Susceptibility of Germfree Phagocyte Oxidase- and Nitric Oxide Synthase 2-Deficient Mice, Defective in the Production of Reactive Metabolites of Both Oxygen and Nitrogen, to Mucosal and Systemic Candidiasis of Endogenous Origin

Abstract

defective in the production of both reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), were used to investigate the role of phagocytic cells during mucosal and systemic candidiasis of endogenous origin. The alimentary tracts of germfree mice were colonized with Candida albicans wild type or each of two hyphal signaling-defective mutants (efg1/efg1 and efg1/efg1 cph1/cph1). All Candida-colonized gp91 phox؊/؊ /NOS2 ؊/؊ mice were moribund within 12 to 15 days after oral inoculation. C. albicans wild-type and mutant strains colonized the alimentary tracts equally well and were able to translocate, most likely via Peyer's patches and mesenteric lymph nodes, to the internal organs and trigger the formation of abscesses; however, the wild-type and mutant strains did not survive in the abscessed murine tissues. Surprisingly, there was no significant difference in the ability of peritoneal exudate cells from gp91 phox؊/؊ /NOS2 ؊/؊ , NOS2 ؊/؊ , gp91 phox؊/؊ , or immunocompetent C57BL/6 mice to kill C. albicans in vitro. This suggests that anti-Candida factors other than ROI and RNI can control the growth of C. albicans and that gp91 phox؊/؊ /NOS2 ؊/؊ mice die due to the inability of the host to control its inflammatory response to Candida. Correspondingly, reverse transcription-PCR analysis showed increased expression of the cytokines gamma interferon, tumor necrosis factor alpha, and the chemokines MIP-2 and KC at the site of infection, while interleukin-15 expression remained relatively unchanged between germfree and infected tissues. These studies indicate that defects in ROI and RNI enabled C. albicans to translocate and disseminate to the internal organs, resulting in an uncontrolled immune response, severe pathology, and death; however, ROI and RNI were not required for the killing of phagocytized C. albicans, indicating that other anti-Candida factors either compensate or are sufficient for the killing of phagocytized Candida.

Live Imaging of Disseminated Candidiasis in Zebrafish Reveals Role of Phagocyte Oxidase in Limiting Filamentous Growth

“…The efg1⌬/⌬ cph1⌬/⌬ mutant retained its ability to grow in a filamentous form as pseudohyphae (Fig. 3C), as reported previously for oral and disseminated mammalian infections (8,67). Although the transcription factors encoded by these genes regulate a number of genes (32), these data provide a further indication that hyphal growth, seen early during infection and in larvae that succumbed to infection, plays an important role in virulence in zebrafish larval candidemia.…”

Normal Adaptation of Candida albicans to the Murine Gastrointestinal Tract Requires Efg1p-Dependent Regulation of Metabolic and Host Defense Genes

“…7). When mice deficient in the production of ROS were orally inoculated with C. albicans, both the efg1 Ϫ null mutant and WT cells killed mice with equal efficiency (84). This observation suggests that a major defect of the efg1 Ϫ null mutant strain is its sensitivity to ROS production by the host.…”

LiveCandida albicansSuppresses Production of Reactive Oxygen Species in Phagocytes

“…An immunomodulatory role for ROS is supported by studies in which mice deficient in production of both ROS and reactive nitrogen intermediates were inoculated with Candida via the gastrointestinal tract (3). Although all of these mice died after inoculation, the cause of death appeared to be an exaggerated immune response rather than overwhelming fungal infection.…”