PLoS Pathogens最新文献

{"title":"Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses.","authors":"Martin V Hamann, Lisa Brauckmann, Christoph Schwarz, Michael Spohn, Ramon Stoeck, Sabrina M Leddy, Julie Frouard, Maisha Adiba, Riekje Winzer, Fabian Hausmann, Sanamjeet Virdi, Adam Grundhoff, Cedric Feschotte, Daniel Sauter, Frauke Muecksch, Nadia R Roan, Eva Tolosa, Ulrike C Lange","doi":"10.1371/journal.ppat.1014618","DOIUrl":"10.1371/journal.ppat.1014618","url":null,"abstract":"<p><p>People living with HIV (PLWH) on antiretroviral therapy (ART) accumulate primarily defective proviral sequences in genomes of often clonally expanded CD4 + HIV-1 target cells. The majority of viral-derived DNA is transcriptionally active and preferentially found at distinct genomic loci suggesting a selective process driven by integration site-specific crosstalk between viral and host sequences. Focusing on one of the most prominent selected integration loci, the BTB Domain and CNC Homolog 2 (BACH2) gene, we here show mechanistic insights how CD4 + T cells are functionally reprogrammed via exaptation of provirus-derived regulatory sequences during long-term ART. Using a cellular model of BACH2-integrated proviruses, we find that proviral transcription drives aberrant BACH2 protein levels that escape autoregulatory feedback and impose BACH2-dependent transcriptomic changes. By mimicking these changes in primary CD4 + T lymphocytes, we observe that BACH2 drives reprogramming of cells toward a proliferative, precursor memory-like type. These reprogrammed CD4 + T cells possess traits of immune evasion and cellular survival that are signatures of persistent HIV reservoir cells in PLWH. Inhibition of provirus transcriptional activity can mitigate exaptation, suggesting a strategy to offset HIV-driven differentiation and expansion of CD4 + T cells. Finally, our data suggest that provirus exaptation at a second prominently selected proviral integration gene, the Signal Transducer And Activator of Transcription 5B (STAT5B) gene, drives a contrary, effector-like T cell fate, suggesting a multifaceted impact of exaptation on immune homeostasis. Overall, our data suggest that transcriptionally active proviruses, even if structurally defective, modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the complex immune modulation and dysregulation experienced by ART-suppressed PLWH.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014618"},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venom vesicles from the parasitoid Ganaspis hookeri facilitate venom protein entry into host immune cells.","authors":"Nicholas M Bretz, Chris Lark, Sarah Perkel, Rebecca Jackson, Jeremy D Driskell, James A Mobley, Nathan T Mortimer","doi":"10.1371/journal.ppat.1014707","DOIUrl":"10.1371/journal.ppat.1014707","url":null,"abstract":"<p><p>The parasitoid wasp Ganaspis hookeri infects Drosophila melanogaster larvae, laying an egg and injecting venom directly into the host body cavity. While infected hosts mount an immune response in an attempt to eliminate the parasitoid egg, parasitoid venom proteins act to inhibit these host responses and manipulate host physiology to ensure infection success. A key immune suppressive venom protein in G. hookeri is a venom-specific isoform of the SERCA (Sarco/endoplasmic reticulum calcium-ATPase) calcium pump. However, SERCA is a large hydrophobic protein, and the mechanism by which it and other venom proteins are transported into host cells is not well understood. Electron microscopy and nanoparticle tracking analysis of G. hookeri venom revealed the presence of venom extracellular vesicles (vEVs) as a putative transport mechanism. We characterized the biophysical properties of vEVs, and found that G. hookeri venom contains multiple vesicle types that are distinguishable by size, zeta potential, protein content, and density. A subset of these vEVs contain SERCA, and we found that fluorescently labeled vEVs are able to enter into host immune cells and alter host intracellular calcium levels, and that disruption of vesicle integrity results in the loss of this SERCA activity in host cells. Together, our data support a model in which G. hookeri venom proteins, including SERCA, are packaged into an array of venom vesicles, and are transported into host cells for immune suppression.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014707"},"PeriodicalIF":4.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors.","authors":"Maura Manion, Camille M Lange, Ana M Ortega-Villa, Christine M Fennessey, Brandon F Keele, Matthew Moeser, Helene Highbarger, Kristi Huik, Natalie Lindo, Christian Gonsalves, James Virga, David B Meya, Sarah B Joseph, David R Boulware, Irini Sereti, Frank Maldarelli","doi":"10.1371/journal.ppat.1014697","DOIUrl":"10.1371/journal.ppat.1014697","url":null,"abstract":"<p><p>Opportunistic infections in the central nervous system (CNS), such as cryptococcal meningitis (CM) have profound consequences for people living with HIV-1 (PWH), including blood-brain barrier impairment and neuroinflammation. To investigate how CM may shape the HIV-1 populations in the CNS, we characterized viral variants in the blood and cerebrospinal fluid (CSF) compartments in PWH with active CM. Thirty-nine participants with CM had paired plasma and CSF viral load measurements prior to the start of anti-retroviral therapy (pre-ART), with overall significantly higher HIV-1 viral loads in plasma compared to the CSF. Among those with CSF pleocytosis, CSF viral loads were relatively higher and CCR5 coreceptor-utilizing HIV-1 were more frequently detected. To investigate whether these differences were due to sustained HIV-1 replication in the CNS that generated genetically distinct viral lineages in the CSF (i.e., viral compartmentalization), we characterized pre-ART HIV-1 env populations in a subgroup of eighteen PWH with CSF HIV-1 RNA levels > blood (N = 9) and CSF RNA levels < blood (N = 9). Compartmentalization between CSF and plasma viral populations was detected in participants from both groups and was associated with higher interleukin-2 (IL-2) levels in CSF. In some cases, HIV-1 populations in CSF were compartmentalized from plasma, were exclusively macrophage-tropic and reached levels exceeding 105 copies/ml CSF. In other cases, HIV-1 infected cells trafficking across the plasma and CSF compartments seemed the most likely source of virus in the CSF. Post-ART analysis in one participant demonstrated emergence of distinct HIV-1 populations. This study demonstrates that opportunistic infections may have diverse effects in shaping HIV-1 viral populations.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014697"},"PeriodicalIF":4.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pathogenicity factor of DNA virus interacts with Arabidopsis deubiquitinases UBP12/13 to promote viral infection.","authors":"Shun Li, Fangqin Yu, Yi Zhang, Siqi Liu, Hui-Wen Wu, Nam-Hai Chua, Shulin Deng","doi":"10.1371/journal.ppat.1014686","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014686","url":null,"abstract":"<p><p>Plant DNA viruses, such as Cauliflower mosaic virus (CaMV) and Cabbage leaf curl virus (CaLCuV), are devastating pathogens that cause substantial yield losses in crops worldwide. These viruses assemble their genomes into minichromosomes with host histones. Histone post-translational modifications (PTMs) are important for viral replication and host resistance. In this study, we demonstrate that the CaMV pathogenicity factor P6 interacts with Arabidopsis deubiquitinases UBP12 and UBP13, which are typically negative regulators of plant immunity. Using affinity purification-mass spectrometry (AP-MS), we identified UBP12/13 as prominent P6 interactors and confirmed their nuclear association. CaMV infection and P6 overexpression increased UBP12 abundance, suggesting the latter promotes viral infection. By contrast, ubp12/13 mutants exhibited enhanced resistance, characterized by reduced accumulation of viral DNA and transcripts. Chromatin immunoprecipitation (ChIP)-qPCR showed that the monoubiquitinated H2A (H2Aub) and H3K27me3 modifications on the CaMV 35S promoter, but not the 19S promoter, were significantly elevated in ubp12/13 mutants compared with wild-type plants. Furthermore, UBP12/13 are also targeted by AC2, a transcriptional activator from CaLCuV, indicating a conserved strategy among plant DNA viruses. Our findings support a working model in which viral pathogenicity factors hijack UBP12/13, which in turn may alter H2Aub homeostasis on viral minichromosomes to relieve epigenetic silencing and promote infection. Together, these findings point to a previously unrecognized route by which plant DNA viruses may influence host chromatin-associated pathways and identify UBP12/13 as potential targets for engineering virus-resistant crops.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014686"},"PeriodicalIF":4.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies.","authors":"Fengjuan Li, Shanquan Wu, Shulun Huang, Lv Lv, Yimei Cao, Huifang Bao, Pu Sun, Xingwen Bai, Jiaxin Yang, Jingjing Zha, Qiongqiong Zhao, Hehe Zhang, Dong Li, Jijun He, Zaixin Liu, Pinghua Li, Zengjun Lu, Dongsheng Lei, Kun Li","doi":"10.1371/journal.ppat.1014650","DOIUrl":"10.1371/journal.ppat.1014650","url":null,"abstract":"<p><p>The porcinophilic O/Cathay topotype variants of foot-and-mouth disease virus (FMDV) continuously accumulated mutations over time and produced antigenic drift, leading to diminished serum neutralization and compromised vaccine efficacy. However, the structural basis underlying this divergence remains poorly defined. Herein, we observed that the newly emerging O/Cathay variants in China exhibited marked neutralization escape from porcine immune sera. Furthermore, using a panel of seven porcine-derived neutralizing monoclonal antibodies (pnAbs), we mapped two antigenic regions with crucial determinants responsible for neutralization escape in recent O/Cathay variants. The charge change at +2 residue (Q → H/R) downstream of the conserved RGD receptor-binding motif on VP1, which modulates sensitivity to multiple pnAbs (pO18-34, pO18-40 and pO18-43) and vaccine-induced sera. Cryo-electron microscopy (cryo-EM) structures of pO18-29 in complex with the ancient O/HN/CHA/93 strain and the recent variant O/18074 revealed a novel VP3-centered antigenic structure and showed that mutations at positions 73 (V → K) and 134 (K → T) on VP3 mediated neutralization escape in O/Cathay variants via disruption of hydrophobic interaction as well as the hydrogen bonds and salt bridge networks. Moreover, residues 73 and 134 synergistically regulate pnAbs (pO18-2, pO18-18, pO18-28 and pO18-29) recognition. Together, our findings elucidate structural basis of neutralizing evasion in O/Cathay FMDV and provide a molecular framework for the rational design of next-generation broad-spectrum FMDV vaccine against emerging O/Cathay variants.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014650"},"PeriodicalIF":4.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling.","authors":"Seth Frietze, Cameron Lunn, Dean Oldham, Joseph R Boyd, Andrew N Bubak, Amalia Bustillos Saucedo, Maria A Nagel, Diego Restrepo, Kimberley D Bruce, Christy S Niemeyer","doi":"10.1371/journal.ppat.1014684","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014684","url":null,"abstract":"<p><p>Herpes simplex virus type 1 (HSV-1) is a neurotropic pathogen capable of invading the central nervous system (CNS) and is associated with chronic neuroinflammation, cognitive impairment, and neurodegenerative disease. While microglia orchestrate the initial immune response to HSV‑1, the molecular mechanisms that regulate their sustained neuroinflammatory activity in vivo remain poorly understood. To define the transcriptional and epigenetic mechanisms that shape microglial responses during acute HSV-1 infection in vivo, we have, for the first time, integrated single‑nucleus RNA sequencing, chromatin accessibility profiling, and spatial proteomics and transcriptomics in an intranasal HSV‑1 infection model. Single-cell multiome analysis of CD11b⁺ nuclei identified transcriptionally and epigenetically distinct microglial and macrophage populations. HSV-1 infection redistributed monocyte-lineage states, with a marked overrepresentation of interferon (IFN)‑responsive microglia and macrophage-associated populations characterized by amplification of Stat1/2, Irf1, and Cebpb rather than reflecting uniform inflammatory activation. In parallel, homeostatic microglial gene signatures (e.g., ApoE, Cst3) were reduced following HSV-1 infection. Spatial transcriptomics localized HSV‑1 antigen to discrete brainstem regions, which were enriched for predicted STAT1/2, IRF1, and CEBPB‑regulated targets identified through single‑nuclei analysis, demonstrating that these inferred transcriptional networks are activated within anatomically defined regions in vivo. Complementary spatial proteomics further confirmed increased microglial activation and astrocytic responses specifically within HSV-1 antigen-positive regions. Together, these integrated multiomic analyses demonstrate that HSV-1 induces localized transcriptional and epigenetic remodeling of microglia dominated by IFN-driven regulatory programs and a loss of homeostatic signatures. By linking single-cell regulatory architecture to spatially restricted tissue responses, our findings provide mechanistic insight into how localized viral infection sustains neuroinflammation, contributing to long-term neurological vulnerability and neurodegenerative disease risk.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014684"},"PeriodicalIF":4.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human cytomegalovirus exploits host chromatin remodeler MORC2 to promote the DNA damage response on viral genomes.","authors":"Jiseok Jeong, Dongjoon Jeong, Sungwon Lee, Junhyun Park, Hyewon Kim, Kwangseog Ahn","doi":"10.1371/journal.ppat.1014693","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014693","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) harbors a 230-kb double-stranded DNA genome whose replication induces extensive DNA damage during lytic infection. Because HCMV lacks canonical DNA repair machinery, it relies on host DNA damage response (DDR) pathways. However, the mechanisms that govern the preferential recruitment and function of host DDR proteins on viral genomes remain poorly understood. Here, we show that HCMV co-opts the host chromatin remodeler MORC Family CW-type zinc finger 2 (MORC2) to promote DDR activation on viral genomes. HCMV infection induces MORC2 expression, which is important for efficient viral DNA replication and progeny virus production. We found that MORC2 redistributes to viral replication compartments (vRCs) in HCMV-infected cells and enhances viral chromatin accessibility in an ATPase-dependent manner, thereby facilitating γH2AX accumulation and the recruitment of DNA repair factors to vRCs. Furthermore, we found that HCMV UL112-113-mediated phase separation facilitates MORC2 recruitment to vRCs, promoting efficient DDR signaling on viral genomes. Together, these findings provide a mechanistic framework for how DNA viruses alleviate replication stress by hijacking host chromatin remodelers.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014693"},"PeriodicalIF":4.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N-terminus of alpha-1 giardin, a parasitic annexin orthologue, is essential for oligomerization and lipid-binding activity.","authors":"Dawid Warmus, Corina D Wirdnam, Erina A Balmer, Tendai Muronzi, Manfred Heller, Özlem Tastan Bishop, Carmen Faso","doi":"10.1371/journal.ppat.1014407","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014407","url":null,"abstract":"<p><p>Annexins are Ca² ⁺ - and membrane-binding proteins conserved across eukaryotes and involved in diverse membrane-associated processes, including unconventional protein secretion (UPS). In the intestinal parasite Giardia lamblia, annexins are represented by a family of 21 proteins termed alpha-giardins (αGs), all of which lack classical signal peptides yet are detected at the parasite surface and in the secretome. Here, we present a comprehensive functional analysis of αGs, with a particular focus on α1-giardin (α1G), a leading vaccine candidate against giardiasis and a putative virulence-associated UPS substrate. We show that αGs localize to peripheral endocytic compartments (PECs-PVs), specialized endo-lysosomal organelles implicated in protein release, and engage in multiprotein complexes enriched in UPS substrates. Using lipid-binding assays, cross-linking mass spectrometry (XL-MS), and structural modelling, we define conserved and divergent features of αG membrane interactions. Focusing on α1G, we combine site-directed mutagenesis, confocal microscopy, and mass photometry to demonstrate a critical role for its short N-terminal region in oligomerization and membrane association. Integration of these data with molecular dynamics simulations reveals how α1G oligomeric state and membrane occupancy could be regulated at PECs-PVs membranes. Taken together, our findings provide structural insights relevant to parasite virulence and vaccine development and contribute to a mechanistic model for annexin-mediated UPS in Giardia.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014407"},"PeriodicalIF":4.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses.","authors":"Shijin Wang, Yubin Tang, Songyang Lai, Jiaxin Yang, Qingran Yang, Xize Liu, Xiao-Fang Yu, Haoran Guo, Wei Wei","doi":"10.1371/journal.ppat.1014699","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014699","url":null,"abstract":"<p><p>Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are leading causes of severe hand, foot, and mouth disease (HFMD) with high childhood mortality and no specific antiviral therapy. SCARB2 is the essential uncoating receptor, yet extracellular SCARB2-Fc decoys fail to block infection, representing a decade-old paradox in enterovirus therapeutics. Here, we overcome this limitation by engineering RMP(R8), a cell-penetrating SCARB2 mimetic peptide comprising the minimal VP2-binding domain (W146-K166) fused to an octa-arginine transporter. RMP(R8) shows potent antiviral activity (EC50 = 0.156 μg/mL), outstanding safety (selectivity index > 2003), and excellent aqueous solubility, a critical asset for clinical translation. It broadly inhibits genetically divergent EV-A71 isolates and CV-A16 in intestinal and neural cells by blocking viral entry. In a lethal neonatal mouse model, RMP(R8) increases survival against EV-A71 and CV-A16 challenge in vivo. Intracellular receptor mimicry thus establishes a generalizable strategy for viruses refractory to extracellular intervention. RMP(R8) is a promising clinical candidate to address the unmet need for targeted anti-enterovirus treatment, and our findings redefine how to drug virus-receptor interactions that act inside cells.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014699"},"PeriodicalIF":4.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-1246 regulates macrophage lipid metabolism and is involved in resistance to human Mycobacterium tuberculosis infection.","authors":"Ashutosh Tripathi, Venkata Sanjeev Kumar Neela, Rajesh Kumar Radhakrishnan, Kamakshi Prudhula Devalraju, Anvesh Kumar Bogam, Tanmoy Mukherjee, Varalakshmi Mallidi, Abhinav Vankayalapati, Mohammed Soheb Sadath Ansari, Carlos Arana, Sindhu Joshi, Karan P Singh, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati, Deepak Tripathi","doi":"10.1371/journal.ppat.1014454","DOIUrl":"https://doi.org/10.1371/journal.ppat.1014454","url":null,"abstract":"<p><p>We determined whether microRNAs (miRNAs) regulate resistance to Mycobacterium tuberculosis (Mtb) infection in healthy household contacts (HHCs) of patients with tuberculosis (TB). As shown in our previously published study, we recruited 460 HHCs from 443 index cases of active pulmonary TB, with 293 (64.8%) remaining IGRA-negative throughout a two-year follow-up. Whole-transcriptome sequencing at baseline (0 months) and follow-up (24 months) and confirmation studies identified miRNA-1246 (downregulated) and miRNA-125b (upregulated) as potential candidates for the development of resistance in nonconverters compared with converters and progressors. Mechanistic studies using proteomics and computational analysis revealed that miRNA-1246 inhibitor reduce Mtb growth in macrophages by regulating lipase activity, specifically through targeting alpha/beta hydrolase domain-containing protein 2 (ABHD2). Inhibition of miRNA-1246 increased glycolytic activity and promoted a metabolic shift in macrophages conducive to pathogen clearance, suggesting its critical role in metabolic regulation and resistance to tuberculosis. These findings highlight potential miRNA-based therapeutic strategies to enhance immunity against Mtb.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 10","pages":"e1014454"},"PeriodicalIF":4.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}