Intracellular Pathogenesis of Histoplasma capsulatum

Simon L. Newman

doi:10.1128/9781555815776.ch35

Chapter 35 : Intracellular Pathogenesis of Histoplasma capsulatum

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Affiliations: 1: Department of Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267

Content Type: Monograph

Publication Year: 2006

Category: Fungi and Fungal Pathogenesis

Book DOI: 10.1128/9781555815776

Chapter DOI: 10.1128/9781555815776.ch35

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Abstract:

This chapter reviews what is known about the strategies used by Histoplasma capsulatum yeasts to survive within human and animal murine macrophages, how murine macrophages become activated, and the mechanisms by which activated murine macrophages kill H. capsulatum yeasts. The interaction of H. capsulatum with dendritic cells (DC) is also discussed, as are the different roles that murine macrophages and DC may play in the development of cell-mediated immunity to H. capsulatum. Recent studies demonstrate that the ligand on the surface of H. capsulatum yeasts and conidia that is recognized by murine macrophages CD18 receptors is heat shock protein 60 (hsp60). Once inside the phagosome, H. capsulatum must avoid the microbicidal armamentarium of the murine macrophages that consists of the generation of toxic oxygen molecules (respiratory burst) and lysosomal hydrolases (phagolysosomal fusion [PL fusion]). Intracellular pathogens have evolved numerous strategies to avoid these murine macrophages defense mechanisms, including inhibition of phagolysosomal fusion (PL) (e.g., Mycobacterium tuberculosis), escaping from the phagocytic vacuole into the cytoplasm (e.g., Listeria monocytogenes), and initiating phagocytosis without stimulating the respiratory burst (e.g., Toxoplasma gondii). The intracellular replication of H. capsulatum yeasts in human monocytes and murine macrophages occurs at a similar rate even though murine macrophages have lost their myeloperoxidase and are unable to make toxic oxygen metabolites distal to H2O2. In contrast to our knowledge of murine immunology, the cytokines required to activate human murine macrophages fungistatic or fungicidal activity against H. capsulatum remain obscure.

Citation: Newman S. 2006. Intracellular Pathogenesis of Histoplasma capsulatum, p 527-536. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch35

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Intracellular Pathogenesis of Histoplasma capsulatum

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Figure 1.

Differential response of human and murine Mϕ to H. capsulatum yeasts. Upon ingestion of H. capsulatum yeasts, the respiratory burst of murine Mϕ is not stimulated, but PL fusion does occur. In contrast, there is production of toxic oxygen radicals by human Mϕ, but minimal PL fusion. Further, murine Mϕ are activated by IFN-γ to inhibit the intracellular replication of yeasts, whereas IFN-γ does not activate human Mϕ. In both human and murine Mϕ, the intraphagosomal pH is maintained at 6.5.

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Figure 1.

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Figure 2.

Differential recognition and response of human Mϕ and DC to H. capsulatum yeasts. Mϕ utilize the CD18 receptor family to recognize the ligand Hsp60 on the surface of H. capsulatum yeasts. Upon ingestion of the yeasts, PL fusion is blocked and the yeasts replicate. In contrast, DC use the VLA-5 receptor to recognize cyclophilin A on the surface of H. capsulatum yeasts. Upon ingestion of the yeasts, PL fusion takes place and the yeasts are killed and degraded.

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Figure 2.

References

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