Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans

Lermann, Ulrich; Morschhäuser, Joachim

doi:10.1099/mic.0.2008/022525-0

Cited by 105 publications

(87 citation statements)

References 44 publications

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“…It stands to reason that pathogens would expand gene families that mediate specific interactions with the host, but this has long been very difficult to demonstrate experimentally because of technical limitations in knocking out multigene families. C. albicans has 10 secreted aspartyl proteases (SAPs) with different expression profiles and pH optima, but conclusive evidence of a role in pathogenesis has been elusive (56)(57)(58). In C. glabrata, a compelling virulence phenotype is not observed until one deletes many members of a cell wall-associated protease family (yapsins) (59).…”

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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“…Monolayer cultures of oral keratinocytes have been extensively used to examine the interaction of C. albicans with host cells [21][22][23][24][25], but such studies provide limited information because the oral mucosa is a multi-layered complex tissue and signalling between cells may be important in host defence. Recently, the increased use of the RHOE multi-layered in vitro mucosal model has enabled more complex studies to be performed.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, multi-layered organotypic three-dimensional in vitro culture systems have been developed to mimic the oral mucosa [17][18][19][20]. The reconstituted human oral epithelial (RHOE) model, which is based upon the TR146 buccal carcinoma cell line cultured on a porous polycarbonate insert, has been widely used in C. albicans infection studies [21][22][23][24][25]. More advanced, alternative tissue engineered mucosal models have since been developed that consist of oral keratinocytes cultured on a fibroblast-containing extracellular matrix [20,26,27].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis

Yadev

Murdoch

Saville

et al. 2011

Microbial Pathogenesis

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Candida albicans is a commensal organism that can be isolated from the majority of healthy individuals. However, in certain susceptible individuals C.albicans can become pathogenic leading to the mucocutaneous infection; oral candidiasis. Murine models and in vitro monolayer cultures have generated some data on the likely virulence and host factors that contribute to oral candidiasis but these models have limitations. Recently, tissue engineered oral mucosal models have been developed to mimic the normal oral mucosa but little information is available on their true representation. In this study we assessed the histological features of three different tissue engineered oral mucosal models compared to the normal oral mucosa and analysed both cell damage and cytokine release following infection with C.albicans. Models comprised of normal oral keratinocytes and a fibroblast-containing matrix displayed more similar immunohistological and proliferation characteristics to normal mucosa compared to models composed of an oral carcinoma cell line. Although all models were invaded and damaged by C.albicabs in a similar manner, the cytokine response was much more pronounced in models containing normal keratinocytes. These data suggest that models based on normal keratinocytes atop a fibroblast-containing connective tissue will significantly aid in dissecting the molecular pathogenesis of oral candidiasis.

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“…Furthermore, the level of SAP4 expression does not correlate with the importance of this gene for invasion. As shown Lermann and Morschhäuser [40], Saps are not required for invasion of reconstituted human epithelia (RHE) by C. albicans. Moreover, Langford et al [3] observed the enhanced SAP4 expression in the single null mutants: efg1/efg1 and cph1/cph1 in Lee's medium, which suggested existence of hyphaeindependent regulation pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, of the three genes examined, SAP4 expression had minimal study in C. albicans during epithelial cells colonisation and infection [36]. Moreover, the role of Sap4/5 proteins as the epithelial activating factors was doubtful [40]. Thus, we undertook investigation on the role of SAP4 during hyphae formation and adhesion to epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

The expression of the Candida albicans gene SAP4 during hyphal formation in human serum and in adhesion to monolayer cell culture of colorectal carcinoma Caco-2 (ATCC)

et al. 2014

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Candida albicans SAP4 gene encodes secretory aspartyl protease Sap4 which is involved in hyphae formation and virulence. Transcriptional factors Cph1 and Efg1 govern the expression of several C. albicans genes and contribute to morphogenesis. We investigated the expression of SAP4 in C. albicans clinical isolate and mutants lacking Efg1 or/ and Cph1 grown in human serum and during contact with Caco-2 cell line. mRNA was analyzed with the use of RT-PCR; relative quantification was normalized against an ACT1 in cells after 18-h growth either in serum or on monolayer as well as in their counterparts in YEPD medium. We assessed the role of Sap4, Efg1 and Cph1 in adhesion of C. albicans to epithelial cells. Additionally, adherence assay was performed with sap4/sap4. Adhesion was expressed as a percent of adherent cells to monolayer at 90 min vs. total cells added (100%). No differences were observed in adhesion of efg1/efg1 and sap4/sap4 compared with SC5314 (P≥0.05 statisitically insignificant). SAP4 expression indicated that it is not involved in adapting to the tested conditions. SAP4 expression can be strainspecific and is not solely controlled by the Efg1 pathway but also by the Cph1 pathway. Neither Efg1 nor Sap4 can influence adhesion.

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Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans

Cited by 105 publications

References 44 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

Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis

The expression of the Candida albicans gene SAP4 during hyphal formation in human serum and in adhesion to monolayer cell culture of colorectal carcinoma Caco-2 (ATCC)

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