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Growth and Airborne Transmission of Cell-Sorted Life Cycle Stages of Pneumocystis carinii  [PDF]
Anna Martinez, Marie C. M. Halliez, El Moukhtar Aliouat, Magali Chabé, Annie Standaert-Vitse, Emilie Fréalle, Nausicaa Gantois, Muriel Pottier, Anthony Pinon, Eduardo Dei-Cas, Cécile-Marie Aliouat-Denis
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079958
Abstract: Pneumocystis organisms are airborne opportunistic pathogens that cannot be continuously grown in culture. Consequently, the follow-up of Pneumocystis stage-to-stage differentiation, the sequence of their multiplication processes as well as formal identification of the transmitted form have remained elusive. The successful high-speed cell sorting of trophic and cystic forms is paving the way for the elucidation of the complex Pneumocystis life cycle. The growth of each sorted Pneumocystis stage population was followed up independently both in nude rats and in vitro. In addition, by setting up a novel nude rat model, we attempted to delineate which cystic and/or trophic forms can be naturally aerially transmitted from host to host. The results showed that in axenic culture, cystic forms can differentiate into trophic forms, whereas trophic forms are unable to evolve into cystic forms. In contrast, nude rats inoculated with pure trophic forms are able to produce cystic forms and vice versa. Transmission experiments indicated that 12 h of contact between seeder and recipient nude rats was sufficient for cystic forms to be aerially transmitted. In conclusion, trophic- to cystic-form transition is a key step in the proliferation of Pneumocystis microfungi because the cystic forms (but not the trophic forms) can be transmitted by aerial route from host to host.
Ploidy of Cell-Sorted Trophic and Cystic Forms of Pneumocystis carinii  [PDF]
Anna Martinez,El Moukhtar Aliouat,Annie Standaert-Vitse,Elisabeth Werkmeister,Muriel Pottier,Claire Pin?on,Eduardo Dei-Cas,Cécile-Marie Aliouat-Denis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020935
Abstract: Once regarded as an AIDS-defining illness, Pneumocystis pneumonia (PcP) is nowadays prevailing in immunocompromised HIV-negative individuals such as patients receiving immunosuppressive therapies or affected by primary immunodeficiency. Moreover, Pneumocystis clinical spectrum is broadening to non-severely-immunocompromised subjects who could be colonized by the fungus while remaining asymptomatic for PcP, thus being able to transmit the infection by airborne route to susceptible hosts. Although the taxonomical position of the Pneumocystis genus has been clarified, several aspects of its life cycle remain elusive such as its mode of proliferation within the alveolus or its ploidy level. As no long-term culture model exists to grow Pneumocystis organisms in vitro, an option was to use a model of immunosuppressed rat infected with Pneumocystis carinii and sort life cycle stage fractions using a high-through-put cytometer. Subsequently, ploidy levels of the P. carinii trophic and cystic form fractions were measured by flow cytometry. In the cystic form, eight contents of DNA were measured thus strengthening the fact that each mature cyst contains eight haploid spores. Following release, each spore evolves into a trophic form. The majority of the trophic form fraction was haploid in our study. Some less abundant trophic forms displayed two contents of DNA indicating that they could undergo (i) mating/fusion leading to a diploid status or (ii) asexual mitotic division or (iii) both. Even less abundant trophic forms with four contents of DNA were suggestive of mitotic divisions occurring following mating in diploid trophic forms. Of interest, was the presence of trophic forms with three contents of DNA, an unusual finding that could be related to asymmetrical mitotic divisions occurring in other fungal species to create genetic diversity at lower energetic expenses than mating. Overall, ploidy data of P. carinii life cycle stages shed new light on the complexity of its modes of proliferation.
Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata  [PDF]
Sheena D. Singh-Babak,Tomas Babak,Stephanie Diezmann,Jessica A. Hill,Jinglin Lucy Xie,Ying-Lien Chen,Susan M. Poutanen,Robert P. Rennie,Joseph Heitman,Leah E. Cowen
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002718
Abstract: The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential.
The Pneumocystis life cycle
Aliouat-Denis, Cécile-Marie;Martinez, Anna;Aliouat, El Moukhtar;Pottier, Muriel;Gantois, Nausicaa;Dei-Cas, Eduardo;
Memórias do Instituto Oswaldo Cruz , 2009, DOI: 10.1590/S0074-02762009000300004
Abstract: first recognised as "schizonts" of trypanosoma cruzi, pneumocystis organisms are now considered as part of an early-diverging lineage of ascomycetes. as no robust long-term culture model is available, most data on the pneumocystis cell cycle have stemmed from ultrastructural images of infected mammalian lungs. although most fungi developing in animals do not complete a sexual cycle in vivo, pneumocystis species constitute one of a few exceptions. recently, the molecular identification of several key players in the fungal mating pathway has provided further evidence for the existence of conjugation and meiosis in pneumocystisorganisms. dynamic follow-up of stage-to-stage transition as well as studies of stage-specific proteins and/or genes would provide a better understanding of the still hypothetical pneumocystislife cycle. although difficult to achieve, stage purification seems a reasonable way forward in the absence of efficient culture systems. this mini-review provides a comprehensive overview of the historical milestones leading to the current knowledge available on the pneumocystis life cycle.
Evidence of Airborne Excretion of Pneumocystis carinii during Infection in Immunocompetent Rats. Lung Involvement and Antibody Response  [PDF]
Jean Menotti, Alexandra Emmanuel, Chafia Bouchekouk, Magali Chabe, Firas Choukri, Muriel Pottier, Claudine Sarfati, El Moukhtar Aliout, Francis Derouin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062155
Abstract: To better understand the role of immunocompetent hosts in the diffusion of Pneumocystis in the environment, airborne shedding of Pneumocystis carinii in the surrounding air of experimentally infected Sprague Dawley rats was quantified by means of a real-time PCR assay, in parallel with the kinetics of P. carinii loads in lungs and specific serum antibody titres. Pneumocystis-free Sprague Dawley rats were intratracheally inoculated at day 0 (d0) and then followed for 60 days. P. carinii DNA was detected in lungs until d29 in two separate experiments and thereafter remained undetectable. A transient air excretion of Pneumocystis DNA was observed between d14 and d22 in the first experiment and between d9 and d19 in the second experiment; it was related to the peak of infection in lungs. IgM and IgG anti-P. carinii antibody increase preceded clearance of P. carinii in the lungs and cessation of airborne excretion. In rats receiving a second challenge 3 months after the first inoculation, Pneumocystis was only detected at a low level in the lungs of 2 of 3 rats at d2 post challenge and was never detected in air samples. Anti-Pneumocystis antibody determinations showed a typical secondary IgG antibody response. This study provides the first direct evidence that immunocompetent hosts can excrete Pneumocystis following a primary acquired infection. Lung infection was apparently controlled by the immune response since fungal burdens decreased to become undetectable as specific antibodies reached high titres in serum. This immune response was apparently protective against reinfection 3 months later.
Therapeutic Potential of Caspofungin Combined with Trimethoprim-Sulfamethoxazole for Pneumocystis Pneumonia: A Pilot Study in Mice  [PDF]
Maria Luísa Lobo, Francisco Esteves, Bruno de Sousa, Fernando Cardoso, Melanie T. Cushion, Francisco Antunes, Olga Matos
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070619
Abstract: Pneumocystis pneumonia (PcP) is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole (TMP-SMX) which is the standard first line therapy/prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin/TMP-SMX was evaluated in Balb/c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg/kg, 0.05 mg/kg, and 0.001 mg/kg and TMP-SMX was administered by oral gavage (12.25 mg/62.5 mg/day), for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR (qPCR). Serum β-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin/TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin/TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg/kg/day with TMP-SMX 12.5 mg–62.5 mg/day, which reduced the parasite burden to undetectable levels immediately at the 14th day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance.
Pneumocystis diversity as a phylogeographic tool
Derouiche, S;Deville, M;Taylor, ML;Akbar, H;Guillot, J;Carreto-Binaghi, LE;Pottier, M;Aliouat, EM;Aliouat-Denis, CM;Dei-Cas, E;Demanche, C;
Memórias do Instituto Oswaldo Cruz , 2009, DOI: 10.1590/S0074-02762009000100017
Abstract: parasites are increasingly used to complement the evolutionary and ecological adaptation history of their hosts. pneumocystis pathogenic fungi, which are transmitted from host-to-host via an airborne route, have been shown to constitute genuine host markers of evolution. these parasites can also provide valuable information about their host ecology. here, we suggest that parasites can be used as phylogeographic markers to understand the geographical distribution of intra-specific host genetic variants. to test our hypothesis, we characterised pneumocystis isolates from wild bats living in different areas. bats comprise a wide variety of species; some of them are able to migrate. thus, bat chorology and migration behaviour can be approached using pneumocystis as phylogeographic markers. in the present work, we find that the genetic polymorphisms of bat-derived pneumocystis are structured by host chorology. therefore, pneumocystis intra-specific genetic diversity may constitute a useful and relevant phylogeographic tool.
Neumonía por Pneumocystis jirovecii
Zunen Hernández Puentes,Yaimara; Pi?era,Bárbara Mercedes Paula; Salinas Olivares,Mercedes; Vila González,William; Casa de Valle Castro,Midalys;
Revista Cubana de Medicina Militar , 2010,
Abstract: objective: to present the atypical case of a hiv-negative patient, deceased from pneumocystis jirovecii more frequent in persons infected with the aids virus and in those underwent transplantation. description: a patient with a history of alcoholism, asthma, respiratory symptoms and fever, hiv-negative, with a torpid course deceased at 11 days after admission. lung: peripheral emphysema, scattered zones of a fleshy red appearance mixed with not much aired zones and impasted. intervention: a clinical necropsy was carried out where the direct cause of death was from pneumocystis jirovecii, diagnosed using hematoxylin-esosin stain proving the presence of a characteristic foamy edema. in the silver methenamine stain it was possible to corroborate the presence of the microorganism. conclusions: in this case the leading cause of death was pneumocystis jirovecii pneumonia, an opportunistic pathogen frequently reported a cause of death in hiv-aids patients and also in those immunocompromised due to other causes, e.g. those with transplantation.
ANALYSIS OF ADMINISTRATIVE BURDENS FOR COMPANIES IN SELECTED SEE COUNTRIES  [PDF]
Barbara BRADA? HOJNIK,Miroslav REBERNIK
Scientific Annals of the Alexandru Ioan Cuza University of Iasi : Economic Sciences Series , 2011,
Abstract: The institutional framework in which companies have to act establishes the rules of the game. It is limited and controlled by a public administration system, which may be more or less open and contemporary for companies. The aim of this paper is to analyse administrative procedures and costs for companies when dealing with public administration from a theoretical and empirical point of view. The paper’s goals are to compare administrative burdens and to find the advantages and weaknesses of administrative systems in selected countries. During a company’s operation, from its establishment to its closure, entrepreneurs are constantly exposed to administrative systems and their requirements. They have to carry out different procedures regarding the company’s establishment, the hiring and firing of employees, obtaining various licenses, state regulatory statistical and tax reporting, tax burdens etc. Fulfilling all those administrative procedures may negatively impact the establishment and operation of companies in particular countries.
Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin  [PDF]
Sheena D. Singh,Nicole Robbins,Aimee K. Zaas,Wiley A. Schell,John R. Perfect,Leah E. Cowen
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000532
Abstract: Candida albicans is the leading fungal pathogen of humans, causing life-threatening disease in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs whose efficacy is compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. We previously established that the molecular chaperone Hsp90, which regulates the form and function of diverse client proteins, potentiates resistance to the azoles in C. albicans and in the model yeast Saccharomyces cerevisiae. Genetic studies in S. cerevisiae revealed that Hsp90's role in azole resistance is to enable crucial cellular responses to the membrane stress exerted by azoles via the client protein calcineurin. Here, we demonstrate that Hsp90 governs cellular circuitry required for resistance to the only new class of antifungals to reach the clinic in decades, the echinocandins, which inhibit biosynthesis of a critical component of the fungal cell wall. Pharmacological or genetic impairment of Hsp90 function reduced tolerance of C. albicans laboratory strains and resistance of clinical isolates to the echinocandins and created a fungicidal combination. Compromising calcineurin function phenocopied compromising Hsp90 function. We established that calcineurin is an Hsp90 client protein in C. albicans: reciprocal co-immunoprecipitation validated physical interaction; Hsp90 inhibition blocked calcineurin activation; and calcineurin levels were depleted upon genetic reduction of Hsp90. The downstream effector of calcineurin, Crz1, played a partial role in mediating calcineurin-dependent stress responses activated by echinocandins. Hsp90's role in echinocandin resistance has therapeutic potential given that genetic compromise of C. albicans HSP90 expression enhanced the efficacy of an echinocandin in a murine model of disseminated candidiasis. Our results identify the first Hsp90 client protein in C. albicans, establish an entirely new role for Hsp90 in mediating resistance to echinocandins, and demonstrate that targeting Hsp90 provides a promising therapeutic strategy for the treatment of life-threatening fungal disease.
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