Institut Pasteur of Shanghai

Anti-melanoma differentiation-associated gene 5 antibody-positive (MDA5+) dermatomyositis (DM) is characterized by a high incidence of rapidly progressive interstitial lung disease (RP-ILD). Unique transcriptomic signatures in patients with MDA5+ DM were investigated. Peripheral blood mononuclear cells (PBMCs), skin, and muscle biopsies from 28 patients with MDA5+/- DM were sequenced. Uniquely expressed transcripts identified using RNA sequencing analysis of PBMCs were further validated using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Receiver operating characteristic analysis was used to determine the diagnostic potential of the target genes. In MDA5+ DM samples, components of antiviral defense, neutrophil migration, and immune-associated pathways (in PBMCs), fatty acid metabolic processes (in skin), and antigen recognition (in muscle tissue) were upregulated. The expressions of defensin alpha 3 (DEFA3), ribonuclease family member 2 (RNASE2), and interferon alpha inducible protein 27 (IFI27) were upregulated and exhibited good predictive values for RP-ILD in MDA5+ DM. The activation of the IFN, virus-associated, and aberrant immune response pathways, as well as fatty acid metabolic processes may be involved in MDA5+ DM pathogenesis. IFI27, DEFA3, and RNASE2 may contribute to RP-ILD pathogenesis and serve as biomarkers of MDA5+ DM.

Host-derived factors ingested during mosquito blood feeding are poorly understood modulators of malaria transmission. Here, we demonstrated that host complement C3, acquired by mosquitoes during Plasmodium infection, significantly enhanced rodent malaria infection in laboratory-reared mosquitoes. This effect was recapitulated in field-caught Anopheles sinensis mosquitoes, confirming its relevance to malaria transmission in a more natural setting. Moreover, host-derived C3 significantly reduced the efficacy of anti-Pfs25 antibodies in blocking malaria transmission. Mechanistically, host-derived C3 lyses the mosquito midgut symbiont Elizabethkingia anophelis (E. anophelis)-a bacterium that intrinsically suppresses parasite development by blocking the zygote-to-ookinete transition. Strikingly, host-derived C3 in mosquitoes appears to be activated by the alternative pathway, and inhibiting Factor B with Iptacopan (LNP023) reduced Plasmodium falciparum (P. falciparum) infection, while increased the efficacy of anti-Pfs25 antibodies to blocking P. falciparum transmission in the standard membrane-feeding assay. Therefore, this study describes a strategy of the malaria parasite to utilize host complement C3 to promote its transmission and provides us with an avenue to block malaria transmission and improve the blocking efficacy of anti-Pfs25 antibodies by the inhibition of C3 activation.

Traditional histological methods for identifying ectopic thymus (ET) have significant limitations including high risk of false negatives. This study aims to evaluate the effectiveness of flow cytometry in detecting ETs in patients undergoing total thymectomy. We analyzed 864 samples from 103 patients using flow cytometry and hematoxylin and eosin (H&E) staining. ETs were identified by the presence of CD3mediumTCRvβmediumCD4+CD8+ T cells in flow cytometry or Hassall's corpuscles in H&E staining. In the discovery set, flow cytometry detected ETs in 69.2% of samples, compared to 23.6% by histological methods. The validation set showed a higher incidence of ETs in myasthenia gravis (MG) patients than in non-MG patients (73.5% vs. 58.0%, P < 0.0001) and in those with thymic epithelial tumors versus normal thymus (68.1% vs. 58.1%, P =0.0088). MG patients exhibited a higher prevalence of active ETs, characterized by a high proportion of CD4+CD8+ T cells, indicating robust thymopoiesis, compared to those without MG (P =0.0001). Specific regions, such as the left cervical root, areas along the right and left phrenic nerves, and the left innominate vein, showed significantly higher activity (P < 0.05). Additionally, ETs were more frequently found in the cervical region than in the mediastinum (75.0% vs. 60.8%, P =0.0012), and in patients aged 40years or younger compared to those older than 40years (73.0% vs. 60.6%, P =0.0027). Flow cytometry is a viable alternative for ET detection, providing a novel distribution map that enhances surgical decision-making in MG treatment.

ObjectivesViruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.MethodsFaecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome–bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.ResultsThe composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.ConclusionsThis study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.

While spontaneous mutation and gene acquisition are well-established drivers of pathogen adaptation, the role of gene loss remains underexplored. Here, we investigated the emergence and diversification of the pandemic clone (PC) of Vibrio parahaemolyticus through large-scale phylogenomic analysis of 8,684 global isolates. The PC rapidly acquired multiple marker genes and genomic islands, subsequently diverging into successive sublineages mediating independent waves of cross-country transmission, as also observed in V. cholerae. Wave succession in the last two decades was driven by loss of putrescine utilization (Puu) genes, conferring phenotypic advantages for environmental adaptation (enhanced biofilm formation) and human transmission (increased cell adhesion/intestinal colonization, reduced virulence), consistent with the virulence trade-off hypothesis. We identified Puu-gene loss in multiple bacterial genera, with effects on biofilm and adhesion replicated in V. cholerae and Escherichia coli, suggesting convergent evolution and universal phenotypic effects. Our results highlight the indispensable role of gene loss in bacterial pathogen adaptation.

Potential drug-drug interactions (DDI) can lead to adverse drug reactions (ADR), and DDI prediction can help pharmacy researchers detect harmful DDI early. However, existing DDI prediction methods fall short in fully capturing drug information. They typically employ a single-view input, focusing solely on drug features or drug networks. Moreover, they rely exclusively on the final model layer for predictions, overlooking the nuanced information present across various network layers. To address these limitations, we propose a multi-scale dual-view fusion (MSDF) method for DDI prediction. More specifically, MSDF first constructs two views, topological and feature views of drugs, as model inputs. Then a graph convolutional neural network is used to extract the feature representations from each view. On top of that, a multi-scale fusion module integrates information across different graph convolutional layers to create comprehensive drug embeddings. The embeddings from the two views are summed as the final representation for classification. Experiments on two real-world datasets demonstrate that MSDF achieves higher accuracy than state-of-the-art methods, as the dual-view, multi-scale approach better captures drug characteristics.

We described three novel avastroviruses identified in dead wild crows by next-generation and Sanger sequencing. They shared 40-50% nucleotide identities to known avastroviruses, and formed a new cluster in the genus Avastrovirus. This study highlighted the continually expanding host range and increasing genetic diversity of avastroviruses.

BackgroundMast cell degranulation plays a pivotal role in urticaria and is also an early histological characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of IL-17A blockers remains unclear. ObjectiveTo investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. MethodsA retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathological features were assessed. Patterns were compared between patients with ITAUR and non-urticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. ResultsPatients with ITAUR experienced early relapse compared to NUR group after treatment withdrawal. Transcriptomic and histopathological analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A-positive mast cells was inversely correlated with the duration of remission. LimitationsThe mechanism of mast cell activation in ITAUR has not been precisely elucidated. ConclusionIxekizumab treatment increases IL-17A-positive mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.