I want to break free – macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape

Austermeier, Sophie; Kasper, Lydia; Westman, Johannes; Gresnigt, Mark S.

doi:10.1016/j.mib.2020.05.007

Cited by 35 publications

(31 citation statements)

References 65 publications

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“…Growth often implies replication of the pathogen, but in some instances the size of the microorganism increases (Westman et al, 2019a). The latter is the case of fungi such as Candida albicans, which undergoes a yeast-to-hyphal transition inside phagosomes (Austermeier et al, 2020). The rate of hyphal growth can reach several mm/hour, challenging the ability of the phagocyte to contain the infection (Westman et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection

Westman

Walpole

Kasper

et al. 2020

Cell Host & Microbe

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Section: Introductionmentioning

confidence: 99%

Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection

Westman

Walpole

Kasper

et al. 2020

Cell Host & Microbe

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“…The ability of C. albicans to persist in the human host and cause disease requires the capacity to evade and circumvent host defense mechanisms, especially macrophage-mediated clearance (O'Meara et al, 2018;Austermeier et al, 2020). Therefore, the C. albicans-macrophage interaction process offers promising targets for much-needed novel therapeutics to treat fungal infections and has not been exploited as a therapeutic target to date.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages provide the first-line defense against invasive fungal infections, and thus, C. albicans escape from macrophage becoming the basis for establishing systemic infection (Qian et al, 1994;Lionakis et al, 2013;Ngo et al, 2014;Weiss and Schaible, 2015). During the clearance, macrophages restrict the growth of and destroy C. albicans mainly by nutrient deprivation, a low pH, and oxidative stress in the phagosome (Austermeier et al, 2020;Williams and Lorenz, 2020).…”

Section: Introductionmentioning

confidence: 99%

Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance

Zhang

Tang

Zhang

et al. 2021

Front. Cell. Infect. Microbiol.

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Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of Candida albicans invasive infection. Here, we found that deletion of ATP2 (atp2Δ/Δ) in C. albicans resulted in a dramatic decrease from 69.2% (WT) to 1.2% in the escape rate in vitro. The effect of ATP2 on macrophage clearance stands out among the genes currently known to affect clearance. In the normal mice, the atp2Δ/Δ cells were undetectable in major organs 72 h after systemic infection, while WT cells persisted in vivo. However, in the macrophage-depleted mice, atp2Δ/Δ could persist for 72 h at an amount comparable to that at 24 h. Regarding the mechanism, WT cells sustained growth and switched to hyphal form, which was more conducive to escape from macrophages, in media that mimic the glucose-deficient environment in macrophages. In contrast, atp2Δ/Δ cells can remained viable but were unable to complete morphogenesis in these media, resulting in them being trapped within macrophages in the yeast form. Meanwhile, atp2Δ/Δ cells were killed by oxidative stress in alternative carbon sources by 2- to 3-fold more than WT cells. Taken together, ATP2 deletion prevents C. albicans from escaping macrophage clearance, and therefore ATP2 has a functional basis as a drug target that interferes with macrophage clearance.

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“…The ability of J774.1 macrophages to engulf C. albicans cells treated with CWP specific mAbs or an isotype control anti- Candida mAb was significantly higher than non-antibody treated cells (Table 2). A complex interplay between macrophage and C. albicans has been previously reported, with the pathogen sometimes counteracting the macrophage’s defence strategies to eventually break free and kill the macrophage as it escapes (36). In our study, whilst the antibody mediated engulfment did not result in complete killing of C. albicans , a significant inhibition of hyphal filamentation was observed which is tempting to speculate is due in part to an immunomodulatory activity of mAbs involved in pathogen clearance.…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model

Palliyil

Mawer

Alawfi

et al. 2021

Preprint

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MAb based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development with currently no licensed antifungal mAbs available. The cell wall glycoproteins of Candida albicans are potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. We describe phage display based generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans - Utr2 and Pga31, using peptide antigens representing the surface exposed regions of CWPs at elevated levels during in vivo infection. Reformatted mAbs preferentially recognised C. albicans hyphal forms compared to yeast cells and an increased binding in cells pre-treated with caspofungin. In macrophage interaction assays, mAb pre-treatment resulted in a faster engulfment of C. albicans cells suggesting opsonophagocytosis. Finally, in a series of clinically predictive, mouse models of systemic candidiasis, our lead mAb achieved an improved survival (83%) and several log reduction of fungal burden in the kidneys, similar to levels achieved for the fungicidal drug caspofungin, and superior to any anti-Candida mAb.

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I want to break free – macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape

Cited by 35 publications

References 65 publications

Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection

Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection

Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance

Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model

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