Talaromyces Marneffei Infection Research Articles

Establishment of a mathematical model for predicting malignancy of lung cancer complicated with Talaromyces Marneffei infection and its chest imaging characteristics

ObjectiveThis exploration aims to discuss the establishment of mathematical model for predicting malignancy of lung cancer complicated with Talaromyces Marneffei infection and its chest imaging characteristics, and improve clinicians' understanding of the disease. Method: the lung cancer patients with Talaromyces Marneffei infection (observation group) and the patients only with Talaromyces Marneffei infection (control group) were selected as the research objects. The clinical features and chest computed tomography (CT) imaging features of the two groups were compared and summarized. Meanwhile, the clinical classification and the number of T lymphocytes in peripheral blood of the two groups were observed. Finally, the mathematical model of malignant prediction was constructed. Results: the number of male patients infected with Talaromyces Marneffei is significantly higher than that of female patients (P < 0.05); the symptoms of cough and expectoration in the observation group are significantly more than those in the control group (P < 0.05); the clinical classification of the two groups are all disseminated infection of Talaromyces Marneffei, reaching 100%; the main imaging features of the observation group are obvious enhancement of focus enhancement scanning, strip shape and nodule, and the situation of obvious enhancement of focus enhancement scanning in the observation group is significantly higher than that in the control group (P < 0.05). Moreover, the accuracy of the mathematical model for predicting malignancy is 86.59%, and the fitting effect is excellent. Conclusion: the clinical and imaging findings of Talaromyces Marneffei infection and lung cancer overlap. The possibility of lung cancer should be considered when there are obvious signs of malignancy in patients with Talaromyces Marneffei.

An inexpensive point-of-care immunochromatographic test for Talaromyces marneffei infection based on the yeast phase specific monoclonal antibody 4D1 and Galanthus nivalis agglutinin.

Talaromyces marneffei is a thermally dimorphic fungus that causes opportunistic systemic mycoses in patients with AIDS or other immunodeficiency syndromes. The purpose of this study was to develop an immunochromatographic strip test (ICT) based on a solid phase sandwich format immunoassay for the detection of T. marneffei antigens in clinical urine specimens. The T. marneffei yeast phase specific monoclonal antibody 4D1 (MAb4D1) conjugated with colloidal gold nanoparticle was used as a specific signal reporter. Galanthus nivalis Agglutinin (GNA) was adsorbed onto nitrocellulose membrane to serve as the test line. Similarly, a control line was created above the test line by immobilization of rabbit anti-mouse IgG. The immobilized GNA served as capturing molecule and as non-immune mediated anti-terminal mannose of T. marneffei antigenic mannoprotein. The MAb4D1–GNA based ICT showed specific binding activity with yeast phase antigen of T. marneffei, and it did not react with other common pathogenic fungal antigens. The limit of detection of this ICT for T. marneffei antigen spiked in normal urine was approximately 0.6 μg/ml. The diagnostic performance of the ICT was validated using 341 urine samples from patents with culture- confirmed T. marneffei infection and from a control group of healthy individuals and patients with other infections in an endemic area. The ICT exhibited 89.47% sensitivity, 100% specificity, and 97.65% accuracy. Our results demonstrate that the urine-based GNA–MAb4D1 based ICT produces a visual result within 30 minutes and that the test is highly specific for the diagnosis of T. marneffei infection. The findings validate the deployment of the ICT for clinical use.

Gastrointestinal manifestations of Talaromyces marneffei infection in an HIV-infected patient rapidly verified by metagenomic next-generation sequencing: a case report

BackgroundThe manifestation of Talaromyces marneffei infection in some HIV-infected patients may be atypical. Cases with gastrointestinal involvement have rarely been reported. It is hard to make a diagnosis when patients are lacking the characteristic rash and positive blood culture.Case presentationHere, we described a patient living with HIV who complained of fever and abdominal pain, and was rapidly diagnosed with Talaromyces marneffei infection by metagenomic next-generation sequencing (mNGS) using formalin-fixation and paraffin-embedded (FFPE) samples of omentum majus tissue. We also reviewed reported related cases.ConclusionsTalaromyces marneffei is an unusual cause of clinical presentations involving obvious abdominal pain and lower gastrointestinal bleeding, but can be included in the differential diagnosis. As an important diagnostic tool, the significance of mNGS using FFPE samples of lesions provides a more targeted diagnosis.

Characteristic CD86 stain for organisms in cutaneous lesions of Talaromyces marneffei infection

To the Editor: Talaromyces marneffei (previously Penicillium marneffei) infection is endemic to Southeast Asia.1 The change in name reflects the recent taxonomic work in which many members of a subgenus of Penicillium were reassigned to the genus Taloromyces.2 A common sign of the T marneffei infection is the presence of cutaneous lesions, and the diagnosis is often made by skin biopsy. We studied macrophage polarization by performing immunohistochemical staining of cutaneous sections of deep mycosis.

The Presence of Secondary Evans Syndrome in AIDS Patients with Talaromyces marneffei Infection.

ObjectiveTalaromyces marneffei (T.M) is a common opportunistic fungus in human immunodeficiency virus (HIV) infection individual. Secondary Evans syndrome in AIDS patients with Talaromyces marneffei infection has not been reported before. Here, we described cases related to this comorbidity.MethodsAIDS patients diagnosed with Talaromyces marneffei infection from 2016 to 2020 at Xixi Hospital of Hangzhou were included in this retrospective study.ResultsTotal 76 AIDS patients with T.M infection were enrolled. The most common symptoms were fever and cough (70/76; 55/76, respectively). 53/76 (69.74%) patients got positive results of direct antiglobulin test. 14/76 AIDS-T.M patients combined with secondary Hemophagocytic lymphohistiocytosis (HLH). Five patients were diagnosed with AIDS-T.M associated Evans syndrome. There were severe inflammatory reaction, liver dysfunction, coagulation dysfunction and immunodeficiency status in AIDS-T.M patients with secondary Evans syndrome. All patients received antifungal therapy and three patients received corticosteroids for Evans syndrome treatment. One patient died due to sepsis.ConclusionAIDS-T.M patients with secondary Evans syndrome is extremely rare and we need to be alert to the occurrence of secondary Evans syndrome in AIDS-T.M patients. Clinicians should timely start effective antifungal treatments with suspicious T.M infection in AIDS patients.

Voriconazole Versus Amphotericin B as Induction Therapy for Talaromycosis in HIV/AIDS Patients: A Retrospective Study.

Disseminated talaromycosis caused by Talaromyces marneffei is a life-threatening opportunistic infection. Although amphotericin B deoxycholate (dAmB) remains the first-line induction treatment, voriconazole can also be used. However, no clinical trials have compared dAmB and voriconazole in the administration of talaromycosis. We retrospectively evaluated the efficacy and safety of voriconazole or dAmB as induction therapy for talaromycosis in HIV-infected patients. We enrolled HIV-infected patients with a confirmed Talaromyces marneffei infection who received intravenous dAmB (0.6 to 0.7mg/kg daily for 2weeks) or voriconazole (6mg/kg every 12h on day 1 and 4mg/kg every 12h afterward) as induction therapy, followed by oral itraconazole as consolidation and maintenance therapy. Drug efficacy was evaluated based on response rate. Drug safety was evaluated based on the occurrence of adverse events. In total, 58 patients who received voriconazole and 82 who received dAmB were enrolled from two hospitals. The voriconazole and dAmB treatment groups had similar response rates at the primary and follow-up efficacy evaluations. However, the durations of induction antifungal therapy and hospital stay were shorter for patients in the voriconazole group than in the dAmB group. Few adverse reactions occurred in either the voriconazole or dAmB group. Our retrospective study indicated that voriconazole is an effective and safe induction antifungal drug for HIV-associated disseminated talaromycosis. The duration of induction treatment with voriconazole was shorter, indicating its potential as a better choice in clinical practice. The duration of voriconazole induction therapy is 11 to 13days.

An Iris Tumor Secondary to Talaromyces Marneffei Infection in a Patient with AIDS and Syphilis

ABSTRACT Purpose To report a case of iris tumor secondary to Talaromyces marneffei infection in a patient with AIDS and syphilis. Case report A 25-year-old man presented with gradual vision decrease in the right eye for 2 months. Ocular examination revealed best-corrected visual acuity (BCVA) of 0.12 and a vascularized and solid tumor at inferotemporal iris base in the right eye. There were some papulonecrotic skin lesions. Both serum treponema pallidum particle agglutination and human immunodeficiency virus antibody were positive. Non-target metagenome next-generation sequencing detected Talaromyces marneffei in the skin lesion and aqueous humor. After 8 weeks of oral voriconazole and fluconazole eyedrop treatment, the iris tumor completely subsided, and the BCVA improved to 1.0. Conclusion Talaromyces marneffei infection may present as an iris tumor. Metagenome next-generation sequencing is helpful in diagnosis. Oral and topical anti-fungus therapy was sufficient to regress the disease without intraocular injection.

Identification and analysis of lncRNA, microRNA and mRNA expression profiles and construction of ceRNA network in Talaromyces marneffei-infected THP-1 macrophage

BackgroundCompetitive endogenous RNA (ceRNA) reveals new mechanisms for interactions between RNAs, which have been considered to play a significant role in pathogen-host innate immune response. However, knowledge of ceRNA regulatory networks in Talaromyces marneffei (TM)-macrophages is still limited.MethodsNext-generation sequencing technology (NGS) was used to obtain mRNA, miRNA and lncRNA expression profiles in TM-infected macrophages. The R package DESeq2 was used to identify differentially expressed lncRNA, miRNA and mRNA. The R package GOseq was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the ceRNA network of lncRNA–miRNA–mRNA interaction was constructed in Cytoscape. Similarly, functional enrichment analysis on mRNA in the ceRNA network. Finally, two mRNAs and four lncRNAs in the ceRNA network were randomly selected to verify the expression using qRT-PCR.ResultsIn total, 119 lncRNAs, 28 miRNAs and 208 mRNAs were identified as differentially expressed RNAs in TM-infected macrophages. The constructed ceRNA network contains 38 lncRNAs, 10 miRNAs and 45 mRNAs. GO and KEGG analysis of mRNA in the ceRNA network indicated that activated pathways in TM-infected macrophages were related to immunity, inflammation and metabolism. The quantitative validation of the expression of four randomly selected differentially expressed lncRNAs, AC006252.1, AC090197.1, IL6R-AS1, LINC02009 and two mRNAs, CSF1, NR4A3 showed that the expression levels were consistent with those in the RNA-sequencing.ConclusionsThe ceRNA network related to immunity, inflammation and metabolism plays an important role in TM-macrophage interaction. This study may provide effective and novel insights for further understanding the underlying mechanism of TM infection.

Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.

To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.

Bioinformatic analysis of the pathogenic mechanism of talaromyces marneffei infection.

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.

Unusual disseminated Talaromyces marneffei infection mimicking lymphoma in a non-immunosuppressed patient in East China: a case report and review of the literature

BackgroundTalaromyces marneffei infection is an important opportunistic infection associated with acquired immune deficiency syndrome (AIDS). However, it is unusual in patients with non-AIDS and other non-immunosuppressed conditions. We report a case of delayed diagnosis of disseminated T. marneffei infection in non-AIDS, non-immunosuppressive and non-endemic conditions.Case presentationWe describe a previously healthy 24-year-old man who complained of a 3-month history of intermittent diarrhea and a recent week of uncontrollable high fever. The HIV antibody test was negative. Enhanced abdominal computed tomography (CT) and integrated 18F-2-deoxy-2-fluoro-D-glucose position emission tomography/computed tomography (FDG PET/CT) both suspected malignant lymphoma. However, a large number of yeast-like cells were found in macrophages in cervical lymph node samples by hematoxylin and eosin stain and silver hexamine stain. Subsequent blood culture suggested T. marneffei infection. Metagenomic Next Generation Sequencing (mNGS) results suggested T. marneffei as the dominant pathogen. Unfortunately, the patient continued to develop acute liver failure and died due to adverse events associated with amphotericin B.ConclusionsEarly diagnosis in HIV-negative patients who are otherwise not immunosuppressed and endemic poses a serious challenge. T. marneffei infection is an FDG-avid nonmalignant condition that may lead to false-positive FDG PET/CT scans. Nevertheless, integrated FDG PET/CT is necessary in patients with fever of unknown origin in the early period to perform earlier biopsy for histopathology and culture in highly avid sites and to avoid delays in diagnosis and treatment.

Effect of combination antiretroviral therapy on the clinical manifestations, radiological characteristics, and disease severity of HIV-associated Talaromyces marneffei infection.

The objective of this study was to evaluate whether combination antiretroviral therapy (cART) has an effect on the clinical manifestations, radiological characteristics, and disease severity of human immunodeficiency virus (HIV)-associated Talaromyces marneffei infection. The clinical manifestations, chest computed tomography (CT) images, and disease severity were compared between 14 patients with culture-confirmed T. marneffei infections who received cART and 38 patients who did not receive cART. Clinical manifestations included high fever (>38°C), cough, shortness of breath, chills, and skin rash. Chest CT scans were evaluated for the presence of ground-glass opacities, consolidation, miliary nodules, nodules, masses, cavitation, pericardial effusion, pleural effusion, mediastinal lymphadenitis, and the distribution of parenchymal abnormalities. Disease severity was estimated by clinical manifestations and chest CT findings. Fever (>38°C), cough, shortness of breath, and chills were significantly less frequent in patients who received cART than in those who did not receive cART (P < 0.05). The frequencies of miliary nodules, mediastinal lymphadenitis, and the proportion of diffuse lesions were significantly lower in patients who received cART than in those who did not receive cART (P < 0.05). The disease severity was significantly decreased in patients who received cART compared with patients who did not receive cART (P < 0.001). T. marneffei-infected patients who received cART had fewer clinical manifestations and decreased disease severity compared with those who did not receive this treatment. The use of cART is associated with modified chest CT characteristics in HIV-associated T. marneffei infections.

Disseminated Talaromyces marneffei infection presenting as multiple intestinal perforations and diffuse hepatic granulomatous inflammation in an infant with STAT3 mutation: a case report

BackgroundTalaromyces marneffei is a highly pathogenic fungus that can cause life-threatening fatal systemic mycosis. Disseminated Talaromycosis marneffei affects multiple organs, including the lungs, skin, and reticuloendothelial system. However, T. marneffei infection has rarely been reported in human immunodeficiency virus (HIV)-negative infants with multiple intestinal perforations and diffuse hepatic granulomatous inflammation.Case presentationWe present the case of an HIV-negative 37-month-old boy who has had recurrent pneumonia since infancy and was infected with disseminated Talaromycosis. Contrast-enhanced computed tomography of the whole abdomen showed hepatomegaly and intestinal wall thickening in the ascending colon and cecum with mesenteric lymphadenopathy. Colonoscopy showed a cobblestone pattern with erosion, ulcer, polypoid lesions, and lumen deformation ranging from the colon to the cecum. T. marneffei was isolated from the mucous membrane of the colon, liver, and bone marrow. After antifungal treatment and surgery, his clinical symptoms significantly improved. Whole-exome sequencing using the peripheral blood of the patient and his parents’ revealed a heterozygous missense mutation in exon 17 of the STAT3 gene (c.1673G>A, p.G558D).ConclusionsIn T. marneffei infection-endemic areas, endoscopic examination, culture, or histopathology from the intestine tissue should be performed in disseminated Talaromycosis patients with gastrointestinal symptoms. Timely and systemic antifungal therapy could improve the prognosis. Immunodeficiency typically should be considered in HIV-negative infants with opportunistic infections.

AIDS-associated Talaromyces marneffei central nervous system infection in patients of southwestern China

BackgroundThe clinical and laboratory characteristics of AIDS-associated Talaromyces marneffei infection, a rare but a fatal mycosis disease of the central nervous system, remain unclear.Case presentationHerein, we conducted a retrospective study of ten AIDS patients with cerebrospinal fluid culture-confirmed central nervous system infection caused by Talaromyces marneffei. All 10 patients were promptly treated with antifungal treatment for a prolonged duration and early antiviral therapy (ART). Among them, seven patients were farmers. Nine patients were discharged after full recovery, while one patient died during hospitalization, resulting in a mortality rate of 10%. All patients initially presented symptoms and signs of an increase in intracranial pressure, mainly manifesting as headache, dizziness, vomiting, fever, decreased muscle strength, diplopia or even altered consciousness with seizures in severe patients. Nine patients (90%) showed lateral ventricle dilatation or intracranial infectious lesions on brain CT. Cerebrospinal fluid findings included elevated intracranial pressure, increased leukocyte count, low glucose, low chloride and high cerebrospinal fluid protein. The median CD4+ T count of patients was 104 cells/μL (IQR, 36–224 cells/μL) at the onset of the disease. The CD4+ T cell counts of three patients who eventually died were significantly lower (W = 6.00, p = 0.020) than those of the patients who survived.ConclusionsThe common clinical symptoms of T. marneffei central nervous system infection are associated with high intracranial pressure and intracranial infectious lesions. Earlier recognition and diagnosis and a prolonged course of amphotericin B treatment followed by itraconazole combined with early ART might reduce the mortality rate.

Assessment of Talaromyces Marneffei Infection of the Intestine in Three Patients and a Systematic Review of Case Reports.

BackgroundHematogenous dissemination of Talaromyces marneffei can result in multiorgan involvement (skin, lung, and reticuloendothelial system involvement); however, few studies have reported intestinal T marneffei infections. We investigated clinical features, management, and patient outcomes concerning Talaromyces-related intestinal infections.MethodsPatients with Talaromycosis between August 2012 and April 2019 at The First Affiliated Hospital of Guangxi Medical University, China, were retrospectively analyzed. Patients presenting with intestinal Talaromycosis and endoscopy-confirmed diagnoses were investigated. We also undertook a systematic review of the relevant English and Chinese literature.ResultsOf 175 patients diagnosed with Talaromycosis, 33 presented with gastrointestinal symptoms, and 31 underwent stool cultures, 1 of which tested positive. Three patients had gastrointestinal symptoms and negative stool cultures, and endoscopic tissue biopsy confirmed a pathological diagnosis. A systematic review of 14 reports on human Talaromycosis identified an additional 16 patients. Fever, weight loss, and anemia were the most common symptoms, along with abdominal pain, diarrhea, and bloody stools. Abdominal computed tomography showed intestinal wall edema and thickening and/or abdominal lymphadenopathy. Endoscopy showed erosion, hyperemia, edema, and multiple intestinal mucosal ulcers. Of the 19 patients, 16 received antifungal therapy, 14 of whom recovered and 2 died. Three patients received no therapy and died.ConclusionsGastrointestinal disseminated Talaromycosis is not rare and can affect the stomach, duodenum, and colon, and may involve the entire digestive tract. Colon is the most common site. Endoscopy is needed for patients presenting with gastrointestinal symptoms in T marneffei-infected endemic areas. Systemic application of effective antifungal therapy can improve the prognosis.

LncSSBP1 Functions as a Negative Regulator of IL-6 Through Interaction With hnRNPK in Bronchial Epithelial Cells Infected With Talaromyces marneffei.

Talaromyces marneffei (TM) is an important opportunistic pathogenic fungus capable of causing disseminated lethal infection. In our previous study, we identified host lncRNAs and mRNAs that are dysregulated in TM-infected bronchial epithelial cells. In this report, we verified that IL-6, a key factor in acute inflammatory response, is down-regulated in TM pathogenesis. To elucidate the mechanism of IL-6 regulation, we analyzed the coding/non-coding network, and identified lncSSBP1, a novel lncRNA that is up-regulated by TM. Our results demonstrate that overexpression of lncSSBP1 decreases IL-6 mRNA expression, whereas knockdown of lncSSBP1 enhances IL-6 mRNA expression. Though lncSSBP1 is primarily localized to the nucleus, bioinformatics analysis suggests that it is unlikely to function as competing endogenous RNA or to interact with IL-6 transcription factors. Instead, RNA pull down and RNA immunoprecipitation assays showed that lncSSBP1 binds specifically to heterogenous nuclear ribonucleoprotein K (hnRNPK), which is involved in IL-6 mRNA processing. Our findings suggest that lncSSBP1 may affect IL-6 mRNA expression during TM infection through interaction with hnRNPk in bronchial epithelial cells. Our results suggest a novel pathway by which TM may suppress the immune response to its advantage.

Activation of autophagy and IL-10 production are regulated by Jun N-terminal kinase 1 and 2 and p38 mitogen activated protein kinase signaling pathways during Talaromyces marneffei infection within dendritic cells

Previous study have shown that Talaromyces marneffei (T. marneffei) induced activation of autophagy. Therefore, we explore signaling pathway that regulates activation of autophagy by intracellular signaling mechanisms during T. marneffei infection. Further, we examine c-Jun N-terminal kinase 1 and 2 (JNK1/2) and p38 signaling pathways that regulate IL-1β and IL-10 production and activation of autophagy during T. marneffei infection in human dendritic cells (DCs). We found that T. marneffei induced activation of JNK1/2 and p38 in human DCs. Furthermore, the inhibition of JNK1/2 and p38 increased activation of autophagy and decreased the replication of T. marneffei in T. marneffei-infected human DCs. Moreover, IL-1β secretion in T. marneffei-infected human DCs was dependent on JNK1/2 and autophagy pathways, whereas IL-10 secretion was dependent on JNK1/2, p38 and autophagy pathways. These data suggest that JNK1/2 and p38 pathways play critical roles in activation of autophagy, the multiplication of T. marneffei and subsequent cytokine production during T. marneffei infection.

Characterization of Anti-Interferon-γ Antibodies in HIV-Negative Patients Infected With Disseminated Talaromyces marneffei and Cryptococcosis.

BackgroundFew reports of Talaromyces marneffei (TM) or cryptococcosis infections among HIV-negative patients with high-titeranti–IFN-γautoantibodies (nAIGAs) have been published. We investigated the clinical manifestations of patients with nAIGAs and TM infections.MethodsHIV-negative adults (≥18 years) were enrolled if they haddisseminated TM infection (group 1; further divided into nAIGAs positive [group 1P] and negative [group 1N]); cryptococcosis(pulmonary cryptococcosis and/or cryptococcosis of the brain)(group 2); pulmonary tuberculosis (group 3); and healthy controls (group 4) with nAIGAs detected. Complete histories, physical examinations, and routine clinical laboratory tests were obtained at baseline.ResultsOverall, 88 participants were in the four groups (20,13,23, and 32 in groups 1 to 4, respectively). Significant differences occurred between groups with higher nAIGAs titers (P < 0.001), and higher total white-cell and absolute neutrophil counts (P < 0.001) in group1. Lungs (90.0%), lymph nodes (60.0%), skin (55.0%), and bones (50.0%) were most common sites of involvement. Significant differences in total white-cell and absolute neutrophil counts occurred between groups IP and 1N.Patients with recurrent TM infections, particularly group 1P, had higher initial nAIGA titer. ConclusionsPatients with persistent infection who died tended to have positive initial nAIGA titer. It suggests that nAIGAs may play a critical role in the pathogenesis of TM infections, and may be associated with more severe, refractory infection.

Application of Flow Cytometry in the Diagnostics Pipeline of Primary Immunodeficiencies Underlying Disseminated Talaromyces marneffei Infection in HIV-Negative Children.

Talaromyces (Penicillium) marneffei is an AIDS-defining infection in Southeast Asia and is associated with high mortality. It is rare in non-immunosuppressed individuals, especially children. Little is known about host immune response and genetic susceptibility to this endemic fungus. Genetic defects in the interferon-gamma (IFN-γ)/STAT1 signaling pathway, CD40/CD40 ligand- and IL12/IL12-receptor-mediated crosstalk between phagocytes and T-cells, and STAT3-mediated Th17 differentiation have been reported in HIV-negative children with talaromycosis and other endemic mycoses such as histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis. There is a need to design a diagnostic algorithm to evaluate such patients. In this article, we review a cohort of pediatric patients with disseminated talaromycosis referred to the Asian Primary Immunodeficiency Network for genetic diagnosis of PID. Using these illustrative cases, we propose a diagnostics pipeline that begins with immunoglobulin pattern (IgG, IgA, IgM, and IgE) and enumeration of lymphocyte subpopulations (T-, B-, and NK-cells). The former could provide clues for hyper-IgM syndrome and hyper-IgE syndrome. Flow cytometric evaluation of CD40L expression should be performed for patients suspected to have X-linked hyper-IgM syndrome. Defects in interferon-mediated JAK-STAT signaling are evaluated by STAT1 phosphorylation studies by flow cytometry. STAT1 hyperphosphorylation in response to IFN-α or IFN-γ and delayed dephosphorylation is diagnostic for gain-of-function STAT1 disorder, while absent STAT1 phosphorylation in response to IFN-γ but normal response to IFN-α is suggestive of IFN-γ receptor deficiency. This simple and rapid diagnostic algorithm will be useful in guiding genetic studies for patients with disseminated talaromycosis requiring immunological investigations.

Interplay of interferon-gamma and macrophage polarization during Talaromyces marneffei infection

Talaromyces marneffei is an increasingly destructive dimorphic fungal pathogen in clinical settings that can cause lethal Talaromycosis. The activation of macrophages is known to be important for host defenses against T. marneffei, and these macrophages are known to be activated in two ways (polarization), known as M1 and M2. We investigated the plasticity of these polarizations, in order to understand if cross-conversion of macrophages may be possible even after they have been programmed. We conducted in vitro experiments using a murine macrophage cell line to investigate the ability of T. marneffei to activate these polarizations. The pre-polarized (M0) macrophage subsets were challenged with LPS as a control, and the sets of M1 markers (iNOS and CD86) and M2 markers (Arg-1 and CD206) were assessed for a possible cross-conversion among M1, M2 and M0 (unstimulated) populations. We found that either conidia or yeast forms of T. marneffei initiate the repression of Arg-1 in M2 cells with no change in the M1 subtype marker molecule iNOS. However, an additional IFN-γ stimulus caused the three macrophage groups to fully exhibit an LPS-induced M2 suppression and a shift to M1 from M0 and M2. We conclude that the conversion of macrophages is required for maintenance of sufficient iNOS production against this organism in the host. The cytokine environment is the key factor that manipulates the plasticity changes among macrophage subtypes. Furthermore, IFN-γ is a crucial host defense factor against pathogenic T. marneffei that has significant therapeutic potential to promote an M1 polarization phenotype.