Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen

Ene, Iuliana V.; Adya, Ashok K.; Wehmeier, Silvia; Brand, Alexandra; MacCallum, Donna M.; Gow, Neil A. R.; Brown, Alistair J. P.

doi:10.1111/j.1462-5822.2012.01813.x

Cited by 260 publications

(349 citation statements)

References 75 publications

(119 reference statements)

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“…Moreover, the available carbon source regulates morphogenesis, cell wall structure and stress responses (22,71,72). Catabolism of amino acids, which appear to be readily available in many host niches, also strongly affects the interaction of C. albicans with the host, by allowing the pathogen to modulate the surrounding pH.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of metabolic adaptation is underscored by the decreased virulence in animal models of C. albicans strains that are defective in the glyoxylate cycle and in ␤-oxidation (18-21). Furthermore, carbon source utilization plays a significant role in cell wall composition, stress susceptibility, and phagocyte recognition (22,23).Our laboratory has demonstrated that C. albicans grown in vitro in medium that mimics the nutrients predicted to be available after phagocytosis rapidly alkalinizes the extracellular environment (24). This process depends upon the utilization of amino acids as a carbon source and leads to the extrusion of ammonia from the cell, which is derived from amino acid catabolism.…”

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The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

Danhof

Lorenz

2015

Infect Immun

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Candida albicans is an opportunistic human fungal pathogen that causes a variety of diseases, ranging from superficial mucosal to life-threatening systemic infections, the latter particularly in patients with defects in innate immune function. C. albicans cells phagocytosed by macrophages undergo a dramatic change in their metabolism in which amino acids are a key nutrient. We have shown that amino acid catabolism allows the cell to neutralize the phagolysosome and initiate hyphal growth. We show here that members of the 10-gene ATO family, which are induced by phagocytosis or the presence of amino acids in an Stp2-dependent manner and encode putative acetate or ammonia transporters, are important effectors of this pH change in vitro and in macrophages. When grown with amino acids as the sole carbon source, the deletion of ATO5 or the expression of a dominantnegative ATO1G53D allele results in a delay in alkalinization, a defect in hyphal formation, and a reduction in the amount of ammonia released from the cell. These strains also form fewer hyphae after phagocytosis, have a reduced ability to escape macrophages, and reside in more acidic phagolysosomal compartments than wild-type cells. Furthermore, overexpression of many of the 10 ATO genes accelerates ammonia release, and an ato5⌬ ATO1 G53D double mutant strain has additive alkalinization and ammonia release defects. Taken together, these results indicate that the Ato protein family is a key mediator of the metabolic changes that allow C. albicans to overcome the macrophage innate immunity barrier. Candida albicans is an opportunistic pathogen that colonizes the skin and gastrointestinal and genitourinary tracts of most healthy individuals but also causes a range of diseases, from nonlethal mucosal infections, such as oral thrush and vaginitis, to disseminated hematogenous candidiasis, the latter in immunocompromised individuals (1-3). As the fourth most prevalent cause of hospital-acquired infection, disseminated candidiasis is very difficult to treat, prolongs hospitalization, and has a mortality rate of ϳ40% (4-6). The high mortality rates and large health care burden associated with C. albicans infection highlight the importance of understanding the physiology, virulence factors, and host-pathogen interactions of C. albicans.The healthy immune system is able to effectively prevent systemic candidiasis; however, advances in health care have increased the population of individuals surviving despite immune dysfunctions. Conditions that predispose individuals to disseminated candidiasis include hematological malignancies, genetic immune disorders, HIV/AIDS, and iatrogenic interventions, including organ transplantation, chemotherapy, and invasive procedures (3, 7). The interaction between the innate immune system and C. albicans is a primary determinant of disease progression, as those with innate immune defects are more susceptible to serious infection (8). Macrophages, along with other professional phagocytes, are key components of the innate immune respons...

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Section: Discussionmentioning

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The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

Danhof

Lorenz

2015

Infect Immun

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“…7 The food source used by Candida in a particular niche is not a trivial detail, as studies have clearly indicated the effects of environmental cues, such as nutrient availability, on cell wall architecture [43][44][45] which impacts interactions between Candida and immune cells. Recent in vitro work has shown that in the presence of lactic acid (as the sole carbon source) C. albicans is taken up by macrophages less efficiently and can alter immune cell cytokine profiles, specifically by increasing IL-10 and decreasing IL-17 production.…”

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The vaginal mycobiome: A contemporary perspective on fungi in women's health and diseases

2016

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Most of what is known about fungi in the human vagina has come from culture-based studies and phenotypic characterization of single organisms. Though valuable, these approaches have masked the complexity of fungal communities within the vagina. The vaginal mycobiome has become an emerging field of study as genomics tools are increasingly employed and we begin to appreciate the role these fungal communities play in human health and disease. Though vastly outnumbered by its bacterial counterparts, fungi are important constituents of the vaginal ecosystem in many healthy women. Candida albicans, an opportunistic fungal pathogen, colonizes 20% of women without causing any overt symptoms, yet it is one of the leading causes of infectious vaginitis. Understanding its mechanisms of commensalism and pathogenesis are both essential to developing more effective therapies. Describing the interactions between Candida, bacteria (such as Lactobacillus spp.) and other fungi in the vagina is fundamental to our characterization of the vaginal mycobiome.

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“…Phenotypic switching (yeast-to-hyphal and white-to-opaque) and variations in growth conditions are likely scenarios in the variety of niches that C. albicans inhabits in the human host. In addition, environmental cues, such as changes in ambient pH or carbon source, drive changes in the C. albicans cell wall proteome (12,13) and the thickness and architecture of the different cell wall layers (14,15,16).…”

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Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

et al. 2013

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bCandida albicans is a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status. C. albicans regularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses to C. albicans have been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth of C. albicans cells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grown C. albicans stimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinical C. albicans isolates from different host niches and from different epidemiological clades. In addition, lactate-grown C. albicans cells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon the C. albicans interaction with the innate immune system.

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Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen

Cited by 260 publications

References 75 publications

The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

The vaginal mycobiome: A contemporary perspective on fungi in women's health and diseases

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

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