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      Mp1p Is a Virulence Factor in Talaromyces (Penicillium) marneffei

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          Abstract

          Background

          Talaromyces marneffei is an opportunistic dimorphic fungus prevalent in Southeast Asia. We previously demonstrated that Mp1p is an immunogenic surface and secretory mannoprotein of T. marneffei. Since Mp1p is a surface protein that can generate protective immunity, we hypothesized that Mp1p and/or its homologs are virulence factors.

          Methodology/Principal Findings

          We examined the pathogenic roles of Mp1p and its homologs in a mouse model. All mice died 21 and 30 days after challenge with wild-type T. marneffei PM1 and MP1 complemented mutant respectively. None of the mice died 60 days after challenge with MP1 knockout mutant (P<0.0001). Seventy percent of mice died 60 days after challenge with MP1 knockdown mutant (P<0.0001). All mice died after challenge with MPLP1 to MPLP13 knockdown mutants, suggesting that only Mp1p plays a significant role in virulence. The mean fungal loads of PM1 and MP1 complemented mutant in the liver, lung, kidney and spleen were significantly higher than those of the MP1 knockout mutant. Similarly, the mean load of PM1 in the liver, lung and spleen were significantly higher than that of the MP1 knockdown mutant. Histopathological studies showed an abundance of yeast in the kidney, spleen, liver and lung with more marked hepatic and splenic necrosis in mice challenged with PM1 compared to MP1 knockout and MP1 knockdown mutants. Likewise, a higher abundance of yeast was observed in the liver and spleen of mice challenged with MP1 complemented mutant compared to MP1 knockout mutant. PM1 and MP1 complemented mutant survived significantly better than MP1 knockout mutant in macrophages at 48 hours (P<0.01) post-infection. The mean fungal counts of Pichia pastoris GS115- MP1 in the liver (P<0.001) and spleen (P<0.05) of mice were significantly higher than those of GS115 at 24 hours post-challenge.

          Conclusions/Significance

          Mp1p is a key virulence factor of T. marneffei. Mp1p mediates virulence by improving the survival of T. marneffei in macrophages.

          Author Summary

          Talaromyces ( Penicillium) marneffei is an opportunistic thermal dimorphic fungus most prevalent in Southeast Asia. Our team has previously shown that Mp1p, a protein encoded by the MP1 gene, is an immunogenic surface and secretory protein of T. marneffei. In this study, we showed that mice challenged with T. marneffei with the MP1 gene died but those challenged with T. marneffei without the MP1 gene did not die. There was also significantly higher fungal load and more necrosis in organs of mice challenged with T. marneffei with the MP1 gene than T. marneffei without the MP1 gene. Furthermore, T. marneffei with the MP1 gene survived better in macrophages than T. marneffei without the MP1 gene and Pichia pastoris with the MP1 gene survived in mice better than P. pastoris without the MP1 gene. Our data support that Mp1p is a key virulence factor of T. marneffei and Mp1p mediates virulence by improving the survival of T. marneffei in macrophages.

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          Most cited references38

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          Aspergillus fumigatus and aspergillosis.

          J P Latgé (1999)
          Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.
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            Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects.

            Penicillium marneffei infection is an important emerging public health problem, especially among patients infected with human immunodeficiency virus in the areas of endemicity in southeast Asia, India, and China. Within these regions, P. marneffei infection is regarded as an AIDS-defining illness, and the severity of the disease depends on the immunological status of the infected individual. Early diagnosis by serologic and molecular assay-based methods have been developed and are proving to be important in diagnosing infection. The occurrence of natural reservoirs and the molecular epidemiology of P. marneffei have been studied; however, the natural history and mode of transmission of the organism remain unclear. Soil exposure, especially during the rainy season, has been suggested to be a critical risk factor. Using a highly discriminatory molecular technique, multilocus microsatellite typing, to characterize this fungus, several isolates from bamboo rats and humans were shown to share identical multilocus genotypes. These data suggest either that transmission of P. marneffei may occur from rodents to humans or that rodents and humans are coinfected from common environmental sources. These putative natural cycles of P. marneffei infection need further investigation. Studies on the fungal genetics of P. marneffei have been focused on the characterization of genetic determinants that may play important roles in asexual development, mycelial-to-yeast phase transition, and the expression of antigenic determinants. Molecular studies have identified several genes involved in germination, hyphal development, conidiogenesis, and yeast cell polarity. A number of functionally important genes, such as the malate synthase- and catalase-peroxidase protein-encoding genes, have been identified as being upregulated in the yeast phase. Future investigations pertaining to the roles of these genes in host-fungus interactions may provide the key knowledge to understanding the pathogenicity of P. marneffei.
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              Disseminated Penicillium marneffei infection in southeast Asia.

              Disseminated infection with the fungal pathogen Penicillium marneffei is, after extrapulmonary tuberculosis and cryptococcal meningitis, the third most common opportunistic infection in HIV disease in northern Thailand. We report the clinical, microbiological, and therapeutic features of a large series of HIV-infected adults with disseminated P marneffei infection. From August, 1987, to June, 1992, 92 patients with P marneffei infection confirmed by culture were seen at Chiang Mai University Hospital, of whom 86 were also infected with HIV. Clinical information was available for 80 of these patients. The most common presenting symptoms and signs were fever (92%), anaemia (77%), weight loss (76%), and skin lesions (71%). 87% of patients presenting with skin lesions had generalised papules with central umbilication. Presumptive diagnosis was made in 50 patients by microscopic examination of Wright's-stained bone-marrow aspirate and/or touch smears of skin biopsy or lymph-node biopsy specimens. Most patients who were diagnosed responded initially to amphotericin or itraconazole, whereas most who were not diagnosed and treated died. 12 patients relapsed within 6 months of cessation of treatment. P marneffei has become an important pathogen of HIV-associated opportunistic infection in Thailand.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                25 August 2016
                August 2016
                : 10
                : 8
                : e0004907
                Affiliations
                [1 ]Department of Microbiology, The University of Hong Kong, Hong Kong
                [2 ]State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong
                [3 ]Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong
                [4 ]Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong
                [5 ]School of Biomedical Sciences, The University of Hong Kong, Hong Kong
                [6 ]Department of Pathology, The University of Hong Kong, Hong Kong
                [7 ]Department of Pathology, United Christian Hospital and Tseung Kwan O Hospital, Hong Kong
                [8 ]Department of Medicine, University of British Columbia, Vancouver, Canada
                University of California San Diego School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PCYW SKPL KYY. Performed the experiments: CCYL ETKT KTKC HZ RKCL FY JPC MKT WHL. Analyzed the data: RKHAY WFN. Contributed reagents/materials/analysis tools: HT SSYW SX KHS RYK NER QH. Wrote the paper: PCYW SKPL KYY.

                Article
                PNTD-D-16-00185
                10.1371/journal.pntd.0004907
                4999278
                27560160
                e8640b23-7db1-457f-b557-1c15a4702094
                © 2016 Woo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 February 2016
                : 14 July 2016
                Page count
                Figures: 5, Tables: 2, Pages: 16
                Funding
                Funded by: Mona Shaw and the Shaw Foundation
                Award Recipient :
                Funded by: Food and Health Bureau, Government of the Hong Kong Special Administrative Region, China
                Award ID: HKM-15-M07
                Award Recipient :
                Funded by: Strategic Research Theme Fund of the University of Hong Kong
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001692, Croucher Foundation;
                Award Recipient :
                Funded by: HKU Award for CAE Membership and Dr Hector T.G. Ma
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: MOP-125879, to NER
                Award Recipient :
                This work was partly supported by Mona Shaw and the Shaw Foundation; the Health and Medical Research Fund (No. HKM-15-M07 [commissioned project]), Food and Health Bureau, Government of the Hong Kong Special Administrative Region, Hong Kong; the Strategic Research Theme Fund of The University of Hong Kong; Research Grant Council Grant; Croucher Senior Medical Research Fellowship; HKU Award for CAE Membership and Dr Hector T.G. Ma; and a grant from the Canadian Institutes of Health Research (MOP-125879, to NER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Virulence Factors
                Research and Analysis Methods
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                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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