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Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities

Nature Microbiology volume 9, pages 2216–2231 (2024)Cite this article

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Abstract

An important host defence mechanism against pathogens is intracellular killing, which is achieved through phagocytosis, a cellular process for engulfing and neutralizing extracellular particles. Phagocytosis results in the formation of matured phagolysosomes, which are specialized compartments that provide a hostile environment and are considered the end point of the degradative pathway. However, all fungal pathogens studied to date have developed strategies to manipulate phagosomal function directly and also indirectly by redirecting phagosomes from the degradative pathway to a non-degradative pathway with the expulsion and even transfer of pathogens between cells. Here, using the major human fungal pathogens Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum as examples, we discuss the processes involved in host phagosome–fungal pathogen interactions, with a focus on fungal evasion strategies. We also discuss recent approaches to targeting intraphagosomal pathogens, including the redirection of phagosomes towards degradative pathways for fungal pathogen eradication.

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Fig. 1: Intracellular processing of fungal pathogens.
Fig. 2: Fungal strategies for hiding from host recognition.
Fig. 3: Manipulation of phagosome maturation by fungal pathogens.
Fig. 4: Survival of fungal pathogens within phagosomes.
Fig. 5: Escape of fungal pathogens from host cells.
Fig. 6: Strategies to enhance the microbicidal activity of phagosomes.

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Acknowledgements

We thank T. Heinekamp and M. Blango for critical reading of the manuscript. The work in the authors’ laboratories is funded by the Free State of Thuringia and European Social Fund Plus (PhagoInf; 2023FGR0043), the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence Balance of the Microverse (project ID 390713860; Gepris 2051), the DFG–Agence Nationale de la Recherche project AfuInf (316898429), DFG Collaborative Research Center/Transregio 124 (FungiNet) (projects A1 and Z2; 210879364), DFG Collaborative Research Center 1278 (PolyTarget) (project B02; 316213987) and a Leibniz project (K217/2016).

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  1. These authors contributed equally: Katherine González, Thomas Orasch, Franziska Schmidt.

Authors and Affiliations

  1. Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute (Leibniz–HKI), Jena, Germany

    Lei-Jie Jia, Katherine González, Franziska Schmidt & Axel A. Brakhage

  2. Junior Research Group Phagosome Biology and Engineering, Leibniz–HKI, Jena, Germany

    Lei-Jie Jia

  3. Transfer Group Anti-infectives, Leibniz–HKI, Jena, Germany

    Thomas Orasch

  4. Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany

    Axel A. Brakhage

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L.-J.J. and A.A.B. conceptualized and supervised the study. L.-J.J. performed literature research and prepared the figures. All authors wrote and edited the manuscript.

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Jia, LJ., González, K., Orasch, T. et al. Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities. Nat Microbiol 9, 2216–2231 (2024). https://doi.org/10.1038/s41564-024-01780-0

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