Biology subjects

Allatif, O.

Publications and source records attributed to Allatif, O..

7 recordsLinked to original sources

bioRxiv2025

Immunological and clinical markers of post-acute sequelae of COVID-19: Insights from mild and severe cases six months post-infection

Post-acute sequelae of COVID-19 (PASC) is a complex and multifaceted clinical challenge requiring to emphasize its underlying pathophysiological mechanisms. This study assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two patient cohorts who experienced mild (n=270) or severe (n=188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC. Blood analysis showed that mains differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC. However, patients with PASC displayed altered CD4+ and CD8+ memory T-cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA+ effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed. A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy. HighlightsO_LINine months post-initial SARS-CoV-2 infection, over 40% of patients developed PASC C_LIO_LIRegardless of PASC, the initial disease form influenced the main immune differences C_LIO_LIPASC led to altered memory T-cell subsets with elevated TEMRA phenotype C_LIO_LIPASC presence is associated with disease form, initial symptom count and duration C_LI

immunology↗

bioRxiv2024

Hepatitis E Virus-induced antiviral response by plasmacytoid dendritic cells is modulated by the ORF2 protein

Type I and III interferons (IFN-I/III) are critical to protect the host during viral infection. Previous studies have shown that IFN-mediated antiviral responses against hepatitis E virus (HEV) are suppressed and defeated by viral escape mechanisms at play in infected hepatocytes. Here, we studied the anti-HEV function of IFN secreted by plasmacytoid dendritic cells (pDCs), which are specialized producers of IFNs. We showed that pDCs co-cultured with HEV-replicating cells secreted IFN in a cell-to-cell contact-dependent manner. Pharmacological inhibitor and antibodies targeting contact proteins revealed that pDC response against HEV required the endosomal nucleic-acid sensor TLR7 and adhesion molecules, such as ICAM-I and L{beta}2-integrin. IFNs secreted by pDCs reduced viral spread. Intriguingly, ORF2, the capsid protein of HEV, can be produced in various forms by the infected cells. During infection, a fraction of the intracellular ORF2 protein localizes into the nucleus while another ORF2 fraction packages viral genomes to produce infectious virions. In parallel, glycosylated forms of ORF2 are also massively secreted by infected cells. Using viral genome expressing ORF2 mutants, we showed that glycosylated ORF2 forms contribute to better recognition of infected cells by pDCs via regulation of contacts between infected cells and pDCs. ORF2 forms may thus modulate pDC-mediated anti-HEV response. Together, our results suggest that liver-resident pDCs, which exhibit comparable IFN-producing ability as blood-derived pDCs, may be essential to control HEV replication.

immunology↗

bioRxiv2023

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease (NLRP3-AID or CAPS) is an heterogenous group of monogenic autoinflammations associated with NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants is a barrier to diagnosis although patients can be efficiently treated with anti-IL-1 approaches. In addition, while NLRP3 inflammasome is controlled by coordinated priming and activation signals, gain-of-functions of NLRP3 variants have been only investigated in response to priming. Here, we functionally characterize 34 NLRP3 variants in vitro by determining their activity in response to induction, priming and/or activation signals, and their sensitivity to inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on their profile of signals required for their activation, that correlate partly with the symptoms severities. We identify a new group of NLRP3 mutants responding to the activation signal without priming, with patients often misdiagnosed. Our results identify key NLRP3 residues controlling the inflammasome activity and sensitivity to inhibitors. The comparison of four inhibitors on the 34 variants identifies inhibitory mechanisms with broader efficiency for future drug design. Altogether, our results provide new insights on NLRP3 activation and an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and anti-inflammatory disease drug development. eTOC SummaryFunctional characterization of 34 CAPS-associated NLRP3 variants identifies polymorphisms versus gain-of-function pathogenic mutants, and highlights diversities in the signals controlling their activation and in their sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.

immunology↗

bioRxiv2021

Immunoprofiling of HTLV-1-infected individuals shows altered innate cell responsiveness in HAM/TSP patients.

The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. A biological blood factor allowing the prediction of the disease occurrence is so far not available. In this study, we analyzed innate immunity responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower responsiveness in dendritic cells to produce IFN. Moreover, we found higher production of IL-12 and Mip-1 by monocytes together with higher levels of IFN{gamma} produced by Natural Killer cells. These deregulations could represent a signature for progression towards HAM/TSP.

immunology↗

bioRxiv2020

Peripheral Natural Killer cells from chronic hepatitis B patients display molecular hallmarks of T cell exhaustion

A significant proportion of individuals infected by HBV develops chronic infection. Antiviral effectors such as Natural Killer (NK) cells have impaired functions in these patients, but the molecular mechanism responsible for this dysfunction remains poorly characterized. Here, we show that peripheral NK cells from chronic hepatitis B (CHB) patients have a defective capacity to produce IFN-{gamma}, MIP1-{beta} and TNF- but retain an intact killing capacity. This functional phenotype was associated with a decrease in the expression of NKp30 and CD16, combined with defects in IL-15 stimulation of the mTOR pathway. Transcriptome analysis of NK cells in CHB patients further revealed a strong enrichment for transcripts typically expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion rely on common molecular mechanisms. In particular, the transcription factor thymocyte selection-associated HMG box protein (TOX) and several of its targets, including immune checkpoints, were over-expressed in NK cells of CHB patients. This T cell exhaustion signature was predicted to be dependent on the calcium (Ca2+)-associated transcription factor NFAT. In line with this, when stimulating the Ca2+-dependent pathway in isolation, we recapitulated the dysfunctional phenotype. Thus, deregulated Ca2+ signalling could be a central event in both T cell exhaustion and NK cell dysfunction that occur during chronic infections.

immunology↗

bioRxiv2020

DGINN, an automated and highly-flexible pipeline for the Detection of Genetic INNovations on protein-coding genes

Adaptive evolution has shaped major biological processes. Finding the protein-coding genes and the sites that have been subjected to adaptation during evolutionary time is a major endeavor. However, very few methods fully automate the identification of positively selected genes, and widespread sources of genetic innovations as gene duplication and recombination are absent from most pipelines. Here, we developed DGINN, a highly-flexible and public pipeline to Detect Genetic INNovations and adaptive evolution in protein-coding genes. DGINN automates, from a genes sequence, all steps of the evolutionary analyses necessary to detect the aforementioned innovations, including the search for homologues in databases, assignation of orthology groups, identification of duplication and recombination events, as well as detection of positive selection using five different methods to increase precision and ranking of genes when a large panel is analyzed. DGINN was validated on nineteen genes with previously-characterized evolutionary histories in primates, including some engaged in host-pathogen arms-races. The results obtained with DGINN confirm and also expand results from the literature, establishing DGINN as an efficient tool to automatically detect genetic innovations and adaptive evolution in diverse datasets, from the users gene of interest to a large gene list in any species range.

evolutionary biology↗

bioRxiv2018

Antiviral Response by Plasmacytoid Dendritic Cells via Interferogenic Synapse with Infected Cells

Type I interferon (IFN-I) is critical for protection against viral infections. Plasmacytoid dendritic cells (pDCs) massively produce IFN-I against viruses. Physical contacts are required for pDC-mediated sensing of cells infected by genetically distant viruses. How and why these contacts are established remains enigmatic. Using dengue, hepatitis C, zika viruses, we demonstrate that the pDC/infected cell interface is a specialized platform for viral immunostimulatory-RNA transfer, which we named interferogenic synapse and required for pDC-mediated antiviral response. This synapse is an exquisitely differentiated territory with polarized adhesion complexes and regulators of actin network and endocytosis. Toll-like receptor 7-induced signaling in pDCs promotes the interferogenic synapse establishment, thus providing a feed-forward regulation that sustains contacts with infected cells. We propose that the interferogenic synapse is crucial to pDC function as it allows scanning of infected cells to locally secrete IFN-I at the infection site, thereby confining a response potentially deleterious to the host.\n\nHighlightsO_LIpDCs adhere to infected cells via L{beta}2 integrin/ICAM-1\nC_LIO_LIRegulators of actin network and endocytosis polarize at contact\nC_LIO_LITLR7-induced signaling potentiates pDC polarity\nC_LIO_LIInfected cells activate pDCs by interferogenic synapse\nC_LI

microbiology↗