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Aspergillus fumigatus is a ubiquitous soil decomposer and an opportunistic pathogen that is characterized by its large metabolic machinery for acquiring nutrients from media. Lately, an ever-increasing number of genes involved in fungal nutrition has been associated with its virulence. Of these, nitrogen, iron, and zinc metabolism-related genes are particularly noteworthy, since 78% of them have a direct implication in virulence. In this review, we describe the sensing, uptake and regulation process of the acquisition of these nutrients, the connections between pathways and the virulence-implicated genes. Nevertheless, only 40% of the genes mentioned in this review have been assayed for roles in virulence, leaving a wide field of knowledge that remains uncertain and might offer new therapeutic and diagnostic targets.
Uxue Perez-Cuesta; Xabier Guruceaga; Saioa Cendon-Sanchez; Eduardo Pelegri-Martinez; Fernando Hernando; Andoni Ramirez-Garcia; Ana Abad-Diaz-De-Cerio; Aitor Rementeria. Nitrogen, Iron, and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence. Journal of Fungi 2021, 7, 518 .
AMA StyleUxue Perez-Cuesta, Xabier Guruceaga, Saioa Cendon-Sanchez, Eduardo Pelegri-Martinez, Fernando Hernando, Andoni Ramirez-Garcia, Ana Abad-Diaz-De-Cerio, Aitor Rementeria. Nitrogen, Iron, and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence. Journal of Fungi. 2021; 7 (7):518.
Chicago/Turabian StyleUxue Perez-Cuesta; Xabier Guruceaga; Saioa Cendon-Sanchez; Eduardo Pelegri-Martinez; Fernando Hernando; Andoni Ramirez-Garcia; Ana Abad-Diaz-De-Cerio; Aitor Rementeria. 2021. "Nitrogen, Iron, and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence." Journal of Fungi 7, no. 7: 518.
Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus Aspergillus fumigatus. This mold is an opportunistic pathogen that can cause invasive aspergillosis, a disease that has high mortality rates linked to it. Its ability to adapt to environmental stresses through the production of secondary metabolites, including several mycotoxins (gliotoxin, fumagillin, pseurotin A, etc.) also seem to play an important role in causing these infections. Since the discovery of the A. fumigatus fumagillin in 1949, many studies have focused on this toxin and in this review we gather all the information currently available. First of all, the structural characteristics of this mycotoxin and the different methods developed for its determination are given in detail. Then, the biosynthetic gene cluster and the metabolic pathway involved in its production and regulation are explained. The activity of fumagillin on its target, the methionine aminopeptidase type 2 (MetAP2) enzyme, and the effects of blocking this enzyme in the host are also described. Finally, the applications that this toxin and its derivatives have in different fields, such as the treatment of cancer and its microsporicidal activity in the treatment of honeybee hive infections with Nosema spp., are reviewed. Therefore, this work offers a complete review of all the information currently related to the fumagillin mycotoxin secreted by A. fumigatus, important because of its role in the fungal infection process but also because it has many other applications, notably in beekeeping, the treatment of infectious diseases, and in oncology.
Xabier Guruceaga; Uxue Perez-Cuesta; Ana Abad-Diaz De Cerio; Oskar Gonzalez; Rosa M. Alonso; Fernando Luis Hernando; Andoni Ramirez-Garcia; Aitor Rementeria. Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications. Toxins 2019, 12, 7 .
AMA StyleXabier Guruceaga, Uxue Perez-Cuesta, Ana Abad-Diaz De Cerio, Oskar Gonzalez, Rosa M. Alonso, Fernando Luis Hernando, Andoni Ramirez-Garcia, Aitor Rementeria. Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications. Toxins. 2019; 12 (1):7.
Chicago/Turabian StyleXabier Guruceaga; Uxue Perez-Cuesta; Ana Abad-Diaz De Cerio; Oskar Gonzalez; Rosa M. Alonso; Fernando Luis Hernando; Andoni Ramirez-Garcia; Aitor Rementeria. 2019. "Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications." Toxins 12, no. 1: 7.
Aspergillus fumigatus is a worldwide-distributed saprophytic fungus and the major cause of invasive aspergillosis. This fungus can produce two types of melanin—dihydroxynaphthalene melanin (DHN-melanin) and pyomelanin. These pigments are considered important resistance mechanisms to stress, as well as virulence factors. The aim of this review is to present the current knowledge of the genetic basis and metabolic pathways of melanin production, their activation, function, and interaction with the host immune system. The DHN-melanin pathway is encoded in a cluster that includes six genes (abr1, abr2, ayg1, arp1, arp2, and pksP/alb1 genes) whose encoded proteins seem to be the origin of the pigment in endosomes. These vesicles are secreted and the pigment is subsequently located in the wall of the conidium beneath the rodlet layer. Unlike DHN-melanin, pyomelanin does not have its own biosynthetic pathway but is related to the activation of the l-tyrosine/l-phenylalanine degradation pathway that includes a cluster of six genes (hppD, hmgX, hmgA, fahA, maiA, and hmgR). Its production is due to the polymerization of homogentisic acid and is linked to conidial germination. Despite the knowledge gained in recent years, further studies will be necessary to confirm the pathways that produce these pigments and their role in the virulence mechanisms of A. fumigatus.
U. Perez-Cuesta; Leire Aparicio-Fernandez; X. Guruceaga; L. Martin-Souto; Ana Abad Diaz DE Cerio; Aitziber Antoran; I. Buldain; F. L. Hernando; Leire Martin-Souto; A. Rementeria. Melanin and pyomelanin in Aspergillus fumigatus: from its genetics to host interaction. International Microbiology 2019, 23, 55 -63.
AMA StyleU. Perez-Cuesta, Leire Aparicio-Fernandez, X. Guruceaga, L. Martin-Souto, Ana Abad Diaz DE Cerio, Aitziber Antoran, I. Buldain, F. L. Hernando, Leire Martin-Souto, A. Rementeria. Melanin and pyomelanin in Aspergillus fumigatus: from its genetics to host interaction. International Microbiology. 2019; 23 (1):55-63.
Chicago/Turabian StyleU. Perez-Cuesta; Leire Aparicio-Fernandez; X. Guruceaga; L. Martin-Souto; Ana Abad Diaz DE Cerio; Aitziber Antoran; I. Buldain; F. L. Hernando; Leire Martin-Souto; A. Rementeria. 2019. "Melanin and pyomelanin in Aspergillus fumigatus: from its genetics to host interaction." International Microbiology 23, no. 1: 55-63.
Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.
Xabier Guruceaga; Guillermo Ezpeleta; Emilio Mayayo; Monica Sueiro-Olivares; Ana Abad-Diaz-De-Cerio; José Manuel Aguirre Urízar; Hong G. Liu; Philipp Wiemann; Jin Woo Bok; Scott G. Filler; Nancy P. Keller; Fernando L. Hernando; Andoni Ramirez-Garcia; Aitor Rementeria. A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus. Virulence 2018, 9, 1548 -1561.
AMA StyleXabier Guruceaga, Guillermo Ezpeleta, Emilio Mayayo, Monica Sueiro-Olivares, Ana Abad-Diaz-De-Cerio, José Manuel Aguirre Urízar, Hong G. Liu, Philipp Wiemann, Jin Woo Bok, Scott G. Filler, Nancy P. Keller, Fernando L. Hernando, Andoni Ramirez-Garcia, Aitor Rementeria. A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus. Virulence. 2018; 9 (1):1548-1561.
Chicago/Turabian StyleXabier Guruceaga; Guillermo Ezpeleta; Emilio Mayayo; Monica Sueiro-Olivares; Ana Abad-Diaz-De-Cerio; José Manuel Aguirre Urízar; Hong G. Liu; Philipp Wiemann; Jin Woo Bok; Scott G. Filler; Nancy P. Keller; Fernando L. Hernando; Andoni Ramirez-Garcia; Aitor Rementeria. 2018. "A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus." Virulence 9, no. 1: 1548-1561.
We hereby present experimental and theoretical insights on the use of biomineralized magnetite nanoparticles, called magnetosomes, as heat nanoinductors in the magnetic hyperthermia technique. The heating efficiency or specific absorption rate of magnetosomes extracted from Magnetospirillum gryphiswaldense bacteria and immersed in water and agarose gel, was directly determined from the hysteresis loops obtained at different frequencies and magnetic field amplitudes. We demonstrate that heat production of magnetosomes can be predicted in the framework of the Stoner–Wohlfarth theory of uniaxial magnetic anisotropy subjected to significant dipolar interactions, which can be described in terms of an interaction anisotropy superimposed to that of each particle. Based on these findings, we propose optimal magnetic field amplitude and frequency values in order to maximize the heat production while keeping the undesired eddy current effects below safe and tolerable limits. The efficiency of magnetosomes as heat generators and their impact on cell viability has been checked in macrophage cells. Our results clearly indicate that the hyperthermia treatment causes both cell death and inhibition of cell proliferation. Specifically, only 36% of the treated macrophages remained alive 2 h after alternating magnetic field exposure, and 24 h later the percentage fell to 22%.
Alicia Muela; David Muñoz; Rosa Martín-Rodríguez; Iñaki Orue; Eneko Garaio; Ana Abad Díaz de Cerio; Javier Alonso; José Ángel García; M. Luisa Fdez-Gubieda. Optimal Parameters for Hyperthermia Treatment Using Biomineralized Magnetite Nanoparticles: Theoretical and Experimental Approach. The Journal of Physical Chemistry C 2016, 120, 24437 -24448.
AMA StyleAlicia Muela, David Muñoz, Rosa Martín-Rodríguez, Iñaki Orue, Eneko Garaio, Ana Abad Díaz de Cerio, Javier Alonso, José Ángel García, M. Luisa Fdez-Gubieda. Optimal Parameters for Hyperthermia Treatment Using Biomineralized Magnetite Nanoparticles: Theoretical and Experimental Approach. The Journal of Physical Chemistry C. 2016; 120 (42):24437-24448.
Chicago/Turabian StyleAlicia Muela; David Muñoz; Rosa Martín-Rodríguez; Iñaki Orue; Eneko Garaio; Ana Abad Díaz de Cerio; Javier Alonso; José Ángel García; M. Luisa Fdez-Gubieda. 2016. "Optimal Parameters for Hyperthermia Treatment Using Biomineralized Magnetite Nanoparticles: Theoretical and Experimental Approach." The Journal of Physical Chemistry C 120, no. 42: 24437-24448.
We report a combined structural and magnetic study of the mineral core biomineralized by horse spleen ferritin and three prokaryotic ferritin-like proteins: bacterial ferritin and bacterioferritin from Escherichia coli and archaeal ferritin from Pyrococcus furiosus.
Ana García-Prieto; Javier Alonso; David Muñoz; Lourdes Marcano; Ana Abad Diaz DE Cerio; Roberto Fernández De Luis; Iñaki Orue; O. Mathon; Alicia Muela; M. L. Fdez-Gubieda. On the mineral core of ferritin-like proteins: structural and magnetic characterization. Nanoscale 2016, 8, 1088 -1099.
AMA StyleAna García-Prieto, Javier Alonso, David Muñoz, Lourdes Marcano, Ana Abad Diaz DE Cerio, Roberto Fernández De Luis, Iñaki Orue, O. Mathon, Alicia Muela, M. L. Fdez-Gubieda. On the mineral core of ferritin-like proteins: structural and magnetic characterization. Nanoscale. 2016; 8 (2):1088-1099.
Chicago/Turabian StyleAna García-Prieto; Javier Alonso; David Muñoz; Lourdes Marcano; Ana Abad Diaz DE Cerio; Roberto Fernández De Luis; Iñaki Orue; O. Mathon; Alicia Muela; M. L. Fdez-Gubieda. 2016. "On the mineral core of ferritin-like proteins: structural and magnetic characterization." Nanoscale 8, no. 2: 1088-1099.
Aspergillus fumigatus is considered to be the most prevalent airborne pathogenic fungus and can cause invasive diseases in immunocompromised patients. It is known that its virulence is multifactorial although the mechanisms of pathogenicity remain unclear. With the aim of improving our understanding of these mechanisms, we have designed a new expression microarray covering the entire genome of A. fumigatus. In this first study, we have analyzed the transcriptomes of this fungus at the first steps of germination after being grown at 24 and 37ºC. The microarray data revealed that 1,249 genes were differentially expressed with growth at these two temperatures. According to our results, A. fumigatus modifies significantly the expression of genes related to metabolism to adapt to new conditions. The high percentages of genes that encode hypothetical or unclassified proteins differentially expressed imply that many as yet unknown genes are involved in the establishment of A. fumigatus infection. Furthermore, among the genes implicated in virulence up-regulated at 37ºC on the microarray, we found those that encoded proteins mainly related to allergens (Asp F1, Asp F2 and MnSOD), gliotoxin biosynthesis (GliP and GliZ), nitrogen (NiiA and NiaD) or iron (HapX, SreA, SidD and SidC) metabolism. However, the gene expression in iron and nitrogen metabolisms might be influenced not only by the heat shock but also by the availability of nutrients in the medium, as shown with the addition of fresh medium.
Mónica Sueiro-Olivares; Eva Gorospe; Andoni Ramirez-Garcia; Aitor Rementeria; Fernando L. Hernando; Xabier Guruceaga; Javier Garaizar; Ana Abad Diaz DE Cerio; Javier Margareto; Elisabeth Pascual; Jimena V. Fernandez-Molina. Aspergillus fumigatus transcriptome response to a higher temperature during the earliest steps of germination monitored using a new customized expression microarray. Microbiology 2015, 161, 490 -502.
AMA StyleMónica Sueiro-Olivares, Eva Gorospe, Andoni Ramirez-Garcia, Aitor Rementeria, Fernando L. Hernando, Xabier Guruceaga, Javier Garaizar, Ana Abad Diaz DE Cerio, Javier Margareto, Elisabeth Pascual, Jimena V. Fernandez-Molina. Aspergillus fumigatus transcriptome response to a higher temperature during the earliest steps of germination monitored using a new customized expression microarray. Microbiology. 2015; 161 (3):490-502.
Chicago/Turabian StyleMónica Sueiro-Olivares; Eva Gorospe; Andoni Ramirez-Garcia; Aitor Rementeria; Fernando L. Hernando; Xabier Guruceaga; Javier Garaizar; Ana Abad Diaz DE Cerio; Javier Margareto; Elisabeth Pascual; Jimena V. Fernandez-Molina. 2015. "Aspergillus fumigatus transcriptome response to a higher temperature during the earliest steps of germination monitored using a new customized expression microarray." Microbiology 161, no. 3: 490-502.
Invasive aspergillosis is an opportunistic infection caused primarily by Aspergillus fumigatus. However, other common fungal pathogens belonging to section Fumigati are often misidentified as A. fumigatus. Thus, we have developed a multiplex real-time PCR (qPCR) assay with primers and specific TaqMan probes based on internal transcribed spacer regions or benA gene to discriminate, in less than 3 h, species of section Fumigati and, specifically, A. fumigatus. The multiplex qPCR showed a limit of detection of 20 and 50 fg of DNA for section Fumigati and A. fumigatus, respectively. Moreover, it enabled detection of a single germinated conidia. The inclusion of some PCR facilitators together with the dilution of samples makes it possible to completely avoid PCR inhibitions in all bronchoalveolar lavage (BAL) samples assayed. This technique may be a useful complementary tool in the diagnosis of invasive pulmonary aspergillosis caused by A. fumigatus using BAL fluid.
J.V. Fernandez-Molina; Ana Abad Diaz DE Cerio; M. Sueiro-Olivares; Aize Pellon; Andoni Ramirez-Garcia; J. Garaizar; Javier Pemán; F.L. Hernando; A. Rementeria. Rapid and specific detection of section Fumigati and Aspergillus fumigatus in human samples using a new multiplex real-time PCR. Diagnostic Microbiology and Infectious Disease 2014, 80, 111 -118.
AMA StyleJ.V. Fernandez-Molina, Ana Abad Diaz DE Cerio, M. Sueiro-Olivares, Aize Pellon, Andoni Ramirez-Garcia, J. Garaizar, Javier Pemán, F.L. Hernando, A. Rementeria. Rapid and specific detection of section Fumigati and Aspergillus fumigatus in human samples using a new multiplex real-time PCR. Diagnostic Microbiology and Infectious Disease. 2014; 80 (2):111-118.
Chicago/Turabian StyleJ.V. Fernandez-Molina; Ana Abad Diaz DE Cerio; M. Sueiro-Olivares; Aize Pellon; Andoni Ramirez-Garcia; J. Garaizar; Javier Pemán; F.L. Hernando; A. Rementeria. 2014. "Rapid and specific detection of section Fumigati and Aspergillus fumigatus in human samples using a new multiplex real-time PCR." Diagnostic Microbiology and Infectious Disease 80, no. 2: 111-118.
There is currently increasing concern about the relation between microbial infections and cancer. More and more studies support the view that there is an association, above all, when the causal agents are bacteria or viruses. This review adds to this, summarizing evidence that the opportunistic fungus Candida albicans increases the risk of carcinogenesis and metastasis. Until recent years, Candida spp. had fundamentally been linked to cancerous processes as it is an opportunist pathogen that takes advantage of the immunosuppressed state of patients particularly due to chemotherapy. In contrast, the most recent findings demonstrate that C. albicans is capable of promoting cancer by several mechanisms, as described in the review: production of carcinogenic byproducts, triggering of inflammation, induction of Th17 response and molecular mimicry. We underline the need not only to control this type of infection during cancer treatment, especially given the major role of this yeast species in nosocomial infections, but also to find new therapeutic approaches to avoid the pro-tumor effect of this fungal species.
Andoni Ramirez-Garcia; Aitor Rementeria; Jose Manuel Aguirre-Urizar; Maria-Dolores Moragues; Aitziber Antoran; Aize Pellon; Ana Abad-Diaz-De-Cerio; Fernando Luis Hernando. Candida albicansand cancer: Can this yeast induce cancer development or progression? Critical Reviews in Microbiology 2014, 42, 1 -13.
AMA StyleAndoni Ramirez-Garcia, Aitor Rementeria, Jose Manuel Aguirre-Urizar, Maria-Dolores Moragues, Aitziber Antoran, Aize Pellon, Ana Abad-Diaz-De-Cerio, Fernando Luis Hernando. Candida albicansand cancer: Can this yeast induce cancer development or progression? Critical Reviews in Microbiology. 2014; 42 (2):1-13.
Chicago/Turabian StyleAndoni Ramirez-Garcia; Aitor Rementeria; Jose Manuel Aguirre-Urizar; Maria-Dolores Moragues; Aitziber Antoran; Aize Pellon; Ana Abad-Diaz-De-Cerio; Fernando Luis Hernando. 2014. "Candida albicansand cancer: Can this yeast induce cancer development or progression?" Critical Reviews in Microbiology 42, no. 2: 1-13.
The filamentous fungus Scedosporium prolificans is an emerging multidrug resistant pathogen related to serious infections mainly affecting immunocompromised individuals. Considering that it is frequently isolated from anthropic environments and penetrates mainly through the airways, the human mucosal immune system may play an important protective role against S. prolificans. To advance in the search for biomarkers and targets both for diagnosis and treatment, we analysed the S. prolificans immunomes recognized by human salivary Immunoglobulin A. Using indirect immunofluorescence, it was observed that conidia were strongly recognized, while hyphae were not. By 2-D immunoblotting and peptide mass fingerprinting, 25 immunodominant antigens in conidia and 30 in hyphae were identified. These included catalase, putative glyceronetransferase, translation elongation factor-1α, serine/threonine protein kinase, putative superoxide dismutase, putative mitochondrial cyclophilin 1 and peptidyl-prolyl cis-trans isomerase in conidiospores, and putative Hsp60, ATP synthase β chain, 40S ribosomal protein S0, citrate synthase and putative ATP synthase in hyphae. The functional study showed that metabolism - and protein fate - related enzymes were the most abundant antigens in conidia, whereas metabolism - , translation - , or energy production - related enzymes were in hyphae. The immunogenic proteins identified are proposed as candidates for the development of novel diagnostic tools or therapeutic strategies.
Aize Pellon; Andoni Ramirez-Garcia; Aitziber Antoran; Jimena Victoria Fernandez-Molina; Ana Abad-Diaz-De-Cerio; Dalila Montañez; Maria Jesus Sevilla; Aitor Rementeria; Fernando L. Hernando. Scedosporium prolificans immunomes against human salivary immunoglobulin A. Fungal Biology 2014, 118, 94 -105.
AMA StyleAize Pellon, Andoni Ramirez-Garcia, Aitziber Antoran, Jimena Victoria Fernandez-Molina, Ana Abad-Diaz-De-Cerio, Dalila Montañez, Maria Jesus Sevilla, Aitor Rementeria, Fernando L. Hernando. Scedosporium prolificans immunomes against human salivary immunoglobulin A. Fungal Biology. 2014; 118 (1):94-105.
Chicago/Turabian StyleAize Pellon; Andoni Ramirez-Garcia; Aitziber Antoran; Jimena Victoria Fernandez-Molina; Ana Abad-Diaz-De-Cerio; Dalila Montañez; Maria Jesus Sevilla; Aitor Rementeria; Fernando L. Hernando. 2014. "Scedosporium prolificans immunomes against human salivary immunoglobulin A." Fungal Biology 118, no. 1: 94-105.
Ana Abad-Diaz-De-Cerio; Jimena V. Fernandez-Molina; Andoni Ramirez-Garcia; Javier Sendino; Fernando L. Hernando; Javier Pemán; Javier Garaizar; Aitor Rementeria. TheaspHSgene as a new target for detectingAspergillus fumigatusduring infections by quantitative real-time PCR. Medical Mycology 2013, 51, 545 -554.
AMA StyleAna Abad-Diaz-De-Cerio, Jimena V. Fernandez-Molina, Andoni Ramirez-Garcia, Javier Sendino, Fernando L. Hernando, Javier Pemán, Javier Garaizar, Aitor Rementeria. TheaspHSgene as a new target for detectingAspergillus fumigatusduring infections by quantitative real-time PCR. Medical Mycology. 2013; 51 (5):545-554.
Chicago/Turabian StyleAna Abad-Diaz-De-Cerio; Jimena V. Fernandez-Molina; Andoni Ramirez-Garcia; Javier Sendino; Fernando L. Hernando; Javier Pemán; Javier Garaizar; Aitor Rementeria. 2013. "TheaspHSgene as a new target for detectingAspergillus fumigatusduring infections by quantitative real-time PCR." Medical Mycology 51, no. 5: 545-554.
The dimorphic fungus Candida albicans is able to trigger a cytokine-mediated pro-inflammatory response that increases tumor cell adhesion to hepatic endothelium and metastasis. To check the intraspecific differences in this effect, we used an in vitro murine model of hepatic response against C. albicans, which made clear that tumor cells adhered more to endothelium incubated with blastoconidia, both live and killed, than germ tubes. This finding was related to the higher carbohydrate/protein ratio found in blastoconidia. In fact, destruction of mannose ligand residues on the cell surface by metaperiodate treatment significantly reduced tumor cell adhesion induced. Moreover, we also noticed that the effect of clinical strains was greater than that of the reference one. This finding could not be explained by the carbohydrate/protein data, but to explain these differences between strains, we analyzed the expression level of ten genes (ADH1, APE3, IDH2, ENO1, FBA1, ILV5, PDI1, PGK1, QCR2 and TUF1) that code for the proteins identified previously in a mannoprotein-enriched pro-metastatic fraction of C. albicans. The results corroborated that their expression was higher in clinical strains than the reference one. To confirm the importance of the mannoprotein fraction, we also demonstrate that blocking the mannose receptor decreases the effect of C. albicans and its mannoproteins, inhibiting IL-18 synthesis and tumor cell adhesion increase by around 60%. These findings could be the first step towards a new treatment for solid organ cancers based on the role of the mannose receptor in C. albicans-induced tumor progression and metastasis.
Andoni Ramirez-Garcia; Beatriz Arteta; Ana Abad-Diaz-De-Cerio; Aize Pellon; Aitziber Antoran; Joana Marquez; Aitor Rementeria; Fernando L. Hernando. Candida albicans Increases Tumor Cell Adhesion to Endothelial Cells In Vitro: Intraspecific Differences and Importance of the Mannose Receptor. PLOS ONE 2013, 8, e53584 .
AMA StyleAndoni Ramirez-Garcia, Beatriz Arteta, Ana Abad-Diaz-De-Cerio, Aize Pellon, Aitziber Antoran, Joana Marquez, Aitor Rementeria, Fernando L. Hernando. Candida albicans Increases Tumor Cell Adhesion to Endothelial Cells In Vitro: Intraspecific Differences and Importance of the Mannose Receptor. PLOS ONE. 2013; 8 (1):e53584.
Chicago/Turabian StyleAndoni Ramirez-Garcia; Beatriz Arteta; Ana Abad-Diaz-De-Cerio; Aize Pellon; Aitziber Antoran; Joana Marquez; Aitor Rementeria; Fernando L. Hernando. 2013. "Candida albicans Increases Tumor Cell Adhesion to Endothelial Cells In Vitro: Intraspecific Differences and Importance of the Mannose Receptor." PLOS ONE 8, no. 1: e53584.
Candida albicans is an opportunistic dimorphic fungus commonly present in the human oral cavity that causes infections in immunocompromised patients. The antigen variability, influenced by growth conditions, is a pathogenicity factor. To determine the effect of nutritional and heat stress on the antigen expression of C. albicans, and to identify major antigens recognized by human salivary secretory immunoglobulin A (sIgA). Under various different nutritional conditions, heat shock was induced in C. albicans cells in stationary and exponential growth phases. The expression of protein determinants of C. albicans was assessed by Western blot analysis against human saliva. The antigens were purified and characterized by two-dimensional electrophoresis and identified by protein microsequencing. Five antigens recognized by salivary IgA were characterized as mannoproteins due to their reactivity with concanavalin A. They did not show reactivity with anti-heat shock protein monoclonal antibodies. Two of them (42 and 36 kDa) were found to be regulated by heat shock and by nutritional stress and they were identified as phosphoglycerate kinase and fructose bisphosphate aldolase, respectively. These glycolytic enzymes are major antigens of C. albicans, and their differential expression and recognition by the mucosal immune response system could be involved in protection against oral infection.
Roberto Calcedo; Andoni Ramirez-Garcia; Ana Abad; Aitor Rementeria; José Pontón; Fernando Luis Hernando. Phosphoglycerate kinase and fructose bisphosphate aldolase of Candida albicans as new antigens recognized by human salivary IgA. Revista Iberoamericana de Micología 2012, 29, 172 -174.
AMA StyleRoberto Calcedo, Andoni Ramirez-Garcia, Ana Abad, Aitor Rementeria, José Pontón, Fernando Luis Hernando. Phosphoglycerate kinase and fructose bisphosphate aldolase of Candida albicans as new antigens recognized by human salivary IgA. Revista Iberoamericana de Micología. 2012; 29 (3):172-174.
Chicago/Turabian StyleRoberto Calcedo; Andoni Ramirez-Garcia; Ana Abad; Aitor Rementeria; José Pontón; Fernando Luis Hernando. 2012. "Phosphoglycerate kinase and fructose bisphosphate aldolase of Candida albicans as new antigens recognized by human salivary IgA." Revista Iberoamericana de Micología 29, no. 3: 172-174.
Systemic candidiasis remains a major complication among patients suffering from hematological malignancies and favors the development of hepatic metastasis. To contribute to the understanding of the underlying mechanisms, the aim of this study was to identify molecules that may increase tumor cell adhesion to hepatic endothelial cells. To this end, a well-established in vitro model was used to determine the enhancement of tumor cell adhesion induced by Candida albicans and its fractions. Different fractions were obtained according to their molecular weight (M(r)) (five) or to their isoelectric point (pI) (four), using preparative electrophoresis and preparative isoelectric focusing, respectively, followed by affinity chromatography. The fraction that most enhanced melanoma cell adhesion to endothelium had an M(r) range from 45 to 66 kDa. It was characterized using two-dimensional electrophoresis, and 14 proteins were identified by peptide mass fingerprinting: Dor14p, Fba1p, Pdi1p, Pgk1p, Idh2p, Mpg1p, Sfa1p, Ape3p, Ilv5p, Tuf1p, Act1p, Eno1p, Qcr2p, and Adh1p. Of these, several are related to the immunogenic response, and the latter seven belonged to the most reactive fraction according to their pI range, from 5 to 5.6. These findings could represent a step forward in the search for new targets, to suppress the pro-metastatic effect of C. albicans.
Andoni Ramirez-Garcia; Natalia Gallot; Ana Abad; Lorea Mendoza; Aitor Rementeria; Fernando Luis Hernando. Molecular fractionation and characterization of a Candida albicans fraction that increases tumor cell adhesion to hepatic endothelium. Applied Microbiology and Biotechnology 2011, 92, 133 -145.
AMA StyleAndoni Ramirez-Garcia, Natalia Gallot, Ana Abad, Lorea Mendoza, Aitor Rementeria, Fernando Luis Hernando. Molecular fractionation and characterization of a Candida albicans fraction that increases tumor cell adhesion to hepatic endothelium. Applied Microbiology and Biotechnology. 2011; 92 (1):133-145.
Chicago/Turabian StyleAndoni Ramirez-Garcia; Natalia Gallot; Ana Abad; Lorea Mendoza; Aitor Rementeria; Fernando Luis Hernando. 2011. "Molecular fractionation and characterization of a Candida albicans fraction that increases tumor cell adhesion to hepatic endothelium." Applied Microbiology and Biotechnology 92, no. 1: 133-145.
Aspergillus fumigatus is an opportunistic pathogen that causes 90% of invasive aspergillosis (IA) due to Aspergillus genus, with a 50-95% mortality rate. It has been postulated that certain virulence factors are characteristic of A. fumigatus, but the "non-classical" virulence factors seem to be highly variable. Overall, published studies have demonstrated that the virulence of this fungus is multifactorial, associated with its structure, its capacity for growth and adaptation to stress conditions, its mechanisms for evading the immune system and its ability to cause damage to the host. In this review we intend to give a general overview of the genes and molecules involved in the development of IA. The thermotolerance section focuses on five genes related with the capacity of the fungus to grow at temperatures above 30°C (thtA, cgrA, afpmt1, kre2/afmnt1, and hsp1/asp f 12). The following sections discuss molecules and genes related to interaction with the host and with the immune responses. These sections include β-glucan, α-glucan, chitin, galactomannan, galactomannoproteins (afmp1/asp f 17 and afmp2), hydrophobins (rodA/hyp1 and rodB), DHN-melanin, their respective synthases (fks1, rho1-4, ags1-3, chsA-G, och1-4, mnn9, van1, anp1, glfA, pksP/alb1, arp1, arp2, abr1, abr2, and ayg1), and modifying enzymes (gel1-7, bgt1, eng1, ecm33, afpigA, afpmt1-2, afpmt4, kre2/afmnt1, afmnt2-3, afcwh41 and pmi); several enzymes related to oxidative stress protection such as catalases (catA, cat1/catB, cat2/katG, catC, and catE), superoxide dismutases (sod1, sod2, sod3/asp f 6, and sod4), fatty acid oxygenases (ppoA-C), glutathione tranferases (gstA-E), and others (afyap1, skn7, and pes1); and efflux transporters (mdr1-4, atrF, abcA-E, and msfA-E). In addition, this review considers toxins and related genes, such as a diffusible toxic substance from conidia, gliotoxin (gliP and gliZ), mitogillin (res/mitF/asp f 1), hemolysin (aspHS), festuclavine and fumigaclavine A-C, fumitremorgin A-C, verruculogen, fumagillin, helvolic acid, aflatoxin B1 and G1, and laeA. Two sections cover genes and molecules related with nutrient uptake, signaling and metabolic regulations involved in virulence, including enzymes, such as serine proteases (alp/asp f 13, alp2, and asp f 18), metalloproteases (mep/asp f 5, mepB, and mep20), aspartic proteases (pep/asp f 10, pep2, and ctsD), dipeptidylpeptidases (dppIV and dppV), and phospholipases (plb1-3 and phospholipase C); siderophores and iron acquisition (sidA-G, sreA, ftrA, fetC, mirB-C, and amcA); zinc acquisition (zrfA-H, zafA, and pacC); amino acid biosynthesis, nitrogen uptake, and cross-pathways control (areA, rhbA, mcsA, lysF, cpcA/gcn4p, and cpcC/gcn2p); general biosynthetic pathway (pyrG, hcsA, and pabaA), trehalose biosynthesis (tpsA and tpsB), and other regulation pathways such as those of the MAP kinases (sakA/hogA, mpkA-C, ste7, pbs2, mkk2, steC/ste11, bck1, ssk2, and sho1), G-proteins (gpaA, sfaD, and cpgA), cAMP-PKA signaling (acyA, gpaB, pkaC1, and pkaR), His kinases (fos1 and tcsB), Ca(2+) signaling (calA/cnaA, crzA, gprC and gprD), and Ras family (rasA, rasB, and rhbA), and others (ace2, medA, and srbA). Finally, we also comment on the effect of A. fumigatus allergens (Asp f 1-Asp f 34) on IA. The data gathered generate a complex puzzle, the pieces representing virulence factors or the different activities of the fungus, and these need to be arranged to obtain a comprehensive vision of the virulence of A. fumigatus. The most recent gene expression studies using DNA-microarrays may be help us to understand this complex virulence, and to detect targets to develop rapid diagnostic methods and new antifungal agents.
Ana Abad; Jimena Victoria Fernández-Molina; Joseba Bikandi; Andoni Ramírez; Javier Margareto; Javier Sendino; Fernando Luis Hernando; Jose Pontón; Javier Garaizar; Aitor Rementeria. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Revista Iberoamericana de Micología 2010, 27, 155 -182.
AMA StyleAna Abad, Jimena Victoria Fernández-Molina, Joseba Bikandi, Andoni Ramírez, Javier Margareto, Javier Sendino, Fernando Luis Hernando, Jose Pontón, Javier Garaizar, Aitor Rementeria. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Revista Iberoamericana de Micología. 2010; 27 (4):155-182.
Chicago/Turabian StyleAna Abad; Jimena Victoria Fernández-Molina; Joseba Bikandi; Andoni Ramírez; Javier Margareto; Javier Sendino; Fernando Luis Hernando; Jose Pontón; Javier Garaizar; Aitor Rementeria. 2010. "What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis." Revista Iberoamericana de Micología 27, no. 4: 155-182.
Candida albicans infections are very frequent in cancer patients, whose immune system is often compromised, but whether this fungal pathogen affects cancer progression is unknown. C. albicans infection involves endogenous production of inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-18 (IL-18). Increased levels of these cytokines have already been correlated with metastasis of most common cancer types. In this study, a well-established model of IL-18-dependent hepatic melanoma metastasis was used to study whether C. albicans can alter the ability of murine B16 melanoma (B16M) cells to colonize the liver. First, we determined the ability of intrasplenically (IS) injected B16M cells to metastasize into the liver of mice challenged with 5 × 104C. albicans cells by three different routes (intravenous, IV; intrasplenic, IS; or intraperitoneal, IP) 12 h prior to injection of B16M cells. We demonstrated that C. albicans significantly increased metastasis of B16M cells with all three fungal injection routes. Pro-metastatic effects occurred when hepatic colonization with B16M cells place after the peak of TNF-α and IL-18 levels had been reached in the hepatic blood of fungal challenged mice. In a second set of experiments, mice were fungal challenged 4 days after injection of B16M cells. In these mice, C. albicans also potentiated the growth of established micro-metastases. Significantly, the fungal challenge had pro-metastatic effects without the C. albicans being able to reach the liver, suggesting that soluble factors can promote metastasis in remote sites. Mouse treatment with antifungal ketoconazol abrogated hepatic TNF-α stimulation by C. albicans and prevented the enhancement of hepatic metastasis in fungal challenged-mice. Therefore, the pro-inflammatory microenvironment generated by the host’s systemic response to C. albicans stimulates circulating cancer cells to metastasize in the liver.
Juan Rodríguez-Cuesta; Fernando L. Hernando; Lorea Mendoza; Natalia Gallot; Ana Abad Díaz De Cerio; Guillermo Martínez-De-Tejada; Fernando Vidal-Vanaclocha. Candida albicans enhances experimental hepatic melanoma metastasis. Clinical & Experimental Metastasis 2009, 27, 35 -42.
AMA StyleJuan Rodríguez-Cuesta, Fernando L. Hernando, Lorea Mendoza, Natalia Gallot, Ana Abad Díaz De Cerio, Guillermo Martínez-De-Tejada, Fernando Vidal-Vanaclocha. Candida albicans enhances experimental hepatic melanoma metastasis. Clinical & Experimental Metastasis. 2009; 27 (1):35-42.
Chicago/Turabian StyleJuan Rodríguez-Cuesta; Fernando L. Hernando; Lorea Mendoza; Natalia Gallot; Ana Abad Díaz De Cerio; Guillermo Martínez-De-Tejada; Fernando Vidal-Vanaclocha. 2009. "Candida albicans enhances experimental hepatic melanoma metastasis." Clinical & Experimental Metastasis 27, no. 1: 35-42.