Occult Talaromyces marneffei Infection Unveiled by the Novel Mp1p Antigen Detection Assay.
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ABSTRACT:
SUBMITTER: Ly VT
PROVIDER: S-EPMC7686654 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Occult <i>Talaromyces marneffei</i> Infection Unveiled by the Novel Mp1p Antigen Detection Assay.
Ly Vo Trieu VT Thanh Nguyen Tat NT Thu Nguyen Thi Mai NTM Chan Jasper J Day Jeremy N JN Perfect John J Nga Cao Ngoc CN Vinh Chau Nguyen Van NV Le Thuy T
Open forum infectious diseases 20201019 11
<i>Talaromyces marneffei</i> causes fatal invasive mycosis in Southeast Asia. Diagnosis by culture has limited sensitivity and can result in treatment delay. We describe the use of a novel Mp1p enzyme immunoassay (EIA) to identify blood culture-negative talaromycosis, subsequently confirmed by bone marrow cultures. This EIA has the potential to speed diagnosis, enabling early therapy initiation. ...[more]
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Project description:BackgroundTalaromyces 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 findingsWe 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/significanceMp1p is a key virulence factor of T. marneffei. Mp1p mediates virulence by improving the survival of T. marneffei in macrophages.
| S-EPMC4999278 | biostudies-literature
Project description:Talaromycosis is a life-threatening fungal disease commonly seen in patients with acquired immunodeficiency syndrome (AIDS), which is endemic in Southern China and Southeast countries. The diagnostic methods available for talaromycosis are relatively time-consuming and yield a high mortality. Therefore, early diagnosis of talaromycosis is extremely important. We aimed to determine a potential method for assisting in its early diagnosis. A total of 283 patients with AIDS admitted to our hospital were prospectively included in this cross-sectional study and divided into those with Talaromyces marneffei (TSM group, n = 93) and those without Talaromyces marneffei (non-TSM group, n = 190). The diagnostic accuracy of the Mp1p enzyme immunoassay (EIA), galactomannan (GM) assay, and blood culture performed within 3 days of hospitalisation were evaluated, using talaromycosis confirmed by culture and/or pathology as the gold standard. The positivity rates in the Mp1p EIA, GM assay, and blood culture were 72%, 64.5%, and 81.7%, respectively, in the TSM group. The sensitivity, specificity, and positive and negative predictive values of the Mp1p EIA were 72.0% (67/93), 96.8% (184/190), 91.8% (67/73), and 87.6% (184/210), respectively. The Mp1p EIA showed a substantial agreement with the gold standard (kappa: 0.729) and superiority to the GM assay (kappa: 0.603); it also showed a superior diagnostic accuracy in the patients with CD4+ counts of < 50 cells/µL compared to those with CD4+ counts ranged from 50-100 cells/µL. The Mp1p EIA has the advantage of assisting in the early diagnosis of talaromycosis in patients with AIDS, especially those with low CD4+ counts.
| S-EPMC8890818 | biostudies-literature
Project description:Talaromyces (Penicillium) marneffei is an important pathogenic thermally dimorphic fungus causing systemic mycosis in Southeast Asia. The clinical significance of T. marneffei became evident when the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome epidemic arrived in Southeast Asia in 1988. Subsequently, a decline in the incidence of T. marneffei infection among HIV-infected patients was seen in regions with access to highly active antiretroviral therapy and other control measures for HIV. Since the 1990s, an increasing number of T. marneffei infections have been reported among non-HIV-infected patients with impaired cell-mediated immunity. Their comorbidities included primary adult-onset immunodeficiency due to anti-interferon-gamma autoantibodies and secondary immunosuppressive conditions including other autoimmune diseases, solid organ and hematopoietic stem cell transplantations, T-lymphocyte-depleting immunsuppressive drugs and novel anti-cancer targeted therapies such as anti-CD20 monoclonal antibodies and kinase inhibitors. Moreover, improved immunological diagnostics identified more primary immunodeficiency syndromes associated with T. marneffei infection in children. The higher case-fatality rate of T. marneffei infection in non-HIV-infected than HIV-infected patients might be related to delayed diagnosis due to the lack of clinical suspicion. Correction of the underlying immune defects and early use of antifungals are important treatment strategies. Clinicians should be familiar with the changing epidemiology and clinical management of T. marneffei infection among non-HIV-infected patients.
| S-EPMC4820671 | biostudies-other
Project description:Background: Talaromyces marneffei (T marneffei), known as a significant pathogen in patients with AIDS in Southeast Asia, is a dimorphic fungus, which can cause deadly systematic infection in immunocompromised hosts. What is more, the dimorphic phase transition has been reported as a conspicuous process linked with virulence. Interestingly, the yeast form was found in infected individuals, representing the pathogenic phase. However, few researches were found to study the mechanism of dimorphic transition. Thus, a diverse insight into the dimorphic switch mechanism, is urgently needed and we are the first one to research the mechanism of dimorphism.Methods: Firstly, we investigated the microarray of T. marneffei in the Gene Expression Omnibus database (GEO) for differentially expressed genes (DEGs). Then Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 was employed to analyze the underlying enrichment and pathway in biological process of DEGs. Meanwhile, protein-protein interaction (PPI) network was constructed using STRING database. On the strength of the theory that similar amino acid sequences share similar structures, which play a decisive role on the function of protein, three dimensional structures of hub-genes were predicted to further investigate the likely function of hub-genes.Results: GSE51109 was elected as the eligible series for the purpose of our research, including GSM1238923 (GSM23), GSM1238924 (GSM24), and GSM1238925 (GSM25). PMAA_012920, PMAA_028730, PMAA_068140, PMAA_092900, PMAA_032350 were the most remarkable genes in all of the three PPI networks, thus, were viewed as hub-genes. With regard to the three-dimensional construction, except that there was no significant prediction structure of PMAA_092900 with the criterion seq identify >?30%, GMQE: 0-1, QMEAN4: -4-0, the parallel templates for four structures were Crystal structure of Saccharomyces cerevesiae mitochondrial NADP(+)-dependent isocitrate dehydrogenase in complex with isocitrate, Organellar two-pore channels (TPCs), Yeast Isocitrate Dehydrogenase (Apo Form) and Crystal Structure Of ATP-Dependent Phosphoenolpyruvate Carboxykinase From Thermus thermophilus HB8 in order.Conclusion: The dimorphic transition of T. marneffei was viewed as a pathogenic factor and DEGs were observed. In-depth study of the function and pathway of DEGs revealed that PMAA_012920, PMAA_028730, PMAA_068140, PMAA_092900, PMAA_032350 were most likely acting as the hub-genes and were likely taking effect through regulating energy metabolism.
| S-EPMC7710178 | biostudies-literature
Project description:To describe the clinical features and the risk factors for nontuberculous mycobacteria (NTM) and Talaromyces marneffei (TM) co-infections in HIV-negative patients. A multicenter retrospective study in 13 hospitals, and a systematic literature review were performed of original articles published in English related to TM/NTM co-infections. HIV-negative patients with TM and NTM co-infections comprised Group 1; TM-only infection Group 2; NTM-only infection Group 3; and healthy volunteers Group 4. Univariate logistic analysis was used to estimate the potential risk factors of TM/NTM co-infections. A total of 22 cases of TM and NTM co-infections were enrolled. Of these, 17 patients (77.3%) had a missed diagnosis of one of the TM or NTM pathogens. The anti-IFN-γ autoantibodies (AIGAs) titer, white blood cell (WBC), neutrophil counts (N), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), globulin, and immunoglobulin G (IgG) levels of Group 1 were higher than those of the other groups, whereas the levels of CD4+T cells was lower than those of other groups. There was a significant negative correlation between the AIGA titers and the number of CD4+T cells (P < 0.05). Factors including the ratio of the actual values to the cut-off values of AIGAs, WBC, N, HGB, CD4+T cells, IgG, IgM, IgA, serum globulin, ESR, and CRP were taken as potential risk factors for TM and NTM co-infection. Most patients with TM and NTM co-infection had a missed diagnosis of one of the TM or NTM pathogens. The levels of AIGAs, WBC, N, ESR, and CRP in TM and NTM co-infections were remarkably higher than in mono-infection. High-titer AIGAs may be a potential risk factor and susceptibility factor for co-infection of TM and NTM in HIV-negative hosts.
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Project description:Talaromyces marneffei is a dimorphic fungus that has emerged as an opportunistic pathogen particularly in individuals with HIV/AIDS. Since its dimorphism has been associated with its virulence, the transition from mold to yeast-like cells might be important for fungal pathogenesis, including its survival inside of phagocytic host cells. We investigated the expression of yeast antigen of T. marneffei using a yeast-specific monoclonal antibody (MAb) 4D1 during phase transition. We found that MAb 4D1 recognizes and binds to antigenic epitopes on the surface of yeast cells. Antibody to antigenic determinant binding was associated with time of exposure, mold to yeast conversion, and mammalian temperature. We also demonstrated that MAb 4D1 binds to and recognizes conidia to yeast cells' transition inside of a human monocyte-like THP-1 cells line. Our studies are important because we demonstrated that MAb 4D1 can be used as a tool to study T. marneffei virulence, furthering the understanding of the therapeutic potential of passive immunity in this fungal pathogenesis.
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