Nutrient acquisition by pathogenic fungi: Nutrient availability, pathway regulation, and differences in substrate utilization

Fleck, Christian B.; Schöbel, Felicitas; Brock, Matthias

doi:10.1016/j.ijmm.2011.04.007

Cited by 89 publications

(83 citation statements)

References 110 publications

(116 reference statements)

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“…Acquisition and utilization of available nutrients from the host is fundamental to the survival and pathogenicity of microorganisms, and the host uses nutrient deprivation and sequestration as a defense mechanism to limit microbial growth. Pathogens have to identify ready sources of nutrients in a host, and it is clear that some are scarce, such as nucleotides and iron, since mutants impaired in the synthesis or uptake of these compounds are avirulent in many pathogens (47)(48)(49). In contrast, amino acids appear abundant, since many (but not all) auxotrophic mutants retain full virulence (4,50,51).…”

Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

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

Danhof

Lorenz

2015

Infect Immun

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“…It is assumed that the nutritional versatility of C. albicans contributes to its ability to grow in different host niches and to infect virtually all body locations (1). For example, in contrast to its normally nonpathogenic relative Saccharomyces cerevisiae, C. albicans can utilize proteins as a nitrogen source by the secretion of aspartic proteases (SAPs) (2).…”

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confidence: 99%

Roles of Different Peptide Transporters in Nutrient Acquisition in Candida albicans

et al. 2013

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Fungi possess two distinct proton-coupled peptide transport systems, the dipeptide/tripeptide transporters (PTR) and the oligopeptide transporters (OPT), which enable them to utilize peptides as nutrients. In the pathogenic yeast Candida albicans, peptide transporters are encoded by gene families consisting of two PTR genes and eight OPT genes. To gain insight into the functions and importance of specific peptide transporters, we generated mutants lacking the two dipeptide/tripeptide transporters Ptr2 and Ptr22, as well as the five major oligopeptide transporters Opt1 to Opt5. These mutants were unable to grow in media containing peptides as the sole nitrogen source. Forced expression of individual peptide transporters in the septuple mutants showed that Ptr2 and Ptr22 could utilize all tested dipeptides as substrates but differed in their abilities to transport specific tripeptides. Interestingly, several oligopeptide transporters, which are thought to transport peptides consisting of more than three amino acids, also mediated the uptake of tripeptides. Opt1 especially turned out to be a highly flexible transporter that enabled growth on all tripeptides tested and could even utilize a dipeptide, a function that has never been ascribed to this family of peptide transporters. Despite their inability to grow on proteins or peptides, the opt1⌬ opt2⌬ opt3⌬ opt4⌬ opt5⌬ ptr2⌬ ptr22⌬ septuple mutants had no in vivo fitness defect in a mouse model of gastrointestinal colonization. Therefore, the nutritional versatility of C. albicans enables it to utilize alternative nitrogen sources in this host niche, which probably contributes to its success as a commensal and pathogen in mammalian hosts.

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“…Rementaria et al (21), showed that the absence of this protein increased the virulence of the fungus (22). In addition, mutations of gel2 and glfA which encode glucanosyltransferase and UDP galactomutase, respectively, resulted in the hypo-virulence of A. fumigatus (23).…”

Section: Cell Wall Components and Integritymentioning

confidence: 99%

“…An essential requirement for the initiation of infection with pathogenic fungi in the host cells is the availability of nutrients and their uptake to adapt to shifting environments (23). For this condition to occur, A. fumigatus produces various hydrolytic enzymes, including different proteases like aspartic and serine proteases, phospholipases, metalloproteinases and dipeptidyl peptidases which contribute to fungal virulence by facilitating the tissue colonisation process (24).…”

Section: Nutrient Uptake: Iron Uptakementioning

confidence: 99%

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

Ghazaei¹

2017

MJMS

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The virulence of fungi is dependent on multiple factors, including the immune status of patients and biological features of fungi. In particular, the virulence of Aspergillus fumigatus is due to the complex interaction among various molecules involved in thermotolerance (such as ribosomal biogenesis proteins, α-mannosyltransferase and heat shock proteins), pigment production (DHN-melanin), immune evasion (like melanin and hydrophobin) and nutrient uptake (such as siderophores and zinc transporters). Other molecules also play important roles in the virulence of A. fumigatus, including cell wall components and those which maintain its integrity (for instance β-1-3 glucan, α-1-3 glucan, chitin, galactomannan and mannoproteins) and adhesion (such as hydrophobins), as well as various hydrolytic enzymes (such as serine and aspartic protease, phospholipases, metalloproteinase and dipeptidyl peptidases). Signalling molecules (including G-protein, cAMP, Ras protein and calcineurin) also increase the virulence through altering the metabolic response to stress conditions and toxins (such as gliotoxin, fumitremorgins, fumagatin and helvolic acid).

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Nutrient acquisition by pathogenic fungi: Nutrient availability, pathway regulation, and differences in substrate utilization

Cited by 89 publications

References 110 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

Roles of Different Peptide Transporters in Nutrient Acquisition in Candida albicans

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

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