Latest publication

Ann Rheum Dis. 2025 May 20:S0003-4967(25)00823-4. doi: 10.1016/j.ard.2025.03.007. Online ahead of print.

ABSTRACT

OBJECTIVES: To identify and validate gene expression biomarkers of response to methotrexate (MTX) treatment in peripheral blood of children with juvenile idiopathic arthritis (JIA) measured before starting MTX treatment.

METHODS: RNA sequencing was performed on sorted CD4+, CD8+, CD14+, and CD19+ cells, as well as peripheral blood mononuclear cells (PBMC) taken pre-treatment in a discovery cohort (n = 97) and 2 validation cohorts (n = 26 and n = 47, respectively) of patients with non-systemic JIA. Clinical data were recorded at baseline (timepoint 1) prior to treatment and 6 months (timepoint 2) of MTX treatment. Analysis tested the association of gene expression in specific cell types with treatment response using limma-voom, gene set enrichment analysis, and a novel 51-gene score against response to treatment. Parallel analysis, also using pre-treatment gene expression data, was performed in adult rheumatoid arthritis (RA) data (n = 240).

RESULTS: In patients with JIA, the baseline expression of genes driven by interferon (IFN) alpha (type-I) or gamma (type-II) was associated with response to treatment at 6 months in 3 independent JIA cohorts. The direction of the association indicated that children with higher baseline expression of IFN-stimulated genes prior to MTX were more likely to be good responders. Comparison with adult RA indicated differences between PBMC and whole blood gene expression associations with response.

CONCLUSIONS: In children with JIA, a high IFN-driven gene signature is associated with a better response to MTX than those with a low IFN-driven gene signature. These data could pave the way to clinically validated tools to identify those most likely to require medications in addition to MTX to control inflammation.

PMID:40681434 | DOI:10.1016/j.ard.2025.03.007

iScience. 2025 Jun 12;28(7):112897. doi: 10.1016/j.isci.2025.112897. eCollection 2025 Jul 18.

ABSTRACT

Immunotherapy has transformed cancer treatment but benefits only some patients, and predictive biomarkers are lacking. One correlate of response is the reinvigoration of a subset of CD8 T cells that have an exhausted phenotype and impaired functionality. To develop effective therapies, reproducible models are required to identify candidate target genes that enable reversal of T cell exhaustion. Here, we describe an in vitro model by chronically stimulating T cells with their cognate antigen, followed by temporal phenotypic characterization. This model recapitulates many critical hallmarks of exhaustion, including expression of canonical surface markers, impaired proliferation, reduced cytokine production, decreased cytotoxic granule release, and metabolic alterations. Two in vivo models validate these results and establish a gene signature shared by in vitro and in vivo exhausted states. Critically, this signature is observed in tumor infiltrating T cells from multiple human tumor types, validating the translational potential of this model for discovering therapies.

PMID:40678524 | PMC:PMC12268933 | DOI:10.1016/j.isci.2025.112897

Nat Chem Biol. 2025 Jul 15. doi: 10.1038/s41589-025-01965-6. Online ahead of print.

ABSTRACT

Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.

PMID:40664791 | DOI:10.1038/s41589-025-01965-6

Nat Rev Mol Cell Biol. 2025 Jul 14. doi: 10.1038/s41580-025-00870-z. Online ahead of print.

ABSTRACT

Degrons are pivotal components of the ubiquitin-proteasome system, serving as the recognition determinants through which E3 ubiquitin ligases identify their substrates. Degrons have central roles in both protein quality control and intracellular signalling pathways, and mutations that dysregulate degron activity are associated with a wide range of diseases, including cancer, immunological disorders and neurodegeneration. The number of well-defined degrons remains sparse relative to the ~600 E3 ubiquitin ligases encoded in the human genome. Recent advances in high-throughput degron discovery technologies have accelerated progress in this area, expanding the number of N- and C-terminal degrons, internal degrons and ubiquitin-independent degrons defined experimentally at high resolution. In this Review, we discuss the latest insights into the molecular mechanisms through which degrons act, their functional importance and their relevance in human disease, and consider how bifunctional molecules harness degrons to enable targeted protein degradation for therapeutic benefit.

PMID:40659789 | DOI:10.1038/s41580-025-00870-z

PLoS Negl Trop Dis. 2025 Jul 14;19(7):e0013326. doi: 10.1371/journal.pntd.0013326. Online ahead of print.

ABSTRACT

Zika virus (ZIKV) is a neurotropic Orthoflavivirus transmitted by mosquito vectors, which has evolved into two lineages, namely African and Asian. ZIKV from the Asian lineage has been responsible for epidemics in the Pacific and the Americas, the largest of which occurred in Brazil in 2015 and was associated with severe neurological disorders, including cases of microcephaly and other congenital fetal malformations. Although never implicated in human epidemics, African strains exhibit faster replication, higher virus production, and greater virulence in animal models compared to their Asian counterparts. A key feature that may account for the better fitness of African ZIKV strains compared to Asian ones is the fact that they are more resistant to interferon (IFN). IFN response is a major host defense mechanism against viral infections, which culminates in the induction of hundreds of IFN-induced genes (ISGs) whose products inhibit viral replication. By screening an array of ISGs known for their antiviral activity, we show that African ZIKV strains are globally more resistant than their Asian counterparts to ISG-mediated restriction. In particular, SHFL, RTP4 and IFI6, which were the three most active ISGs against Asian viruses, had little or no effect on the replication of African ZIKV strains. These observations therefore suggest that if African strains are more resistant to the antiviral effect of IFN than Asian strains, this is not because they have greater capacity to inhibit IFN signaling, but rather because they are able to escape ISG-mediated restriction. Our results provide an explanation as to why viruses of African origin spread more rapidly and efficiently in vitro than their Asian counterparts as repeatedly demonstrated. However, it remains unclear why, despite their greater virulence and resistance to cellular antiviral defenses, ZIKV strains of the African lineage have never been identified in large-scale epidemics.

PMID:40658726 | DOI:10.1371/journal.pntd.0013326

Front Immunol. 2025 Jun 20;16:1610067. doi: 10.3389/fimmu.2025.1610067. eCollection 2025.

ABSTRACT

Systemic disease caused by nontyphoidal Salmonella (NTS) represents a major cause of death and morbidity, especially in young children in sub-Saharan Africa. No licensed vaccine is yet available, and an increase in antimicrobial resistance makes the development of a vaccine a global health priority. We are developing a bivalent formulation of Salmonella Typhimurium and Salmonella Enteritidis generalized modules for membrane antigens (GMMA)-based vaccine (iNTS-GMMA) and a trivalent formulation (iNTS-TCV) in which iNTS-GMMA is combined with the WHO-prequalified TYPHIBEV (Biological E, India) vaccine to prevent typhoid fever in addition to invasive NTS (iNTS) disease. Here, we measured the ability of antibodies induced by iNTS-GMMA and iNTS-TCV formulations in mice and rabbits to kill a broad panel of Salmonella in vitro in a complement-mediated fashion. These organisms include those causing invasive disease in Africa and Southeast Asia, global representatives causing gastroenteritis and other S. enterica serovars in addition to S. Typhimurium and S. Enteritidis. We characterized the O-antigen of the panel of isolates and demonstrated the sera functionality in both animal species against all isolates, providing evidence of the potential broad coverage of both GMMA-based formulations, which are currently undergoing testing in Phase I/II clinical trials.

PMID:40625744 | PMC:PMC12231430 | DOI:10.3389/fimmu.2025.1610067

NPJ Vaccines. 2025 Jul 1;10(1):132. doi: 10.1038/s41541-025-01196-9.

ABSTRACT

We investigated age-associated effects of SARS-CoV-2 vaccination in elderly individuals (n = 50, mean age 79) after six SARS-CoV-2 vaccine doses. While neutralization titers remained comparable across age groups, Fc-mediated effector functions declined with age. Individuals >80 demonstrated reduced antibody-dependent cellular cytotoxicity (ADCC), via a surrogate ADCC-signaling assay, correlating with diminished IgG1 binding. These findings highlight age-related impairments in Fc-mediated responses, with implications for immune protection and vaccine strategies in older populations.

PMID:40593808 | PMC:PMC12217920 | DOI:10.1038/s41541-025-01196-9

PLoS One. 2025 Jul 1;20(7):e0326658. doi: 10.1371/journal.pone.0326658. eCollection 2025.

ABSTRACT

BACKGROUND: The International Vaccine Institute-led CAPTURA (Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia) project delivered capacity building activities to strengthen antimicrobial resistance surveillance activities in Nepal.

METHODS: The CAPTURA project trained 97 laboratory personnel from 19 hospitals on the use of WHONET/BacLink software to manage microbiology data in Nepal during 2020-2021. Approximately two years later, the trainees were followed up by phone to assess implementation status and effectiveness of the training. An inductive approach was used for coding and categorization of their response, and themes were generated for analysis. Trainees from ten hospitals agreed to respond regarding their experience.

RESULTS: We found that two out of the ten hospitals were using the WHONET/BacLink software, with one each within and outside the national AMR surveillance network. The remaining eight hospitals never implemented the system despite receiving the training. Key barriers to implementation included, hospital administration prioritizing other interoperable software, limited ongoing training, inability to export data from an LIS, limited real-time assistance with technical issues, and poor confidence in analyzing data. In addition, limited human resources and minimal capacity-building activities resulted in a lack of confidence in using the system independently, which were also identified as barriers.

CONCLUSION: Implementing WHONET/BacLink software in hospital settings can be challenging due to various factors, including a lack of knowledge and confidence among users, a lack of time and human resources to use the software effectively, and a lack of interoperability with other hospital management systems. Real-time support and follow-up activities potentially reinforce the skills and knowledge delivered during the training.

PMID:40591673 | PMC:PMC12212552 | DOI:10.1371/journal.pone.0326658

Nat Nanotechnol. 2025 Jun 27. doi: 10.1038/s41565-025-01965-6. Online ahead of print.

ABSTRACT

RNA mutations and modifications have been implicated in a wide range of pathophysiologies. However, current RNA detection methods are hindered by data complexity and error-prone protocols, restricting their widespread use. Here we present a solid-state nanopore-based approach, RNA single-nucleotide characterization and analysis nanolatch (RNA-SCAN) system, which simplifies the detection of nucleotide mutations and modifications in RNA with high resolution. Using phage RNA as a template, we tested multiple sequences and chemical modifications on nanolatches, allowing the detection of mismatches caused by nucleotide mutations through significant changes in positive event ratios using single-molecule nanopore measurements. This approach is also sensitive to modifications that either strengthen or weaken the interaction between the target RNA sequence and the nanolatch. As a proof-of-concept, we demonstrate successful discrimination of Escherichia coli and Salmonella spp. from total RNA based on nucleotide variations in their 16S rRNA, as well as quantification of different Salmonella spp. and detection of m5C1407 modification on E. coli 16S rRNA. The RNA-SCAN approach demonstrates the feasibility of combining RNA/DNA hybrid nanotechnology with nanopore sensing and diagnosing RNA-related health conditions.

PMID:40579472 | DOI:10.1038/s41565-025-01965-6

Annu Rev Biochem. 2025 Jun;94(1):361-386. doi: 10.1146/annurev-biochem-020425-045352.

ABSTRACT

Retroviral and retrotransposon invasion pose a constant threat to genome integrity and have driven the evolution of host defense pathways able to counter these attacks. The human silencing hub (HUSH complex) is an epigenetic transcriptional repressor complex that recognizes and silences newly integrated retroelements through the establishment of ectopic heterochromatin and chromatin compaction. HUSH provides a genome-wide immunosurveillance system whose challenging task is to detect and silence any newly integrated retroelements, and it thus plays a key role in host defense. To distinguish self from nonself genomic DNA, HUSH recognizes long single-exon (intronless) DNA, the essential hallmark of reverse transcription. Retroelements, being RNA derived, lack classical, noncoding cellular introns, so a long, intronless sequence of DNA is the abnormal molecular pattern that allows HUSH to distinguish invading retroelements from intron-containing host genes. As a newly identified component of the innate immune system, HUSH protects the genome from the reverse flow of genetic information from RNA to DNA, revealing an unanticipated mechanism of postintegration genome immunity.

PMID:40540752 | DOI:10.1146/annurev-biochem-020425-045352