Enhancing effect of oxygen radical scavengers on murine macrophage anticryptococcal activity through production of nitric oxide

Tohyama, Masaki; Kawakami, Kazuyoshi; Futenma, Mitsuhiko; Saitô, Atsushi

doi:10.1111/j.1365-2249.1996.tb08299.x

Cited by 55 publications

(18 citation statements)

References 34 publications

(14 reference statements)

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“…IFN-␥ is a required cytokine for elimination of C. neoformans, with a mechanism that works by activating the NO-dependent killing activity of macrophages (6,42). In our model, IFN-␥ production was markedly reduced on day 3 and clearance of C. neoformans was attenuated on day 5 postinfection in CARD9 KO mice.…”

Section: Discussionmentioning

confidence: 76%

Defect of CARD9 Leads to Impaired Accumulation of Gamma Interferon-Producing Memory Phenotype T Cells in Lungs and Increased Susceptibility to Pulmonary Infection with Cryptococcus neoformans

et al. 2014

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e Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule signal that is critical for NF-B activation and is triggered through C-type lectin receptors (CLRs), which are pattern recognition receptors that recognize carbohydrate structures. Previous studies have reported that Cryptococcus neoformans, a fungal pathogen that causes meningoencephalitis in AIDS patients, is recognized through some CLRs, such as mannose receptors or DC-SIGN. However, the role of CARD9 in the host defense against cryptococcal infection remains to be elucidated. In the present study, we analyzed the role of CARD9 in the host defense against pulmonary infection with C. neoformans. CARD9 gene-disrupted (knockout [KO]) mice were highly susceptible to this infection, as shown by the reduced fungal clearance in the infected lungs of CARD9 KO mice, compared to that in wild-type (WT) mice. Gamma interferon (IFN-␥) production was strongly reduced in CARD9 KO mice during the innate-immunity phase of infection. Reduced IFN-␥ synthesis was due to impaired accumulation of NK and memory phenotype T cells, which are major sources of IFN-␥ innate-immunity-phase production; a reduction in the accumulation of these cells was correlated with reduced CCL4, CCL5, CXCL9, and CXCL10 synthesis. However, differentiation of Th17 cells, but not of Th1 cells, was impaired at the adaptive-immunity phase in CARD9 KO mice compared to WT mice, although there was no significant difference in the infection susceptibility between interleukin 17A (IL-17A) KO and WT mice. These results suggest that CARD9 KO mice are susceptible to C. neoformans infection probably due to the reduced accumulation of IFN-␥-expressing NK and memory phenotype T cells at the early stage of infection.

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Section: Discussionmentioning

confidence: 76%

Defect of CARD9 Leads to Impaired Accumulation of Gamma Interferon-Producing Memory Phenotype T Cells in Lungs and Increased Susceptibility to Pulmonary Infection with Cryptococcus neoformans

et al. 2014

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“…Melanin-deficient C. neoformans possess a reduced capacity to kill mice (17), and CuSOD lacking Cryptococcus displaying attenuated growth within macrophages (18). The improved killing of C. neoformans in the absence of ROS has been described previously in vitro, whereby incubation of peritoneal macrophages with SOD and catalase augments anticryptococcal activity owing to a concomitant increase in NO production (38).…”

Section: Discussionmentioning

confidence: 92%

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Snelgrove

Edwards

Williams

et al. 2006

The Journal of Immunology

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In recent years, the prevalence of invasive fungal infections has increased, attributed mostly to the rising population of immunocompromised individuals. Cryptococcus neoformans has been one of the most devastating, with an estimated 6–8% of AIDS-infected patients succumbing to Cryptococcus-associated meningitis. Reactive oxygen species (ROS) are potent antimicrobial agents but also play a significant role in regulating immune cell phenotype, but cause immunopathology when produced in excess. We now show that mice lacking phagocyte NADPH oxidase have heightened macrophage and Th1 responses and improved pathogen containment within pulmonary granulomatous lesions. Consequently, dissemination of this fungus to the brain is diminished, an effect that is independent of IL-12. Similar results are described using the metalloporphyrin antioxidant manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin, which also promoted a protective Th1 response and reduced dissemination to the brain. These findings are in sharp contrast to the protective potential of ROS against other fungal pathogens, and highlight the pivotal role that ROS can fulfill in shaping the profile of the host’s immune response.

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“…Though the response to nitrosative stress has not been studied in Cryptococcus neoformans, it has been implicated in both stress resistance and virulence of this fungal pathogen (10,33,36). It has been shown that macrophages produce nitric oxide in response to cryptococcal cells (20) and that the anticryptococcal activity of macrophages is mostly dependent on RNS (48). Recently, it was determined that during experimental cryptococcosis, the inducible form of nitric oxide synthase (iNOS) is expressed at increasing levels during infection (30).…”

mentioning

confidence: 99%

Posttranslational, Translational, and Transcriptional Responses to Nitric Oxide Stress in Cryptococcus neoformans : Implications for Virulence

Missall¹,

Pusateri²,

Donlin

et al. 2006

Eukaryot Cell

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The ability of the fungal pathogen Cryptococcus neoformans to evade the mammalian innate immune response and cause disease is partially due to its ability to respond to and survive nitrosative stress. In this study, we use proteomic and genomic approaches to elucidate the response of C. neoformans to nitric oxide stress. This nitrosative stress response involves both transcriptional, translational, and posttranslational regulation. Proteomic and genomic analyses reveal changes in expression of stress response genes. In addition, genes involved in cell wall organization, respiration, signal transduction, transport, transcriptional control, and metabolism show altered expression under nitrosative conditions. Posttranslational modifications of transaldolase (Tal1), aconitase (Aco1), and the thiol peroxidase, Tsa1, are regulated during nitrosative stress. One stress-related protein up-regulated in the presence of nitric oxide stress is glutathione reductase (Glr1). To further investigate its functional role during nitrosative stress, a deletion mutant was generated. We show that this glr1⌬ mutant is sensitive to nitrosative stress and macrophage killing in addition to being avirulent in mice. These studies define the response to nitrosative stress in this important fungal pathogen.To survive the oxidative and nitrosative attack initiated by phagocytic cells of the host, pathogens must respond appropriately (reviewed in reference 35). This antimicrobial attack is established by two main systems including the inducible nitric oxide synthase pathway and the NADPH oxidase pathway (14). These two pathways generate either reactive nitrogen species (RNS) or reactive oxygen species. In the absence of either of these two pathways, mammalian hosts are more susceptible to both bacterial and fungal infections (18, 41). To cause infection, pathogens must evade the immune system by initiating a response to the stresses encountered.Previously, transcriptional responses to temperature, osmotic, and hydrogen peroxide stress as well as the stresses encountered in macrophages have been studied in fungi, including Saccharomyces cerevisiae and Candida albicans (13,25,29). A proteomic response to stress has only been determined in S. cerevisiae during hydrogen peroxide exposure (17). Proteomic analysis of the nitrosative stress response has not been studied in fungi, though transcriptional responses to RNS have been recently described in S. cerevisiae, C. albicans, and Histoplasma capsulatum (21,39,46). Though the response to nitrosative stress has not been studied in Cryptococcus neoformans, it has been implicated in both stress resistance and virulence of this fungal pathogen (10,33,36). It has been shown that macrophages produce nitric oxide in response to cryptococcal cells (20) and that the anticryptococcal activity of macrophages is mostly dependent on RNS (48). Recently, it was determined that during experimental cryptococcosis, the inducible form of nitric oxide synthase (iNOS) is expressed at increasing levels during infection (...

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Enhancing effect of oxygen radical scavengers on murine macrophage anticryptococcal activity through production of nitric oxide

Cited by 55 publications

References 34 publications

Defect of CARD9 Leads to Impaired Accumulation of Gamma Interferon-Producing Memory Phenotype T Cells in Lungs and Increased Susceptibility to Pulmonary Infection with Cryptococcus neoformans

Defect of CARD9 Leads to Impaired Accumulation of Gamma Interferon-Producing Memory Phenotype T Cells in Lungs and Increased Susceptibility to Pulmonary Infection with Cryptococcus neoformans

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Posttranslational, Translational, and Transcriptional Responses to Nitric Oxide Stress in Cryptococcus neoformans : Implications for Virulence

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