The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen <i>Candida glabrata</i>

Bernardo, Ruben; Cunha, Diana V.; Wang, Can; Pereira, Leonel; Silva, Sónia; Salazar, Sara B.; Schröder, Markus S.; Okamoto, Michiyo; Takahashi‐Nakaguchi, Azusa; Chibana, Hiroji; Aoyama, Toshihiro; Sá‐Correia, Isabel; Azeredo, Joana; Butler, Geraldine; Mira, Nuno P.

doi:10.1534/g3.116.034660

Cited by 26 publications

(32 citation statements)

References 58 publications

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“…The homolog of S. cerevisiae Aqr1 in C. glabrata , CgAqr1, has been linked to flucytosine and clotrimazole resistance, as well as resistance against acetic acid [ 27 ]. Such a role in the resistance to acetic acid is also performed by the MFS-MDR CgDtr1 and CgTpo3 transporters [ 139 , 140 ], being the later controlled by the CgHaa1 transcription factor, known to regulate the response of C. glabrata to acetic acid [ 140 ]. These different roles of MFS transporters [ 14 , 20 ] point out their importance for the survival of such pathogens in acidic human microenvironments.…”

Section: Mdr Transporters In Fungal Pathogens: Mediating the Transmentioning

confidence: 99%

Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

Cavalheiro

Pais

Galocha

et al. 2018

Genes

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Fungal infections caused by Candida, Aspergillus, and Cryptococcus species are an increasing problem worldwide, associated with very high mortality rates. The successful prevalence of these human pathogens is due to their ability to thrive in stressful host niche colonization sites, to tolerate host immune system-induced stress, and to resist antifungal drugs. This review focuses on the key role played by multidrug resistance (MDR) transporters, belonging to the ATP-binding cassette (ABC), and the major facilitator superfamilies (MFS), in mediating fungal resistance to pathogenesis-related stresses. These clearly include the extrusion of antifungal drugs, with C. albicans CDR1 and MDR1 genes, and corresponding homologs in other fungal pathogens, playing a key role in this phenomenon. More recently, however, clues on the transcriptional regulation and physiological roles of MDR transporters, including the transport of lipids, ions, and small metabolites, have emerged, linking these transporters to important pathogenesis features, such as resistance to host niche environments, biofilm formation, immune system evasion, and virulence. The wider view of the activity of MDR transporters provided in this review highlights their relevance beyond drug resistance and the need to develop therapeutic strategies that successfully face the challenges posed by the pleiotropic nature of these transporters.

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Section: Mdr Transporters In Fungal Pathogens: Mediating the Transmentioning

confidence: 99%

Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

Cavalheiro

Pais

Galocha

et al. 2018

Genes

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“…Consistent with this, a drop in internal pH has been reported to occur when C. glabrata cells are challenged with inhibitory concentrations of acetic acid ( Bairwa and Kaur, 2011 ; Ullah et al, 2013b ). To counter-act the acid-induced intracellular acidification C. glabrata cells rely on the activity of the plasma membrane H + -ATPase CgPma1 which pumps the exceeding protons to the outside of the cell, this response also contributing to maintain the electrochemical gradient across the plasma membrane which is essential for the activity of secondary transporters ( Ullah et al, 2013b ; Bernardo et al, 2017 ). Because acetate and lactate cannot cross the plasma membrane by passive diffusion due to their negative charge, their accumulation inside C. glabrata is expected.…”

Section: Introductionmentioning

confidence: 99%

“…Because acetate and lactate cannot cross the plasma membrane by passive diffusion due to their negative charge, their accumulation inside C. glabrata is expected. It was recently shown the important role of the multidrug resistance transporter CgTpo3 in contributing to reduce the internal concentration of acetic acid when cells are subjected to inhibitory concentration of this acid ( Bernardo et al, 2017 ). CgAqr1, also recently characterized as a drug efflux pump, was also found to provide protection against acetic acid in C. glabrata , however, in this case this did not resulted from a role of this transporter in mediating the extrusion of the acid anion ( Costa et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights Underlying Tolerance to Acetic Acid Stress in Vaginal Candida glabrata Clinical Isolates

et al. 2017

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During colonization of the vaginal tract Candida glabrata cells are challenged with the presence of acetic acid at a low pH, specially when dysbiosis occurs. To avoid exclusion from this niche C. glabrata cells are expected to evolve efficient adaptive responses to cope with this stress; however, these responses remain largely uncharacterized, especially in vaginal strains. In this work a cohort of 18 vaginal strains and 2 laboratory strains (CBS138 and KUE100) were phenotyped for their tolerance against inhibitory concentrations of acetic acid at pH 4. Despite some heterogeneity has been observed among the vaginal strains tested, in general these strains were considerably more tolerant to acetic acid than the laboratory strains. To tackle the mechanistic insights behind this differential level of tolerance observed, a set of vaginal strains differently tolerant to acetic acid (VG281∼VG49 < VG99 < VG216) and the highly susceptible laboratory strain KUE100 were selected for further studies. When suddenly challenged with acetic acid the more tolerant vaginal strains exhibited a higher activity of the plasma membrane proton pump CgPma1 and a reduced internal accumulation of the acid, these being two essential features to maximize tolerance. Based on the higher level of resistance exhibited by the vaginal strains against the action of a β-1,3-glucanase, it is hypothesized that the reduced internal accumulation of acetic acid inside these strains may originate from them having a different cell wall structure resulting in a reduced porosity to undissociated acetic acid molecules. Both the vaginal and the two laboratory strains were found to consume acetic acid in the presence of glucose indicating that metabolization of the acid is used by C. glabrata species as a detoxification mechanism. The results gathered in this study advance the current knowledge on the mechanisms underlying the increased competitiveness of C. glabrata in the vaginal tract, a knowledge that can be used to guide more suitable strategies to treat infections caused by this pathogenic yeast.

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“…Besides CgHog1, other components such as, for example, CgHaa1 might contribute to the variation of intrinsic resistance of isolates observed here. CgHaa1 regulates about 75% of all acetic acid induced genes (Bernardo et al, 2017) and deletion of Haa1 resulted in a growth phenotype on lactic acid and other weak organic acids. However, our results confirm Cg HOG1 as a bottleneck in the complex regulative pattern of weak acid resistance.…”

Section: Discussionmentioning

confidence: 99%

Competition ofCandida glabrataagainstLactobacillusis Hog1 dependent

Beyer

Jandric

Zutz

et al. 2018

Cellular Microbiology

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Candida glabrata is a common human fungal commensal and opportunistic pathogen. This fungus shows remarkable resilience as it can form recalcitrant biofilms on indwelling catheters, has intrinsic resistance against azole antifungals, and is causing vulvovaginal candidiasis. As a nosocomial pathogen, it can cause life‐threatening bloodstream infections in immune‐compromised patients. Here, we investigate the potential role of the high osmolarity glycerol response (HOG) MAP kinase pathway for C. glabrata virulence. The C. glabrata MAP kinase CgHog1 becomes activated by a variety of environmental stress conditions such as osmotic stress, low pH, and carboxylic acids and subsequently accumulates in the nucleus. We found that CgHog1 allows C. glabrata to persist within murine macrophages, but it is not required for systemic infection in a mouse model. C. glabrata and Lactobacilli co‐colonise mucosal surfaces. Lactic acid at a concentration produced by vaginal Lactobacillus spp. causes CgHog1 phosphorylation and accumulation in the nucleus. In addition, CgHog1 enables C. glabrata to tolerate different Lactobacillus spp. and their metabolites when grown in co‐culture. Using a phenotypic diverse set of clinical C. glabrata isolates, we find that the HOG pathway is likely the main quantitative determinant of lactic acid stress resistance. Taken together, our data indicate that CgHog1 has an important role in the confrontation of C. glabrata with the common vaginal flora.

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The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen Candida glabrata

Cited by 26 publications

References 58 publications

Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

Mechanistic Insights Underlying Tolerance to Acetic Acid Stress in Vaginal Candida glabrata Clinical Isolates

Competition ofCandida glabrataagainstLactobacillusis Hog1 dependent

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