Hung Chiung-Yu, Xue Jianmin, Cole Garry T
Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0662, USA.
Ann N Y Acad Sci. 2007 Sep;1111:225-35. doi: 10.1196/annals.1406.020. Epub 2007 May 18.
Coccidioides is a fungal respiratory pathogen of humans that can cause disease in both immunosuppressed and immunocompetent individuals. We describe here three mechanisms by which the pathogen survives in the hostile host environment: production of a dominant spherule outer wall glycoprotein (SOWgp) that modulates host immune response and results in compromised cell-mediated immunity to coccidioidal infection, depletion of SOWgp presentation on the surface of endospores, which prevents host recognition of the pathogen when the fungal cells are most vulnerable to phagocytic defenses, and induction of elevated production of host arginase I and coccidioidal urease, which contribute to tissue damage at sites of infection. Arginase I competes with inducible nitric oxide synthase (iNOS) in macrophages for the common substrate, L-arginine, and thereby reduces nitric oxide (NO) production and increases the synthesis of host orinithine and urea. Host-derived L-ornithine may promote pathogen growth and proliferation by providing a pool of the monoamine, which could be taken up and used for synthesis of polyamines via metabolic pathways of the parasitic cells. We have shown that high concentrations of Coccidioides- and host-derived urea at infection sites in the presence of urease produced and released by the pathogen, results in secretion of ammonia and contributes to alkalinization of the microenvironment. We propose that ammonia and enzymatically active urease released from spherules during the parasitic cycle of Coccidioides exacerbate the severity of coccidioidal infection by contributing to a compromised immune response to infection and damage of host tissue at foci of infection.
球孢子菌是一种人类呼吸道真菌病原体，可在免疫抑制和免疫功能正常的个体中引发疾病。我们在此描述该病原体在恶劣宿主环境中存活的三种机制：产生一种占主导地位的球形体外壁糖蛋白（SOWgp），它可调节宿主免疫反应并导致对球孢子菌感染的细胞介导免疫受损；减少内生孢子表面SOWgp的呈现，这可防止在真菌细胞最易受到吞噬防御时宿主识别该病原体；诱导宿主精氨酸酶I和球孢子菌脲酶的产量升高，这会导致感染部位的组织损伤。精氨酸酶I与巨噬细胞中的诱导型一氧化氮合酶（iNOS）竞争共同底物L-精氨酸，从而减少一氧化氮（NO）的产生，并增加宿主鸟氨酸和尿素的合成。宿主来源的L-鸟氨酸可能通过提供单胺池来促进病原体的生长和增殖，该单胺池可被寄生虫细胞摄取并用于通过代谢途径合成多胺。我们已经表明，在病原体产生和释放脲酶的情况下，感染部位高浓度的球孢子菌和宿主来源的尿素会导致氨的分泌，并有助于微环境的碱化。我们提出，在球孢子菌的寄生周期中，从球形体释放的氨和具有酶活性的脲酶会加剧球孢子菌感染的严重程度，这是因为它们会导致对感染的免疫反应受损以及感染灶处宿主组织的损伤。
