fumigatus, but from neutrophilic infiltration causing detrimental tissue-damage.…”

Section: C1q and Mbl Inhibition In Serum From Immunocompromised Patientsmentioning

confidence: 98%

Complementary roles of the classical and lectin complement pathways in the defense against Aspergillus fumigatus

et al. 2016

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Aspergillus fumigatus infections are associated with a high mortality rate for immunocompromised patients. The complement system is considered to be important in protection against this fungus, yet the course of activation is unclear. The aim of this study was to unravel the role of the classical, lectin, and alternative pathways under both immunocompetent and immunocompromised conditions to provide a relevant dual-perspective on the response against A. fumigatus. Conidia (spores) from a clinical isolate of A. fumigatus were combined with various human serum types (including serum deficient of various complement components and serum from umbilical cord blood). We also combined this with inhibitors against C1q, mannose-binding lectin (MBL), and ficolin-2 before complement activation products and phagocytosis were detected by flow cytometry. Our results showed that alternative pathway amplified complement on A. fumigatus, but required classical and/or lectin pathway for initiation. In normal human serum, this initiation came primarily from the classical pathway. However, with a dysfunctional classical pathway (C1q-deficient serum), lectin pathway activated complement and mediated opsonophagocytosis through MBL. To model the antibody-decline in a compromised immune system, we used serum from normal umbilical cords and found MBL to be the key complement initiator. In another set of experiments, serum from patients with different kinds of immunoglobulin insufficiencies showed that the MBL lectin pathway contribution was highest in the samples with the lowest IgG/IgM binding. In conclusion, lectin pathway appears to be the primary route of complement activation in the absence of anti-A. fumigatus antibodies, whereas in a balanced immune state classical pathway is the main activator. This suggests a crucial role for the lectin pathway in innate immune protection against A. fumigatus in immunocompromised patients.

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Resistance of MBL gene-knockout mice to experimental systemic aspergillosis

Cited by 22 publications

References 33 publications

Effective Neutrophil Phagocytosis of <b><i>Aspergillus</i></b> <b><i>fumigatus</i></b> Is Mediated by Classical Pathway Complement Activation

Effective Neutrophil Phagocytosis of <b><i>Aspergillus</i></b> <b><i>fumigatus</i></b> Is Mediated by Classical Pathway Complement Activation

A role for macrophage migration inhibitory factor in protective immunity against Aspergillus fumigatus

Complementary roles of the classical and lectin complement pathways in the defense against Aspergillus fumigatus

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