Marneffei Infection Research Articles

Clinical characteristics of HIV-associated tracheobronchial Talaromyces marneffei infection in seven patients in Guangxi, China.

Tracheobronchial Talaromyces marneffei (T. marneffei) infections among HIV-infected patients are rare. To improve understanding, we analyzed the clinical features, immune mechanisms, treatment, and prognosis of these patients. We collected clinical information from HIV-positive patients with talaromycosis admitted to the Fourth People's Hospital of Nanning from January 2015 to June 2022. Patients who presented with culture and/or histopathological proof of tracheobronchial T. marneffei infection were included. A total of 108 patients with respiratory infections who underwent bronchoscopy were enrolled. Seven patients with tracheobronchial T. marneffei infection, all of whom were men with a median age of 48 years (range 39-50 years), were analyzed. Cough, sputum, fever, and weight loss were the most common symptoms. The total white blood cell count was normal or decreased, and all lymphocyte counts were decreased. All patients had reduced CD4+ T-cell counts, with values less than 50 cells/µL. The chest CT imaging signs included patchy signals or large areas of exudation, bronchial stenosis and occlusion. This was different from the lack of bronchial involvement. Endoscopically, the trachea and bronchial mucosa showed congestion, edema, surface attachment, nodules, lumen stenosis, obstruction, etc. T. marneffei spores were found via bronchial mucosal pathology in all 7 patients. Five patients were initially treated with intravenous infusion of amphotericin B for 2 weeks, followed by oral itraconazole capsules (200mg) twice daily, and two patients were initially treated with itraconazole. Six patients were remission, and 1 died. The clinical features of trachea invasion and nontracheal invasion are not unique, but chest CT reveals manifestations such as masses, solid shadows, and bronchial stenosis/obstruction. Bronchoscopy should be performed if possible, and the presence or absence of trachea T. marneffei infection should be confirmed. Antiviral therapy combined with antifungal therapy can improve patient prognosis.

Emergence and Rapid Diagnosis of Talaromyces marneffei Infections in Renal Transplant Recipients by Next-Generation Sequencing

In the last few years, next-generation sequencing (NGS) has emerged as a technology for laboratory diagnosis of many culture-negative infections and slow-growing microorganisms. In this study, we describe the use of metagenomic NGS (mNGS) for rapid diagnosis of T. marneffei infection in a 37-year-old renal transplant recipient who presented with chronic pneumonia syndrome. Bronchoalveolar lavage for mNGS was positive for T. marneffei sequence reads. Prolonged incubation of the bronchoalveolar lavage revealed T. marneffei colonies after 6 days of incubation. Analysis of 23 cases of T. marneffei infections in renal transplant recipients from the literature revealed that the number of cases ranged from 1 to 4 cases per five years from 1990 to 2020; but increased rapidly to 9 cases from 2021 to 2023, with 7 of them diagnosed by NGS. Twenty of the 23 cases were from T. marneffei-endemic areas [southern part of mainland China (n = 9); Hong Kong (n = 4); northeastern India (n = 2); Indonesia (n = 1) and Taiwan (n = 4)]. For the 3 patients from non-T. marneffei-endemic areas [United Kingdom (n = 2) and Australia (n = 1)], they had travel histories to China and Vietnam respectively. The time taken for diagnosis by mNGS [median 1 (range 1 to 2) day] was significantly shorter than that for fungal culture [median 6 (range 3 to 15) days] (P = 0.002). mNGS is useful for picking up more cases of T. marneffei infections in renal transplant recipients as well as providing a rapid diagnosis. Talaromycosis is an emerging fungal infection in renal transplant recipients.

Characteristics of Endemic Mycoses Talaromyces marneffei Infection Associated with Inborn Errors of Immunity.

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen that causes endemic mycoses, which could lead to multiple organ damage. Talaromycosis is frequently disregarded as an early cautionary sign of immune system disorders in non-HIV-infected children. We conduct a comprehensive review of the genotypes and clinical features of talaromycosis in patients with IEI to enhance clinical awareness regarding T. marneffei as a potential opportunistic pathogen in individuals with immune deficiencies. A systematic literature review was performed by searching PubMed, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, and Scopus. Data on IEI patients with talaromycosis, including genotypes and their immunological and clinical features, were collected. Fifty patients with talaromycosis and IEI were included: XHIM (30.0%), STAT3-LOF deficiency (20.0%), STAT1-GOF (20.0%), IL2RG (6.00%), IFNGR1 (6.0%), IL12RB1 (4.0%), CARD9 (4.0%), COPA (4.0%), ADA (2.0%), RELB deficiency (2.0%), and NFKB2 (2.0%). Common symptoms of respiratory (43/50, 86.0%), skin (17/50, 34.0%), lymph node (31/50, 62.0%), digestive (34/50, 68.0%), and hematologic (22/50, 44.0%) systems were involved. The CT findings of the lungs may include lymph node calcification (9/30), interstitial lesions (8/30), pulmonary cavities (8/30), or specific pathogens (4/30), which could be easily misdiagnosed as tuberculosis infection. Amphotericin B (26/43), Voriconazole (24/43) and Itraconazole (22/43) were used for induction therapy. Ten patients were treated with Itraconazole sequentially and prophylaxis. 68.0% (34/50) of patients were still alive, and 4.0% (2/50) of were lost to follow-up. The disseminated T. marneffei infection resulted in the deaths of 14 individuals. The XHIM, STAT1-GOF, and STAT3-LOF demonstrated the highest susceptibility to talaromycosis, indicating the potential involvement of cellular immunity, IL-17 signaling, and the IL-12/IFN-γ axis in T. marneffei defense. T. marneffei infection may serve as an early warning indicator of IEI. For IEI patients suspected of T. marneffei, metagenomic next-generation sequencing (mNGS) could rapidly and effectively identify the causative pathogen. Prompt initiation of antifungal therapy is crucial for optimizing patient outcomes.

Clinical usefulness of metagenomic next-generation sequencing for Talaromyces marneffei diagnosis in China: a retrospective study.

Metagenomic next-generation sequencing (mNGS) has been widely used in the diagnosis of infectious diseases. However, studies on Talaromyces marneffei detection using mNGS remain scarce. Therefore, this study aimed to explore the diagnostic performance of mNGS in T. marneffei. Between March 2021 and June 2023, patients who were discharged with a final diagnosis of talaromycosis, or confirmed T. marneffei infection by mNGS, culture or pathological examination were included in the study. Culture and mNGS were performed simultaneously for all patients. Clinical data were retrieved for analysis. A total of 78 patients were enrolled, with 40 in the talaromycosis group and 38 in the suspected-talaromycosis group. In the talaromycosis group, mNGS showed a higher positivity rate(40/40, 100.0%) compared to culture(34/40, 85.0%)(P = 0.111). All patients in the suspected-talaromycosis group tested negative via culture, while mNGS yielded positive results. The T. marneffei reads in the talaromycosis group were significantly higher than in the suspected-talaromycosis group (4399 vs. 28, P < 0.001). In the suspected-talaromycosis group, of the four patients with low reads who did not receive antifungal therapy, one died and one lung lesion progressed; most patients(31/34, 91.2%) recovered after receiving appropriate antifungal therapy. mNGS proves to be a rapid and highly sensitive method for detecting T. marneffei. Higher reads of T. marneffei correspond to a higher likelihood of infection. However, cases with low reads necessitate a comprehensive approach, integrating clinical manifestations, laboratory tests, and imaging examinations to confirm T. marneffei infection.

Disseminated Talaromyces marneffei infection initially presenting as cutaneous and subcutaneous lesion in an HIV-Negative renal transplant recipient: a case report and literature review

BackgroundThe incidence of Talaromyces marneffei (T. marneffei) infection has increased in recent years with the development of organ transplantation and the widespread use of immunosuppressive agents. However, the lack of clinical suspicion leading to delay or misdiagnosis is an important reason for the high mortality rate in non-human immunodeficiency virus (HIV) and non-endemic population. Herein, we report a case of disseminated T. marneffei infection in a non-HIV and non-endemic recipient after renal transplant, who initially presented with skin rashes and subcutaneous nodules and developed gastrointestinal bleeding.Case presentationWe describe a 54-year-old renal transplantation recipient presented with scattered rashes, subcutaneous nodules and ulcerations on the head, face, abdomen, and right upper limb. The HIV antibody test was negative. The patient had no obvious symptoms such as fever, cough, etc. Histopathological result of the skin lesion sites showed chronic suppurative inflammation with a large number of fungal spores. Subsequent fungal culture suggested T. marneffei infection. Amphotericin B deoxycholate was given for antifungal treatment, and there was no deterioration in the parameters of liver and kidney function. Unfortunately, the patient was soon diagnosed with gastrointestinal bleeding, gastrointestinal perforation and acute peritonitis. Then he rapidly developed multiple organ dysfunction syndrome and abandoned treatment.ConclusionsThe risk of fatal gastrointestinal bleeding can be significantly increased in kidney transplant patients with T. marneffei infection because of the long-term side effects of post-transplant medications. Strengthening clinical awareness and using mNGS or mass spectrometry technologies to improve the detection rate and early diagnosis of T. marneffei are crucial for clinical treatment in non-HIV and non-endemic population.

Morphology, Development, and Pigment Production of Talaromyces marneffei are Diversely Modulated Under Physiologically Relevant Growth Conditions.

Talaromyces marneffei is an opportunistic pathogenic fungus that mainly affects HIV-positive individuals endemic to Southeast Asia and China. Increasing efforts have been made in the pathogenic mechanism and host interactions understanding of this pathogen in the last two decades; however, there are still no conclusions on how T. marneffei was transmitted from the donor bamboo rats to humans. A perception that the failure of fungus isolation from soil was attributed to the low salt tolerance of T. marneffei. Therefore, the effect of environmental fluctuations in fungal growth and development is fundamental for the characterization of its origin and fungal biology understanding. Herein, we characterized high osmolarity, pH, metal ions, nutrients, and oxidative stress have versatile effects on T. marneffei hyphal or yeast growth, conidia generation, and pigment production. Among these, high pH, low glucose amounts, and the inorganic nitrogen ammonium tartrate stimulated the red pigment production, whereas high osmolarity, high pH, and the inorganic nitrogen sodium nitrate could significantly accelerate the conidia generation. Specifically, zinc starvation repressed conidia generation and prevented the wrinkled yeast colony formation, indicating the function of zinc regulators in pathogenicity regulation. Since conidia are recognized as the infectious propagules, the effects characterization of different environmental factors in T. marneffei morphology in this work will not only expand the growth and pathogenic biology understanding of the fungus but also provide more clues for the T. marneffei infection transmission origin investigation.

Th1 cell immune response in Talaromyces marneffei infection with anti-interferon-γ autoantibody syndrome.

Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.

Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection.

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2(YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-αand IL1-β. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.

Disseminated Talaromyces marneffei infection associated with haemophagocytic syndrome in an HIV-negative patient in northern China: a case report

BackgroundTalaromyces marneffei is endemic to eastern India, Southeast Asia, and Guangdong and Guangxi provinces in China. It is common in immunocompromised individuals, especially in HIV-infected patients.Case presentationA 66-year-old male who had a history of hypertension and resided in Shandong Province (Northern China) was admitted for recurrent fever for one month. The patient had recurrent fever, multiple lymphadenopathies, hepatosplenomegaly, a back rash, and a progressive decrease in white blood cells and platelets. Talaromyces marneffei was isolated from peripheral blood and bone marrow after admission, and suspected fungal cells were found via lymph node pathology. The patient’s infection secondary to haemophagocytic syndrome continued to worsen despite antifungal, anti-inflammatory, and symptomatic treatment, leading to death due to multiple-organ failure.ConclusionAlthough rare, infection due to Talaromyces marneffei in HIV-negative patients has been increasing in recent years, and we should be vigilant about “new” infections in nonendemic areas.

Surgical plan selection and efficacy analysis in 32 cases of laryngotracheal stenosis

Objective: To explore the optimization of surgical procedures for laryngotracheal stenosis and its effect analysis. Methods: The data of 32 patients with acquired laryngotracheal stenosis who received surgical treatment from October 2015 to December 2021 were analyzed retrospectively. The age ranged from 19 to 72 years, with an average of (34.0±9.0) years. The medical history ranged from 1 to 32 months (median 3 months). As for etiology, there were 30 cases of iatrogenic laryngotracheal stenosis, including 20 cases of tracheal intubation and 10 cases of tracheotomy (7 cases of percutaneous tracheotomy and 3 cases of traditional tracheotomy). There were 1 case of laryngotracheal trauma and 1 case of airway Penicillium marneffei infection. According to Myer-Cotton grading system, grade Ⅳ stenosis was found in 14 cases, including 12 cases involving trachea and 2 cases involving trachea and subglottic area.There were 18 cases of grade Ⅲ, all of which involved the cervical trachea 5 cases failed in operation in other hospitals. According to stenosis grading, course of disease, primary disease control and the patient's general condition, the surgical plan was determined individually. The operations of end-to-end anastomosis, circumferential tracheal partial resection, T-tube placement and CO2 laser tracheal scar resection were performed respectively. The recovery of airway function and perioperative complications were observed one year after operation. Results: End-to-end anastomosis was performed in 16 cases, and partial circumferential tracheal resection in 2 cases, and tracheal granulation (scar) resection by CO2 laser in 2 cases and T-tube insertion in 12 cases. Eighteen cases which performed end-to-end anastomosis, partial resection of circumferential trachea in and 2 cases which performed laser tracheal scar resection were all recovered airway function at one stage. After 1 year, 19 cases were cured and 1 case was effective. Of 12 patients with T tube implantation, 11 cases were successfully extubated after 6-12 months, 7 cases were cured after 1 year, 2 cases were effective and 3 cases were ineffective. Among the 3 cases of failure, 2 cases were successfully extubated by sleeve resection and end-to-end anastomosis in the second stage, and the other case refused to accept other treatment methods and the T-tube was placed again, and the tube was blocked and the patient survived. During the follow-up period, the total cure rate was 87.5%, the effective rate was 9.4%, and the total extubation rate was 96.9%.The most common complication was subcutaneous emphysema, accounting for 78% (25/32), but no serious mediastinal emphysema or pneumothorax occurred. In the T-tube implantation group, granulation tissue grew in different degrees around the neck wound after operation, and improved or disappeared after 6-9 months. Anterior cervical tracheal fistula occurred in 4 cases of T-tube implantation group after extubation, which were cured by sealing the stoma. There were no complications such as severe bleeding or perioperative death. Conclusion: When there were various factors, the optimization of the surgical plan according to the degree of stenosis, the course of disease, the control of primary disease and the general condition was an important guarantee to improve the curative effect of laryngotracheal stenosis.

A case of TM infection with challenging differential diagnosis from lymphoma post-renal transplant

BackgroundLymphomas involving the gastrointestinal tract may be manifested as anti-inflammatory tract bleeding, abdominal lymph node enlargement, or even perforation of the gastrointestinal tract. After organ transplantation, the likelihood of post-transplant lymphoproliferative disorders increases, and some rare infections may also appear.Case presentationHerein, we report a living transplant patient with talaromycosis marneffei (TSM) or Talaromyces marneffei (TM) infection with gastrointestinal hemorrhage and systemic lymph node enlargement, which presented clinically as lymphoma.ConclusionThis case is TSM in a kidney transplant patient, confirmed by lymph node biopsy and blood culture. The patient discharged from hospital successfully under the treatment of antifungal therapy and immunosuppressive therapy. Physicians should be aware that TSM can mimic lymphoma, and early diagnosis and treatment can benefit the outcomes.

The role and mechanisms of PD-L1 in immune evasion during Talaromyces marneffei infection

Talaromycosis, caused by Talaromyces marneffei (T. marneffei), is a systemic fungal disease that involves dissemination throughout the body. The ability of T. marneffei to evade the immune system is considered a crucial factor in its persistent infection, although the specific mechanisms are not yet fully understood. This study aims to investigate the molecular mechanisms underlying the occurrence of latent T. marneffei infection and immune evasion. The gene expression profile analysis in T. marneffei-infected mouse revealed that Pd-l1 exhibited the highest correlation strength with other hub genes, with a median of 0.60 (IQR: 0.50–0.69). T. marneffei infection upregulated the expression of PD-1 and PD-L1 in PBMCs from HIV patients, which was also observed in the T. marneffei-infected mouse and macrophage models. Treatment with a PD-L1 inhibitor significantly reduced fungal burden in the liver and spleen tissues of infected mice and in the kupffer-CTLL-2 co-culture system. PD-L1 inhibitor treatment increased CTLL-2 cell proliferation and downregulated the expression of PD-1, SHP-2, and p-SHP-2, indicating the activation of T cell viability and T cell receptor signaling pathway. Additionally, treatment with a PI3K inhibitor downregulated PD-L1 in T. marneffei-infected kupffer cells. Similar results were observed with treatment using the T. marneffei cell wall virulence factor β-glucan. Overall, T. marneffei infection upregulated PD-L1 expression in HIV / T. marneffei patients, mice, and kupffer cells. Treatment with a PD-L1 inhibitor significantly reduced fungal burden, while activating T cell activity and proliferation, thereby promoting fungal clearance. Furthermore, the PI3K signaling pathway may be involved in the regulation of PD-L1 by T. marneffei.

Clinical characteristics of tracheobronchial Talaromyces marneffei infection in non-HIV-infected patients in South China

Objectives Tracheobronchial Talaromyces marneffei (T. marneffei) infections among non-HIV-infected patients are rare. To improve understanding, we analysed the clinical features, immune mechanisms, treatment, and prognosis. Methods Data on hospitalized patients with tracheobronchial T. marneffei infections from September 2013 to May 2022 were collected. The clinical and imaging features were analysed. Results Nineteen patients were enrolled, with a median age of 52 years (45–62 years). The most common symptoms were cough, expectoration, fever, weight loss, and anaemia. The total white blood cell and neutrophil counts, erythrocyte sedimentation rate, C-reactive protein, procalcitonin and globulin were increased, and the serum albumin levels were decreased. Chest CT manifestations included patchy shadows, masses, obstructive atelectasis, cavities, pleural effusion, and hilar and mediastinal lymphadenopathy. The fibreoptic bronchoscopy findings included masses, polyps or nodules with mucosal oedema, hypertrophic bulges, lumen stenosis or obstruction, and purulent secretions. T. marneffei infection was confirmed in 10 patients by positive culture, in five by both culture and metagenomic next-generation sequencing (mNGS), in two by mNGS, in one by culture and pathology and in 1 by histopathology. BALF (15/19, 78.9%) had the highest culture positive rate, followed by sputum (3/19), bronchial mucosa (1/1), lung biopsy (1/2); 36.8% of the patients were coinfected with other pathogens. For induction therapy, 7, 6, 2, and 4 patients received voriconazole, amphotericin B, voriconazole combined with amphotericin B, and fluconazole therapy, respectively, and 26.3% received treatment combined with nebulization and/or administration of amphotericin B under fibreoptic bronchoscopy. Four patients were treated for underlying diseases or coinfection, 31.6% were cured, 42.1% improved, and 26.3% died. Conclusions T. marneffei infection is common in the tracheobronchial airway tissue or secretions, and bronchoscopy has important diagnostic and treatment value. Antifungal therapy, including systemic therapy, involves triazoles and amphotericin administration, and aerosol inhalation and administration of amphotericin B under bronchoscopy are important.

Talaromyces marneffei infection with IFNGR1 gene mutation in a patient with negative Anti-Interferon-γ autoantibodies

BackgroundTalaromyces Marneffei (TM) is a rare opportunistic pathogen that mostly infects patients with low immunity compared to those with normal immunity. It may be related to immune deficiency or genetic factors. ObjectiveTo evaluate the gene mutation of a patient infected with TM in an endemic area with negative anti-interferon-γ autoantibodies, and negative human immunodeficiency virus (HIV) infection. MethodsExtract deoxyribonucleic acid (DNA) samples from the patient's peripheral blood, detect the mutation gene by whole exome sequencing (WES), and carry out Sanger sequencing verification for the detected mutation gene. ResultsThe authors detected a mutation in the IFNGR1 gene (NM_001363526.1) and validated the detected gene mutation using Sanger sequencing. The results showed a heterozygous mutation c.4C>T (p.L2F) located in the IFNGR1 gene (NM_001363526.1). Study limitationsThe mechanism of the IFNGR1 gene has not been further investigated in this study. ConclusionsThe IFNGR1 gene mutation may be a potential risk factor for TM infection, and the presence of anti-interferon-γ autoantibodies can aggravate disease symptoms.

Association between Prevalence of Talaromycosis and Economic Status in Asia

Previous studies have shown that geographic niche was a significant risk factor for developing T. marneffei (Tm) infection, and to date there are still lacking data of impact of economic status on the prevalence of Tm. Thus, we conducted this study, aiming to examine the correlation between prevalence of talaromycosis among HIV/AIDS-infected adult population and Asian country income, reported by World Bank data. A comprehensive medical literature review was performed to estimate the prevalence of T. marneffei infection among HIV/AIDS-infected adult population in Tm endemic and non-endemic countries and country income in Asia. Linear regression analyses were used to study the associations between Tm prevalence and Asian country income. Both unadjusted and adjusted models with Tm geographic distribution were analysed. A total of 48 Asian countries were included in the statistical analysis. Geographic distribution of talaromycosis was divided into three main regions: (i) Region 1: Regions of highest incidence of talaromycosis (&gt;100 Tm cases reported in literature); (ii) Region 2: Endemic Tm countries and (iii) Region 3: Countries of imported or travel-associated Tm cases. Estimated Tm prevalence in the three regions were 3.9%, 2% and 0.02%, respectively. There was no statistical difference in GDP among three regions (P = 0.70). The linear regression analyses showed no associations between prevalence estimates of talaromycosis and Asian country income in both unadjusted and adjusted for geographic distribution of T. marneffei (P = 0.83). Most markedly, country geography is still a significant risk factor for T. marneffei infection (P &lt; 0.001). Keywords: Economic status, Invasive fungal infections, Prevalence, Talaromyces marneffei, Vietnam.

The Impacts of Antiretroviral and Antifungal Treatments, and Tuberculosis Co-infection on Mortality and Relapse in Patients with Talaromyces Marneffei Infection

To date, clinical data on long-term clinical outcomes, including 6-month mortality and relapse in talaromycosis (Tm) patients and impacts of ART and secondary antifungal prophylaxis are still lacking. We conducted a secondary data analysis from 6-month prospective observation of patients with culture-confirmed talaromycosis who participated in the Itraconazole versus Amphotericin B for HIV-associated Talaromycosis (IVAP) trial. The primary outcome was 6-month Tm mortality, while the secondary outcome was relapse. Multivariable Cox proportional hazard models were used to identify predictors of outcomes of interest. The median patient age was 34 years (IQR:30 – 38). The median pre-ART CD4 counts at baseline were 10 (IQR: 5-21) cells/µL. The cumulative 76/435 (17.4%) patients died, and Tm relapse was observed in 18/435 (4.1%) patients. The multivariable analyses showed that strong independent predictors of 6-month Tm mortality included ineffective ART (either absence of ART or ART failure) (HR = 6.26, 95% CI: 3.95 – 9.92, P &lt; 0.001), and TB co-infection (HR =1.98, 95% CI: 1.23 – 3.17; P &lt; 0.01). Induction antifungal treatment with itraconazole versus amphotericin B deoxycholate was significantly associated with Tm death in the univariable model, however, it became insignificant in the multivariable model. In addition, the significant risk factors for Tm relapse were ineffective ART, induction antifungal treatment with itraconazole than intravenous amphotericin B, and shorter duration of itraconazole secondary prophylaxis after completing induction therapy in-hospital (all with significant P-values). Antiretroviral therapy, antifungal treatment and tuberculosis co-infection were main predictors for 6-month Tm fatality as well as relapse. Keywords: Invasive fungal infections, Mortality, Relapse, Talaromyces marneffei, Vietnam.

Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing

Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy.

Characteristics and risk factors for readmission in HIV-infected patients with Talaromyces marneffei infection.

Talaromyces marneffei (T. marneffei) is an opportunistic fungal infection (talaromycosis), which is common in subtropical regions and is a leading cause of death in HIV-1-infected patients. This study aimed to determine the characteristics and risk factors associated with hospital readmissions in HIV patients with T. marneffei infection in order to reduce readmissions. We conducted a retrospective study of admitted HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from 2012 to 2019. Kaplan-Meier analyses and Principal component analysis (PCA) were used to evaluate the effects of T. marneffei infection on patient readmissions. Additionally, univariate and multifactorial analyses, as well as Propensity score matching (PSM) were used to analyze the factors associated with patient readmissions. HIV/AIDS patients with T. marneffei-infected had shorter intervals between admissions and longer lengths of stay than non-T. marneffei-infected patients, despite lower readmission rates. Compared with non-T. marneffei-infected patients, the mortality rate for talaromycosis patients was higher at the first admission. Among HIV/AIDS patients with opportunistic infections, the mortality rate was highest for T. marneffei at 16.2%, followed by cryptococcus at 12.5%. However, the readmission rate was highest for cryptococcus infection (37.5%) and lowest for T. marneffei (10.8%). PSM and Logistic regression analysis identified leukopenia and elevated low-density lipoprotein (LDL) as key factors in T.marneffei-infected patients hospital readmissions. The first admission represents a critical window to intervene in the prognosis of patients with T. marneffei infection. Leukopenia and elevated LDL may be potential risk factors impacting readmissions. Our findings provide scientific evidence to improve the long-term outcomes of HIV patients with T. marneffei infection.

Construction of a murine model of latent infection and reactivation induced by Talaromyces marneffei

ObjectiveTo establish a murine model of Talaromyces marneffei (T. marneffei) latent infection and reactivation, providing a foundation for exploring the molecular mechanisms underlying disease relapse. MethodsBALB/c mice were tail vein injected with T. marneffei at 0 days post-infection (dpi) and treated with cyclophosphamide (CTX) intraperitoneally every four days, starting from 21 dpi or 42 dpi. Mice were observed for body weight changes, liver and spleen indices, histological characteristics of liver and spleen, fungal load detection in liver and spleen, and Mp1p qualitation in liver and spleen to assess T. marneffei infection severity. ResultsT. marneffei-infected mice exhibited a trend of initial weight loss followed by recovery and a subsequent decrease in weight after CTX injection throughout the observation period. Liver and spleen indices, as well as tissue damage, significantly increased during infection but later returned to normal levels, with a gradual rise observed after immunosuppression. Fungal load analysis revealed positive T. marneffei cultures in the liver and spleen at 7 dpi and 14 dpi, followed by negative T. marneffei cultures from 21 dpi until day 21 post-immunosuppression (42 dpi or 63 dpi); however, the spleen remained T. marneffei-cultured negative, consistent with the trend observed in Mp1p detection results. ConclusionA latent infection and reactivation model of T. marneffei in mice was successfully established, with the liver likely serving as a key site for latent T. marneffei.

Differential innate immune responses of human macrophages and bronchial epithelial cells against Talaromyces marneffei.

Talaromyces marneffei is a thermally dimorphic fungal pathogen endemic in Southeast Asia. As inhalation of airborne conidia is believed as the major infection route, airway epithelial cells followed by pulmonary macrophages are the first cell types which the fungus encounters inside the host. In this study, we established an in vitro infection model based on human peripheral blood-derived macrophages (hPBDMs) cultured with the supplementation of autologous plasma. Using this model, we determined the transcriptomic changes of hPBDMs in response to T. marneffei infection by quantitative real-time reverse-transcription polymerase chain reaction as well as high-throughput RNA sequencing. Results showed that T. marneffei infection could activate hPBDMs to the M1-like phenotype and trigger a potent induction of chemokine and pro-inflammatory cytokine production as well as the expression of other immunoregulatory genes. In contrast to hPBDMs, there was no detectable innate cytokine response against T. marneffei in human bronchial epithelial cells (hBECs). Using a green fluorescent protein-tagged T. marneffei strain and confocal microscopy, internalization of the fungus by hBECs was confirmed. Live cell imaging further demonstrated that the infected cells exhibited normal cellular physiology, especially that the process of cell division could be observed. Moreover, T. marneffei also survived better inside hBECs than hPBDMs. Our results illustrated a potential role of hBECs to serve as reservoir cells for T. marneffei to evade immunosurveillance by phagocytes, from which the fungus reactivates when the host immunity is weakened and causes infection. Such immunoevasion and reactivation may also help explain the long incubation period observed for talaromycosis, in particular the travel-related cases. IMPORTANCE Talaromyces marneffei is an important fungal pathogen especially in Southeast Asia. To understand the innate immune response to talaromycosis, a suitable infection model is needed. Here, we established an in vitro T. marneffei infection model using human peripheral blood-derived macrophages (hPBDMs). We then examined the transcriptomic changes of hPBDMs in response to T. marneffei infection with this model. We found that contact with T. marneffei could activate hPBDMs to the M1-like phenotype and induced mRNA expressions of five cytokines and eight immunoregulatory genes. Contrary to hPBDMs, such immunoresponse was not elicited in human bronchial epithelial cells (hBECs), despite normal physiology observed in infected cells. We also found that infected hBECs did not eliminate T. marneffei as efficiently as hPBDMs. Our observation suggested that hBECs may potentially serve as reservoir cells for T. marneffei to evade immunosurveillance. When the host immunity deteriorates later, then the fungus reactivates and causes infection.