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Original citation: J Clin Invest. 2022;132(11):e157549. https://doi.org/10.1172/JCI157549. Citation for this corrigendum: J Clin Invest. 2023;133(2):e167843. https://doi.org/10.1172/JCI167843. In Figure 1E, the data for BCL-6 was inadvertently omitted, with a duplicate of [...]

Virus-specific [CD8.sup.+] T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them sternness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory [CD8.sup.+] T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific [CD8.sup.+] T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in [TCF-1.sup.+] less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to [gamma]-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such [CD8.sup.+] T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure., Introduction For activation and differentiation, [CD8.sup.+] T cells require T cell receptor (TCR) signals provided by peptide/MHC class I, together with costimulation, and cytokines. The amount and duration of these [...]

The diversity and circulation of arboviruses are not much studied in Madagascar. The fact is that arboviral emergences are rarely detected. The existing surveillance system primarily relies on serological detection and records only a few human infections annually. The city of Mahajanga, however, experienced a confirmed dengue fever epidemic in 2020 and 2021. This study aimed to characterize and analyze the virome of mosquitoes collected in Mahajanga, near patients with dengue-like syndromes to detect known and unknown viruses as well as investigate the factors contributing to the relative low circulation of arboviruses in the area. A total of 4280 mosquitoes representing at least 12 species from the Aedes, Anopheles, and Culex genera were collected during the dry and the rainy seasons from three sites, following an urbanization gradient. The virome analysis of 2192 female mosquitoes identified a diverse range of viral families and genera and revealed different patterns that are signatures of the influence of the mosquito genus or the season of collection on the composition and abundance of the virome. Despite the absence of known human or veterinary arboviruses, the identification and characterization of viral families, genera, and species in the mosquito virome contribute to our understanding of viral ecology and diversity within mosquito populations in Madagascar. This study serves as a foundation for ongoing surveillance efforts and provides a basis for the development of preventive strategies against various mosquito-borne viral diseases, including known arboviruses. [ABSTRACT FROM AUTHOR]

Arthropod-borne viruses (arboviruses) pose a significant global health threat and are primarily transmitted by mosquitoes. In Cambodia, there are currently 290 recorded mosquito species, with at least 17 of them considered potential vectors of arboviruses to humans. Effective surveillance of virome profiles in mosquitoes from Cambodia is vital, as it could help prevent and control arbovirus diseases in a country where epidemics occur frequently. The objective of this study was to identify and characterize the viral diversity in mosquitoes collected during a one-year longitudinal study conducted in various habitats across Cambodia. For this purpose, we used a metatranscriptomics approach and detected the presence of chikungunya virus in the collected mosquitoes. Additionally, we identified viruses categorized into 26 taxa, including those known to harbor arboviruses such as Flaviviridae and Orthomyxoviridae, along with a group of viruses not yet taxonomically identified and provisionally named "unclassified viruses". Interestingly, the taxa detected varied in abundance and composition depending on the mosquito genus, with no significant influence of the collection season. Furthermore, most of the identified viruses were either closely related to viruses found exclusively in insects or represented new viruses belonging to the Rhabdoviridae and Birnaviridae families. The transmission capabilities of these novel viruses to vertebrates remain unknown. [ABSTRACT FROM AUTHOR]

Viruses have evolved countless mechanisms to subvert and impair the host innate immune response. Measles virus (MeV), an enveloped, non-segmented, negative-strand RNA virus, alters the interferon response through different mechanisms, yet no viral protein has been described as directly targeting mitochondria. Among the crucial mitochondrial enzymes, 5′-aminolevulinate synthase (ALAS) is an enzyme that catalyzes the first step in heme biosynthesis, generating 5′-aminolevulinate from glycine and succinyl-CoA. In this work, we demonstrate that MeV impairs the mitochondrial network through the V protein, which antagonizes the mitochondrial enzyme ALAS1 and sequesters it to the cytosol. This re-localization of ALAS1 leads to a decrease in mitochondrial volume and impairment of its metabolic potential, a phenomenon not observed in MeV deficient for the V gene. This perturbation of the mitochondrial dynamics demonstrated both in culture and in infected IFNAR−/− hCD46 transgenic mice, causes the release of mitochondrial double-stranded DNA (mtDNA) in the cytosol. By performing subcellular fractionation post infection, we demonstrate that the most significant source of DNA in the cytosol is of mitochondrial origin. Released mtDNA is then recognized and transcribed by the DNA-dependent RNA polymerase III. The resulting double-stranded RNA intermediates will be captured by RIG-I, ultimately initiating type I interferon production. Deep sequencing analysis of cytosolic mtDNA editing divulged an APOBEC3A signature, primarily analyzed in the 5'TpCpG context. Finally, in a negative feedback loop, APOBEC3A an interferon inducible enzyme will orchestrate the catabolism of mitochondrial DNA, decrease cellular inflammation, and dampen the innate immune response. Author summary: As viruses evolve within the confines of an arms race with the host immune system, they develop means to evade or counteract detection by the immune systems, thus facilitating their replication. In this light, many viruses have been described to encode proteins which target the mitochondrial network, a key hub in immune signaling. Previous work has highlighted the ability of MeV to interact with mitochondria, although the mechanism of perturbation remained elusive. Here we show that the MeV-V protein antagonizes the mitochondrial ALAS1 enzyme and relocalizes it to the cytosol, leading to an alteration of the mitochondrial network. We found that this disruption will induce a release of mitochondrial DNA (mtDNA), constituting a potential danger signal for the infected cell. By investigating the cascade of innate immune sensors triggered by mtDNA in the cytosol, we further show that the endogenous APOBEC3A cytidine deaminase is induced to target the released cytosolic mtDNA, attenuating the danger signal, and reducing cellular inflammation. Our study provides new mechanistic insight into the interaction of MeV with mitochondrial proteins, adding to the ever-growing repertoire of viral strategies to directly or indirectly target this organelle. [ABSTRACT FROM AUTHOR]

Objectives: Sexual dysfunction has wide‐ranging impacts on the person's functioning and quality of life, being associated with higher severity of psychiatric illnesses and poor therapeutic response. Given the paucity of data on this topic in bipolar disorder (BD), we investigated sexual functioning among males and females with BD and healthy controls (HCs) as well as whether illness severity markers and subthreshold mood symptoms were associated with sexual dysfunctions in BD patients. Methods: The study included 80 BD outpatients and 70 HCs. Sexual functioning was evaluated using the validated, gender‐specific Changes in Sexual Functioning Questionnaire (CSFQ‐14). Results: BD patients had a significantly poorer sexual functioning than HCs (p < 0.00001). The odds of sexual dysfunction doubled given a one‐unit increase in the number of suicide attempts (adjusted OR = 2.01, 95% CI:1.23–3.55; p < 0.01) and increased by 60% for every additional hospitalization (p < 0.05). Greater illness duration was associated with arousal/orgasmic (p < 0.05) and overall sexual dysfunctions (p < 0.01). BD patients with more mixed or (hypo)manic episodes had a lower likelihood of libido loss and arousal/orgasmic disturbances (p < 0.01), respectively. Higher levels of subthreshold depressive symptoms increased by 20% the odds of sexual interest/frequency dysfunctions (p < 0.05), and up to 60% regarding orgasmic disturbances (p < 0.01). Conclusions: Sexual functioning may be a useful proxy of illness severity as well as a relevant dimension to more deeply characterize BD patients. Further studies are warranted to replicate our findings, to evaluate temporal associations between sexual dysfunctions and illness severity across the BD mood and treatment spectrums and to explore neurobiological underpinnings of these associations. [ABSTRACT FROM AUTHOR]

Objectives: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter‐episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic dysregulation and functional impairment. Methods: Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper‐reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data‐driven biomarker selection. Results: BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper‐reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper‐reactivity had significantly lower global and cognitive functioning than those without emotional hyper‐reactivity (P <.0001). Conclusions: A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper‐reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic disturbances and functional impairment. [ABSTRACT FROM AUTHOR]

The commensal gut microbiome is contained by the enteric epithelial barrier, but little is known about the degree of specificity of host immune barrier interactions for particular bacterial taxa. Here, we show that depletion of leucine-rich repeat immune factor APL1 in the Asian malaria mosquito Anopheles stephensi is associated with higher midgut abundance of just the family Enterobacteraceae , and not generalized dysbiosis of the microbiome. The effect is explained by the response of a narrow clade containing two main taxa related to Klebsiella and Cedecea. Analysis of field samples indicate that these two taxa are recurrent members of the wild Anopheles microbiome. Triangulation using sequence and functional data incriminated relatives of C. neteri and Cedecea NFIX57 as candidates for the Cedecea component, and K. michiganensis , K. oxytoca , and K.sp. LTGPAF-6F as candidates for the Klebsiella component. APL1 presence is associated with host ability to specifically constrain the abundance of a narrow microbiome clade of the Enterobacteraceae , and the immune factor may promote homeostasis of this clade in the enteric microbiome for host benefit. [ABSTRACT FROM AUTHOR]

Metabolically quiescent pathogens can persist in a viable non-replicating state for months or even years. For certain infectious diseases, such as tuberculosis, cryptococcosis, histoplasmosis, latent infection is a corollary of this dormant state, which has the risk for reactivation and clinical disease. During murine cryptococcosis and macrophage uptake, stress and host immunity induce Cryptococcus neoformans heterogeneity with the generation of a sub-population of yeasts that manifests a phenotype compatible with dormancy (low stress response, latency of growth). In this subpopulation, mitochondrial transcriptional activity is regulated and this phenotype has been considered as a hallmark of quiescence in stem cells. Based on these findings, we worked to reproduce this phenotype in vitro and then standardize the experimental conditions to consistently generate this dormancy in C. neoformans. We found that incubation of stationary phase yeasts (STAT) in nutriment limited conditions and hypoxia for 8 days (8D-HYPOx) was able to produced cells that mimic the phenotype obtained in vivo. In these conditions, mortality and/or apoptosis occurred in less than 5% of the yeasts compared to 30–40% of apoptotic or dead yeasts upon incubation in normoxia (8D-NORMOx). Yeasts in 8D-HYPOx harbored a lower stress response, delayed growth and less that 1% of culturability on agar plates, suggesting that these yeasts are viable but non culturable cells (VBNC). These VBNC were able to reactivate in the presence of pantothenic acid, a vitamin that is known to be involved in quorum sensing and a precursor of acetyl-CoA. Global metabolism of 8D-HYPOx cells showed some specific requirements and was globally shut down compared to 8D-NORMOx and STAT conditions. Mitochondrial analyses showed that the mitochondrial masse increased with mitochondria mostly depolarized in 8D-HYPOx compared to 8D-NORMox, with increased expression of mitochondrial genes. Proteomic and transcriptomic analyses of 8D-HYPOx revealed that the number of secreted proteins and transcripts detected also decreased compared to 8D-NORMOx and STAT, and the proteome, secretome and transcriptome harbored specific profiles that are engaged as soon as four days of incubation. Importantly, acetyl-CoA and the fatty acid pathway involving mitochondria are required for the generation and viability maintenance of VBNC. Altogether, these data show that we were able to generate for the first time VBNC phenotype in C. neoformans. This VBNC state is associated with a specific metabolism that should be further studied to understand dormancy/quiescence in this yeast. [ABSTRACT FROM AUTHOR]

Background: The human intestinal microbiota contains a vast community of microorganisms increasingly studied using high-throughput DNA sequencing. Standardized protocols for storage and DNA extraction from fecal samples have been established mostly for bacterial microbiota analysis. Here, we investigated the impact of storage and DNA extraction on bacterial and fungal community structures detected concomitantly. Methods: Fecal samples from healthy adults were stored at -80°C as such or diluted in RNAlater® and subjected to 2 extraction protocols with mechanical lysis: the Powersoil® MoBio kit or the International Human Microbiota Standard (IHMS) Protocol Q. Libraries of the 12 samples targeting the V3-V4 16S and the ITS1 regions were prepared using Metabiote® (Genoscreen) and sequenced on GS-FLX-454. Sequencing data were analysed using SHAMAN (). The bacterial and fungal microbiota were compared in terms of diversity and relative abundance. Results: We obtained 171869 and 199089 quality-controlled reads for 16S and ITS, respectively. All 16S reads were assigned to 41 bacterial genera; only 52% of ITS reads were assigned to 40 fungal genera/section. Rarefaction curves were satisfactory in 3/3 and 2/3 subjects for 16S and ITS, respectively. PCoA showed important inter-individual variability of intestinal microbiota largely overweighing the effect of storage or extraction. Storage in RNAlater® impacted (downward trend) the relative abundances of 7/41 bacterial and 6/40 fungal taxa, while extraction impacted randomly 18/41 bacterial taxa and 1/40 fungal taxon. Conclusion: Our results showed that RNAlater® moderately impacts bacterial or fungal community structures, while extraction significantly influences the bacterial composition. For combined bacterial and fungal intestinal microbiota analysis, immediate sample freezing should be preferred when feasible, but storage in RNAlater® remains an option under unfavourable conditions or for concomitant metatranscriptomic analysis; and extraction should rely on protocols validated for bacterial analysis, such as IHMS Protocol Q, and including a powerful mechanical lysis, essential for fungal extraction. [ABSTRACT FROM AUTHOR]

Motivation: With the continued improvement of requisite mass spectrometers and UHPLC systems, Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS) workflows are rapidly evolving towards the investigation of more challenging biological systems, including large protein complexes and membrane proteins. The analysis of such extensive systems results in very large HDX-MS datasets for which specific analysis tools are required to speed up data validation and interpretation. Results: We introduce a web application and a new R-package named 'MEMHDX' to help users analyze, validate and visualize large HDX-MS datasets. MEMHDX is composed of two elements. A statistical tool aids in the validation of the results by applying a mixed-effects model for each peptide, in each experimental condition, and at each time point, taking into account the time dependency of the HDX reaction and number of independent replicates. Two adjusted P-values are generated per peptide, one for the 'Change in dynamics' and one for the 'Magnitude of ▵ D', and are used to classify the data by means of a 'Logit' representation. A user-friendly interface developed with Shiny by RStudio facilitates the use of the package. This interactive tool allows the user to easily and rapidly validate, visualize and compare the relative deuterium incorporation on the amino acid sequence and 3D structure, providing both spatial and temporal information. Availability and Implementation: MEMHDX is freely available as a web tool at the project home page http://memhdx.c3bi.pasteur.fr. [ABSTRACT FROM AUTHOR]

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs) worldwide, causing over 150 million clinical cases annually. There is currently no specific treatment addressing the asymptomatic carriage in the gut of UPEC before they initiate UTIs. This study investigates the efficacy of virulent bacteriophages to decrease carriage of gut pathogens. Three virulent bacteriophages infecting an antibiotic-resistant UPEC strain were isolated and characterized both in vitro and in vivo. A new experimental murine model of gut carriage of E. coli was elaborated and the impact of virulent bacteriophages on colonization levels and microbiota diversity was assessed. A single dose of a cocktail of the three bacteriophages led to a sharp decrease in E. coli levels throughout the gut. We also observed that microbiota diversity was much less affected by bacteriophages than by antibiotics. Therefore, virulent bacteriophages can efficiently target UPEC strains residing in the gut, with potentially profound public health and economic impacts. These results open a new area with the possibility to manipulate specifically the microbiota using virulent bacteriophages, which could have broad applications in many gut-related disorders/diseases and beyond. [ABSTRACT FROM AUTHOR]

Abstract: Large datasets with interactions between objects are common to numerous scientific fields including the social sciences and biology, as well as being a feature of specific phenomena such as the internet. The interactions naturally define a graph, and a common way of exploring and summarizing such datasets is graph clustering. Most techniques for clustering graph vertices use only the topology of connections, while ignoring information about the vertices’ features. In this paper we provide a clustering algorithm that harnesses both types of data, based on a statistical model with a latent structure characterizing each vertex both by a vector of features and by its connectivity. We perform simulations to compare our algorithm with existing approaches, and also evaluate our method using real datasets based on hypertext documents. We find that our algorithm successfully exploits whatever information is found both in the connectivity pattern and in the features. [Copyright &y& Elsevier]

The correct statement is: All RNA sequence data from this study have been submitted to NCBI (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE118549. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD012570 http://proteomecentral.proteomexchange.org/cgi/GetDataset. [Extracted from the article]

HIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication. [ABSTRACT FROM AUTHOR]