Candidiasis in Interferon-  Knockout (IFN- -/-) Mice

Balish, Edward; Rd, Wagner; Vázquez‐Torres, Andrés; Pierson, C; Warner, Thomas F.

doi:10.1086/515645

Cited by 97 publications

(72 citation statements)

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“…The highest fungal loads in both strains of mice were detected in the kidney, with the kidneys of A/J mice containing an approximately 100-fold greater number of fungi at this point in the infection process. The levels of several cytokines that had previously been reported to be elevated during systemic C. albicans infection 8,[23][24][25][26] were measured in A/J and B6. Cytokine levels were measured by ELISA in serum isolated from A/J and B6 mice 48 h after low dose injection with C. albicans blastospores.…”

Section: Resultsmentioning

confidence: 99%

Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

et al. 2005

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The importance of host factors in determining susceptibility to systemic Candida albicans infections is evident in both humans and mice. We have used a mouse model to study the genetic basis of susceptibility, using the inbred strains A/J and C57BL/6J, which are susceptible and resistant, respectively, based on different parameters of the response to infection. To identify genes responsible for this differential host response, brain and kidney fungal load were measured in 128 [A/J Â C57BL/6J] F 2 mice 48 h after infection with 5 Â 10 4 C. albicans blastospores. Segregation analysis in this informative population identified complement component 5 (C5/Hc) as the major gene responsible for this differential susceptibility (LOD of 22.7 for kidney, 19.0 for brain), with a naturally occurring mutation that causes C5 deficiency leading to enhanced susceptibility. C5 was also found to control heart fungal load, survival time, and serum TNF-a levels during infection. Investigation of the response to C. albicans challenge in a series of AcB/BcA recombinant congenic strains validated the importance of C5 in determining the host response. However, the strains BcA67 and BcA72 showed discordant phenotypes with respect to their C5 status, suggesting additional complexity in the genetic control of the inter-strain difference in susceptibility observed in A/J and C57BL/6J following systemic infection with C. albicans. Genes and Immunity (2005) 6, 672-682.

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Section: Resultsmentioning

confidence: 99%

Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

et al. 2005

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“…IFN-γ produced by Th1 lymphocytes is fundamental for stimulating the antifungal activity of neutrophils. The central role of endogenous IFN-γ in the resistance against systemic fungal infection is underscored by the observation that KO mice deficient in IFN-γ are highly susceptible to disseminated C. albicans infection [36]. In addition, mice deficient in IL-18, which plays a crucial role in the induction of IFN-γ, are also more susceptible to disseminated candidiasis [37].…”

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Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

2014

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Human holobiomes are networks of mutualistic interactions between human cells and complex communities of bacteria and fungi that colonize the human body. The immune system must tolerate colonization with commensal bacteria and fungi but defend against invasion by either organism. Molecular ecological surveys of the human prokaryotic microbiota performed to date have revealed a remarkable degree of bacterial diversity and functionality. However, there is a dearth of information regarding the eukaryotic composition of the microbiota. In this review, we describe the ecology and the human niches of our fungal "fellow travelers" in both health and disease, discriminating between passengers, colonizers, and pathogens based on the interaction of these fungi with the human immune system. We conclude by highlighting the need to reconsider the etiology of many fungal and immune-related diseases in the context of the crosstalk between the human system and its resident microbial communities.Keywords: Dysbiosis r Fungal metagenomics r Host-microbe interaction r Mycobiota IntroductionHumans live in close association with a complex community of bacteria, viruses, fungi, and archaea [1][2][3], which inhabit their bodies. Many groups have surveyed these microbial populations using the so-called "next generation" or "deep" sequencing approaches, revealing that the human microbiota differs radically at various body sites and among individuals [2][3][4]. The differences in the human microbiota are influenced by the availability of nutrients, environmental exposure to microorganisms, and other sitespecific features, such as the immunological makeup of a given location. The origin of differences in the microbiota between individuals potentially reflects different patterns of colonization early in life (reviewed in [5]), different dietary regimens [6,7], and different environmental exposures, such as antibiotic use [8,9]. Recently, the application of deep sequencing approaches have genCorrespondence: Dr. Duccio Cavalieri e-mail: duccio.cavalieri@fmach.it erated novel hypotheses about the microbial determinants underlying human disorders of immune origin (reviewed in [10]). Several metabolites of the interaction between diet and host microbiota, such as short-chain fatty acids, have been shown to play a fundamental role in shaping immune responses (reviewed in [11]). The application of microbial ecology concepts is ultimately leading to the conclusion that health and disease can be understood only through an understanding of the ways in which the symbiotic interactions between microbes and human organs harmonically integrate in the context of the hologenome [12].Human microbial diversity is not limited to bacteria; microorganisms such as fungi also play major roles in the stability of microbial communities in human health and disease (reviewed in [13]). Yeasts were detected in human stool samples as far back as 1917, and by the mid-20th century the presence of yeasts in the human intestine was proposed to have a saprotrophic role [14]....

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“…Initial recognition of Candida yeast and filamentous forms occurs through pathogen-associated molecular patterns and corresponding pattern recognition receptors, such as C-type lectin receptors and TLRs, whose synergistic interaction can result in augmented downstream immune activation via NF-kB (70,71). In addition, the protective role for the IFN-g axis in C. albicans infection has been demonstrated by increased susceptibility of mice deficient for IFN-g (72) or IFN-g receptor (73). Signaling by IFN-g activates the JAK-STAT pathway and results in binding of IFN regulatory factors, IRF1 and IRF8, as well as STAT1 to IFN-g activation site elements and IFNstimulated response elements, thereby orchestrating and controlling many facets of innate and adaptive immune responses (74).…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

Radovanovic

Leung

Iliescu

et al. 2014

The Journal of Immunology

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In the immunocompromised host, invasive infection with the fungal pathogen Candida albicans is associated with high morbidity and mortality. Sporadic cases in otherwise normal individuals are rare, and they are thought to be associated with genetic predisposition. Using a mouse model of systemic infection with C. albicans, we identified the SM/J mouse strain as unusually susceptible to infection. Genetic linkage studies in informative [C57BL/6JxSM/J]F2 mice identified a major locus on distal chromosome 15, given the appellation Carg5, that regulates C. albicans replication in SM/J mice. Cellular and molecular immunophenotyping experiments, as well as functional studies in purified cell populations from SM/J and C57BL/6J, and in [C57BL/6JxSM/J]F2 mice fixed for homozygous or heterozygous Carg5 alleles, indicate that Carg5-regulated susceptibility in SM/J is associated with a complex defect in the myeloid compartment of these mice. SM/J neutrophils express lower levels of Ly6G, and importantly, they show significantly reduced production of reactive oxygen species in response to stimulation with fMLF and PMA. Likewise, CD11b+Ly6G−Ly6Chi inflammatory monocytes were present at lower levels in the blood of infected SM/J, recruited less efficiently at the site of infection, and displayed blunted oxidative burst. Studies in F2 mice establish strong correlations between Carg5 alleles, Ly6G expression, production of serum CCL2 (MCP-1), and susceptibility to C. albicans. Genomic DNA sequencing of chromatin immunoprecipitated for myeloid proinflammatory transcription factors IRF1, IRF8, STAT1 and NF-κB, as well as RNA sequencing, were used to develop a “myeloid inflammatory score” and systematically analyze and prioritize potential candidate genes in the Carg5 interval.

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Candidiasis in Interferon- Knockout (IFN- -/-) Mice

Cited by 97 publications

References 0 publications

Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

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