The natural process of human immunodeficiency virus type 1(HIV-1) infection is characterized by high viral load, immune cell exhaustion, and immunodeficiency, which eventually leads to the stage of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. Rapidly progressing HIV-1 individuals often die of AIDS several years after infection without treatment. The promotion of ART greatly prolongs the survival time of HIV-infected persons. However, some patients have incomplete immune function reconstruction after ART due to latent storage of HIV-infected cells. Therefore, how to achieve a functional cure has always been the focus and hot spot of global AIDS research. Fortunately, the emergence of ECs/LTNPs who can control virus replication naturally has ignited new hope for realizing a functional cure for AIDS. Recently, a special category of infected individuals has attracted attention that can delay the progression of the disease more rigorously than the natural progression of HIV-1 infection described above. These patients are characterized by years of HIV-1 infection, long-term asymptomatic status, and normal CD4+T cell count without ART, classified as HIV-infected long-term nonprogressors (LTNPs) and elite controllers (ECs). Numerous studies have shown that the host and virus jointly determine the progression of HIV-1 infection, in which the level of innate immunity activation plays an important role. As the first line of defense against pathogen invasion, innate immunity is also a bridge to induce adaptive immunity. Compared with natural progressors, innate immunity plays an antiviral role in HIV-1 infection by inducing or activating many innate immune-related factors in the natural ECs. Learning the regulation of ECs immunity, especially the innate immunity in different characteristics, and thus studying the mechanism of the control of disease progression naturally, will contribute to the realization of the functional cure of AIDS. Therefore, this review will explore the relationship between innate immunity and disease progression in ECs of HIV-1 infection from the aspects of innate immune cells, signaling pathways, cytokines, which is helpful to provide new targets and theoretical references for the functional cure, prevention and control of AIDS, and development of a vaccine.
Abstract Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N 6 ‐methyladenosine (m 6 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 m 6 A profiles of TM mono‐infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m 6 A levels and upregulation of the m 6 A reader YTH N 6 ‐methyladenosine RNA binding protein C2 (YTHDC2) in TM‐infected macrophages. Knockdown of YTHDC2 in TM‐infected cells showed an elevated expression of TLR2 through m 6 A‐dependence, along with upregulation of TNF‐α and IL1‐β. Overall, we characterized the m 6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m 6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.
Talaromyces marneffei is the third most common infectious pathogen in AIDS patients and leads to the highest death rate in Guangxi, China. The lack of reliable biomarkers is one of the major obstacles in current clinical diagnosis, which largely contributes to this high mortality. Here, we present a study that aimed at identifying diagnostic biomarker candidates through genome-wide prediction and functional annotation of Talaromyces marneffei secreted proteins. A total of 584 secreted proteins then emerged, including 382 classical and 202 nonclassical ones. Among them, there were 87 newly obtained functional annotations in this study. The annotated proteins were further evaluated by combining RNA profiling and a homology comparison. Three proteins were ultimately highlighted as biomarker candidates with robust expression and remarkable specificity. The predicted phosphoinositide phospholipase C and the galactomannoprotein were suggested to play an interactive immune game through metabolism of arachidonic acid. Therefore, they hold promise in developing new tools for clinical diagnosis of Talaromyces marneffei and also possibly serve as molecular targets for future therapy.
Adherence to antiretroviral therapy (ART) is a prerequisite to improve immunity and reduce the morbidity and mortality of people living with HIV (PLWH). To describe ART adherence and associated factors among PLWH, patients who initiated ART in Liuzhou between 1998 and 2013 were recruited. Socio-demographic characteristics, HIV infection-related characteristics and clinical tests were analyzed. Both descriptive and multi-level analyses were used to explore factors related to ART adherence of PLWH who initiated ART in Liuzhou. A total of 8433 patients were recruited in this study. The rate of adherence to ART was 84.9% in PLWH who initiated ART in Liuzhou between 1998 and 2013. The female sex, WHO clinical stage III or IV before ART initiation, longer treatment duration and higher triglyceride were positively associated with ART adherence. Meanwhile, HIV acquired by intravenous drug use, co-infection with tuberculosis and other opportunistic infections were negatively associated with ART adherence. Measures should be adopted to improve the ART adherence of PLWH who are male, acquired HIV by intravenous drug use, and are co-infected with tuberculosis and other opportunistic infections.
ABSTRACT Emerging evidence underscores the pivotal role of long noncoding RNAs (lncRNAs) as crucial regulators within the HIV life cycle. However, the precise functions and detailed mechanisms by which lncRNAs operate in HIV‐1 highly exposed but persistently seronegative (HESN) individuals remain currently unknown. Through RNA sequencing analysis of the HESN individual and the matched control, we identified potential lncRNAs. Then, we conducted validation experiments at the population level, while cellular models of HIV‐1 infection were constructed for functional experimental investigations in vitro. Subcellular localization of the identified lncRNA was determined, followed by an exploration of the specific regulatory mechanism underlying HIV resistance through some experiments, such as RNA pull‐down, western blot and Hirt assays. LncRNA LINC02453 is highly expressed in HESN. Moreover, LINC02453 is identified as a novel lncRNA associated with heightened resistance to HIV‐1. LINC02453 is predominantly localized in the nucleus and binds to SEC13, a component of the nuclear pore complex, leading to the inhibition of HIV‐1 replication by regulating key processes such as late reverse transcription, nuclear import, and DNA integration. Our findings suggest that LINC02453 may serve as a prospective target for the development of innovative anti‐HIV therapeutics.
Abstract Talaromycosis , an invasive mycosis caused by Talaromyces marneffei (Tm), has rapidly increased in recent years, becoming an emerging pathogenic fungal disease. However, The driving factors and potential distribution of global talaromycosis is still unclear. Here, we developed maxent ecology model using environmental variables, Rhizomys distribution and HIV/AIDS epidemic to forecast ecological niche of talaromycosis worldwhile, as well as Identify the drivering factors. The constructed model had excellent performance with the area under the curve (AUC) of the receiver operating curve (ROC) of 0.997 in training data and 0.991 in testing data. Our model revealed that Rhizomys distribution, mean temperature of warmest quarter, precipitation of wettest month, HIV/AIDS epidemic and mean temperature of driest quarter were the top 5 important variables affecting talaromycosis distribution. In addition to traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), our model also identified other potential epidemic regions, inculding parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our findings has redefined global talaromycosis , discovered hidden high-risk areas and prorvided insights about driving factors of talaromycosis distribution, which will help inform surveillance strategies and improve the effectiveness of public health interventions against Tm infections. Author Summary Our study aims to explore the spatial ecology of talaromycosis worldwhile. The diseases burden of Talaromycosis , a neglected zoonotic disease, is continuously rising in recent years because of the sheer size of susceptible population in the setting of increased globalization, rising HIV prevalence, and emerging iatrogenic immunodeficiency conditions. Here, we used historic reported talaromycosis cases from 1964 to 2017, combined with environmental factors, Rhizomys distribution and HIV/AIDS epidemic to build an maxent ecology model to define the ecological niche of talaromycosis , then predicting the potential distribution of the disease. The ecological niche of talaromycosis is characterized by a concentrated distribution, which can be cognitively divided into two regions: traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), while other potential epidemic regions were predicted in parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our model also identified 5 driving factors affecting talaromycosis distribution. These findings will help demonstrate the global distribution of talaromycosis, discover hidden high-risk areas, and improve the effectiveness of public health interventions against Tm infections.
Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in T.marneffei-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.
Objective To understand the spread trend of drug resistant tuberculosis (DR TB) over time in Liuzhou City, Guangxi Zhuang Autonomous Region, and provide evidences to contain the spread and transmission of DR-TB. Methods Data from the DR TB surveillance network in Liuzhou were analyzed. The percentage of DR-TB cases among the newly registered TB cases and the average annual percentage change (APC) were calculated. The regression model was constructed with linear and binomial regression. The hypothesis testing of the average APC was conducted by using line/curve fitting approach. Results A total of 571 DR-TB cases were detected through the DR surveillance network in Liuzhou from 2014 to 2019, accounting for 2.14% (571/26691) of new registered TB cases. The number of DR-TB cases increased from 50 in 2014 to 189 in 2019, an increase of 2.60 times. Of those with drug resistant TB, 30.30% (173/571) were isoniazid resistant, 19.26% (110/571) were rifampin resistant, 29.25% (167/571) were multi-drug resistant (MDR), and 7.01% (40/571) were extensive drug resistant (XDR). In MDR TB cases, XDR TB cases accounted for 23.95%. From 2014 to 2019, the proportion of XDR-TB cases among newly registered TB cases increased from 0.15% to 0.17%. After 2016, the result of APC testing indicated that the total number of DR TB, isoniazid resistant TB cases and rifampin resistant TB were significant increased among new tuberculosis cases (P=0.031, P=0.018, P=0.043). Although the increasing trends of MDR TB and XDR TB cases were observed among new tuberculosis cases, the differences were not significant (PMDR TB=0.098, PXDR TB=0.484). Conclusion The average APCs of DR TB, isoniazid resistant TB and rifampin resistant TB cases significantly increased in Liuzhou overtime, but the difference in case increase over time between MDR TB and XDR TB had no significance. It is necessary to conduct consecutive surveillance to facilitate the development of evidence based prevention and control measures for DR TB and improve the prevention and control of TB and the spread of DR TB.
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