ÓZ

Óscar Zaragoza

Instituto de Salud Carlos III

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Arturo Casadevall

Johns Hopkins University

Manuel Cuenca‐Estrella

Instituto de Salud Carlos III

Nuria Trevijano‐Contador

Instituto de Salud Carlos III

Rocío García‐Rodas

Instituto de Salud Carlos III

Irene García-Barbazán

Instituto de Salud Carlos III

Cristina Rueda

Instituto de Salud Carlos III

Jesús Guinea

Hospital General Universitario Gregorio Marañón

Suélen Andreia Rossi

Fundação Carlos Chagas

Ana Cecilia Mesa-Arango

Universidad de Antioquia

Juan L. Rodrı́guez-Tudela

Instituto de Salud Carlos III

Cooperative Institutions

Instituto de Salud Carlos III

130

Universidad Complutense de Madrid

Centro Nacional de Microbiologia

Centro de Investigación Biomédica en Red

Consejo Superior de Investigaciones Científicas

Albert Einstein College of Medicine

Universitat de Barcelona

Universidad Autónoma de Madrid

Hospital Universitario 12 De Octubre

Hospital General Universitario Gregorio Marañón

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The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing

Infection and Immunity (2011)

Rocío García‐Rodas Fernando González‐Camacho Juan L. Rodrı́guez-Tudela Manuel Cuenca‐Estrella Óscar Zaragoza

ABSTRACT Candida krusei is a fungal pathogen of interest for the scientific community for its intrinsic resistance to fluconazole. Little is known about the interaction of this yeast with host immune cells. In this work, we have characterized the outcome of the interaction between C. krusei and murine macrophages. Once C. krusei was internalized, we observed different phenomena. In a macrophage-like cell line, C. krusei survived in a significant number of macrophages and induced filamentation and macrophage explosion. Phagocytosis of C. krusei led to actin polymerization around the yeast cells at the site of entry. Fluorescent specific staining with anti-Lamp1 and LysoTracker indicated that after fungal internalization, there was a phagolysosome maturation defect, a phenomenon that was more efficient when the macrophages phagocytosed killed yeast cells. Using cell line macrophages, we also observed macrophage fusion after cell division. When we used primary resident peritoneal macrophages in addition to macrophage explosion, we also observed a strong chemotaxis of uninfected macrophages to regions where C. krusei -infected macrophages were present. We also noticed yeast transfer phenomena between infected macrophages. Primary macrophages inhibited pseudohypha elongation more efficiently than the macrophage-like cell line, suggesting that C. krusei infection was better controlled by the former macrophages. Primary macrophages induced more tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) than the macrophage-like cell line. Our results demonstrate that C. krusei can exploit the macrophages for replication, although other different outcomes are also possible, indicating that the interaction of this pathogen with phagocytic cells is very complex and regulated by multiple factors.

Candida krusei

10.1128/iai.00044-11

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Citations (55)

Isolation of the MIG1 Gene from Candida albicans and Effects of Its Disruption on Catabolite Repression

Journal of Bacteriology (2000)

Óscar Zaragoza Cristina Rodrı́guez Carlos Gancedo

ABSTRACT We have cloned a Candida albicans gene ( CaMIG1 ) that encodes a protein homologous to the DNA-binding protein Mig1 from Saccharomyces cerevisiae ( Sc Mig1). The C. albicans Mig1 protein ( Ca Mig1) differs from Sc Mig1, in that, among other things, it lacks a putative phosphorylation site for Snf1 and presents several long stretches rich in glutamine or in asparagine, serine, and threonine and has the effector domain located at some distance (50 amino acids) from the carboxy terminus. Expression of CaMIG1 was low and was similar in glucose-, sucrose-, or ethanol-containing media. Disruption of the two CaMIG1 genomic copies had no effect in filamentation or infectivity. Levels of a glucose-repressible α-glucosidase, implicated in both sucrose and maltose utilization, were similar in wild-type or mig1/mig1 cells. Disruption of CaMIG1 had also no effect on the expression of the glucose-repressed gene CaGAL1. CaMIG1 was functional in S. cerevisiae , as judged by its ability to suppress the phenotypes produced by mig1 or tps1 mutations. In addition, Ca Mig1 formed specific complexes with the URS1 region of the S. cerevisiae FBP1 gene. The existence of a possible functional analogue of CaMIG1 in C. albicans was suggested by the results of band shift experiments.

10.1128/jb.182.2.320-326.2000

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Citations (59)

Two distinct lipid transporters together regulate invasive filamentous growth in the human fungal pathogen Candida albicans

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Miguel A. Basante-Bedoya Stéphanie Bogliolo Rocío García‐Rodas Óscar Zaragoza Robert A. Arkowitz

Abstract Flippases transport lipids across the membrane bilayer to generate and maintain asymmetry. The human fungal pathogen Candida albicans has 5 flippases, including Drs2, which is critical for filamentous growth and phosphatidylserine (PS) distribution. Furthermore, a drs2 deletion mutant is hypersensitive to the antifungal drug fluconazole and copper ions. We show here that such a flippase mutant also has an altered distribution of phosphatidylinositol 4-phosphate [PI(4)P], and ergosterol. Analyses of additional lipid transporters, i.e. the flippases Dnf1-3, and all the oxysterol binding protein (Osh) family lipid transfer proteins, i.e. Osh2-4 and Osh7, indicate that they are not critical for filamentous growth. However, deletion of Osh4 alone, which exchanges PI(4)P for sterol, in a drs2 mutant can bypass the requirement for this flippase in invasive filamentous growth. In addition, deletion of the lipid phosphatase Sac1, which dephosphorylates PI(4)P, in a drs2 mutant results in a synthetic growth defect, suggesting that Drs2 and Sac1 function in parallel pathways. Together, our results indicate that a balance between the activities of two different classes of lipid transporters regulates invasive filamentous growth, via PI(4)P. In contrast, deletion of OSH4 in drs2 does not restore growth on fluconazole, nor on papuamide A, a toxin that binds PS in the outer leaflet of the plasma membrane, suggesting that Drs2 has additional role(s) in plasma membrane organization, independent of Osh4. As we show that C. albicans Drs2 localizes to different structures, including the Spitzenkörper, we sought to determine if a specific localization of Drs2 is critical for different functions, using a synthetic physical interaction approach to restrict/stabilize Drs2 at the Spitzenkörper. Our results suggest that Drs2 plasma membrane localization is critical for C. albicans growth on fluconazole and papuamide A, but not for invasive filamentous growth.

Flippase

Ergosterol

Transport protein

10.1101/2022.08.30.505893

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The Capsule of the Fungal Pathogen Cryptococcus neoformans Paradoxically Inhibits Invasive Growth

The Open Mycology Journal (2008)

Óscar Zaragoza Manuel Cuenca‐Estrella Javier Regadera Juan Luis Rodríguez Tudela

Fungal pathogen

Opportunistic pathogen

10.2174/1874437000802010029

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Citations (3)

Impact of Resistance to Fluconazole on Virulence and Morphological Aspects of Cryptococcus neoformans and Cryptococcus gattii Isolates

Frontiers in Microbiology (2016)

Suélen A. Rossi Nuria Trevijano‐Contador Liliana Scorzoni Ana Cecilia Mesa-Arango Haroldo César de Oliveira

Cryptococcus sp. are responsible for around 1 million cases of meningitis every year. Fluconazole (FLU) is commonly used in the treatment of cryptococcosis, mainly in immunocompromised patients and the resistance is usually reported after long periods of treatment. In this study, the morphological characterization and virulence profile of FLU-susceptible and FLU-resistant clinical and environmental isolates of C. neoformans and C. gattii were performed both in vitro and in vivo using the Galleria mellonella model. FLU-susceptible isolates from C. neoformans were significantly more virulent than the FLU-resistant isolates. FLU-susceptible C. gattii isolates showed a different virulence profile from C. neoformans isolates where only the environmental isolate, CL, was more virulent compared with the resistant isolates. Cell morphology and capsule size were analyzed and the FLU-resistant isolates did not change significantly compared with the most sensitive isolates. Growth at 37°C was also evaluated and in both species, the resistant isolates showed a reduced growth at this temperature, indicating that FLU resistance can affect their growth. Based on the results obtained is possible suggest that FLU resistance can influence the morphology of the isolates and consequently changed the virulence profiles. The most evident results were observed for C. neoformans showing that the adaptation of isolates to antifungal selective pressure influenced the loss of virulence.

Galleria mellonella

Cryptococcus gattii

10.3389/fmicb.2016.00153

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Citations (25)

Role of Catalase Overproduction in Drug Resistance and Virulence in Candida Albicans

Future Microbiology (2016)

Elvira Román Daniel Prieto R Julián Martín Inês Correia Ana Cecilia Mesa Arango

To investigate the role of Cat1 overproduction in Candida albicans.Strains overproducing the CAT1 gene were constructed.Cells overproducing CAT1 were found to be more resistant to some oxidants and mammalian phagocytic cells. They also showed reduced intracellular reactive oxygen species generated by amphotericin B or ciclopirox olamine. CAT1 overproduction did not change the minimum inhibitory concentration of fungal cells to fungistatic or fungicidal azoles nor to amphotericin B although increased twofold the minimum inhibitory concentration to caspofungin. The role of Cat1 overproduction in virulence and colonization was also analyzed in mouse models.The overproduction of Cat1 protects against oxidants, phagocytes and certain antifungals at subinhibitory concentration but does not increase virulence in a systemic infection mouse model.

Overproduction

Antifungal drugs

10.2217/fmb-2016-0067

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Citations (19)

Trehalose accumulation induced during the oxidative stress response is independent of TPS1 mRNA levels in Candida albicans

International Microbiology (2003)

Óscar Zaragoza Pilar Gonz�lez-P�rraga Yolanda Pedre�o Francisco J. Alvarez-Peral Juan-Carlos Arg�elles

Trehalase

10.1007/s10123-003-0119-y

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Citations (19)

Adaptation of the emerging pathogenic yeast Candida auris to high caspofungin concentrations correlates with cell wall changes

Figshare (2021)

Violeta Lara‐Aguilar Cristina Rueda Irene García-Barbazán Sarai Varona Sara Monzón

Candida auris has emerged as a fungal pathogen that causes nosocomial outbreaks worldwide. Diseases caused by this fungus are of concern, due to its reduced susceptibility to several antifungals. C. auris exhibits paradoxical growth (PG; defined as growth at high, but not intermediate antifungal concentrations) in the presence of caspofungin (CPF). We have characterized the cellular changes associated with adaptation to CPF. Using EUCAST AFST protocols, all C. auris isolates tested showed PG to CPF, although in some isolates it was more prominent. Most isolates also showed a trailing effect (TE) to micafungin and anidulafungin. We identified two FKS genes in C. auris that encode the echinocandins target, namely β-1,3-glucan synthase. FKS1 contained the consensus hot-spot (HS) 1 and HS2 sequences. FKS2 only contained the HS1 region which had a change (F635Y), that has been shown to confer resistance to echinocandins in C. glabrata. PG has been characterized in other species, mainly C. albicans, where high CPF concentrations induced an increase in chitin, cell volume and aggregation. In C. auris CPF only induced a slight accumulation of chitin, and none of the other phenomena. RNAseq experiments demonstrated that CPF induced the expression of genes encoding several GPI-anchored cell wall proteins, membrane proteins required for the stability of the cell wall, chitin synthase and mitogen-activated protein kinases (MAPKs) involved in cell integrity, such as BCK2, HOG1 and MKC1 (SLT2). Our work highlights some of the processes induced in C. auris to adapt to echinocandins.

Candida auris

10.6084/m9.figshare.14866869.v1

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Citations (0)

Affinity of cefotiam for the alternative penicillin binding protein PBP3SAL used by Salmonella inside host eukaryotic cells

Journal of Antimicrobial Chemotherapy (2022)

Juan J. Cestero Sónia Castanheira Henar Lanza González Óscar Zaragoza Francisco García‐del Portillo

Abstract Background Following the invasion of eukaryotic cells, Salmonella enterica serovar Typhimurium replaces PBP2/PBP3, main targets of β-lactam antibiotics, with PBP2SAL/PBP3SAL, two homologue peptidoglycan synthases absent in Escherichia coli. PBP3SAL promotes pathogen cell division in acidic environments independently of PBP3 and shows low affinity for β-lactams that bind to PBP3 such as aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefalotin. Objectives To find compounds with high affinity for PBP3SAL to control Salmonella intracellular infections. Methods An S. Typhimurium ΔPBP3 mutant that divides using PBP3SAL and its parental wild-type strain, were exposed to a library of 1520 approved drugs in acidified (pH 4.6) nutrient-rich LB medium. Changes in optical density associated with cell filamentation, a read-out of blockage in cell division, were monitored. Compounds causing filamentation in the ΔPBP3 mutant but not in wild-type strain—the latter strain expressing both PBP3 and PBP3SAL in LB pH 4.6—were selected for further study. The bactericidal effect due to PBP3SAL inhibition was evaluated in vitro using a bacterial infection model of cultured fibroblasts. Results The cephalosporin cefotiam exhibited higher affinity for PBP3SAL than for PBP3 in bacteria growing in acidified LB pH 4.6 medium. Cefotiam also proved to be effective against intracellular Salmonella in a PBP3SAL-dependent manner. Conversely, cefuroxime, which has higher affinity for PBP3, showed decreased effectiveness in killing intracellular Salmonella. Conclusions Antibiotics with affinity for PBP3SAL, like the cephalosporin cefotiam, have therapeutic value for treating Salmonella intracellular infections.

Cefotiam

Salmonella enterica

Penicillin binding proteins

10.1093/jac/dkac422

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Citations (1)

Cryptococcal pathogenic mechanisms: a dangerous trip from the environment to the brain

Memórias do Instituto Oswaldo Cruz (2018)

Shannon K. Esher Óscar Zaragoza James Andrew Alspaugh

Cryptococcus neoformans is an opportunistic pathogenic yeast that causes serious infections, most commonly of the central nervous system (CNS). C. neoformans is mainly found in the environment and acquired by inhalation. It could be metaphorically imagined that cryptococcal disease is a “journey” for the microorganism that starts in the environment, where this yeast loads its suitcase with virulence traits. C. neoformans first encounters the infected mammalian host in the lungs, a site in which it must choose the right elements from its “virulence suitcase” to survive the pulmonary immune response. However, the lung is often only the first stop in this journey, and in some individuals the fungal trip continues to the brain. To enter the brain, C. neoformans must “open” the main barrier that protects this organ, the blood brain barrier (BBB). Once in the brain, C. neoformans expresses a distinct set of protective attributes that confers a strong neurotropism and the ability to cause brain colonisation. In summary, C. neoformans is a unique fungal pathogen as shown in its ability to survive in the face of multiple stress factors and to express virulence factors that contribute to the development of disease.

Fungal pathogen

10.1590/0074-02760180057

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Citations (89)