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Found 37003 matches. Displaying 81-90
Richard JC, Frobert E, Destras G, Yonis H, Mezidi M, Dhelft F, Trouillet-Assant S, Bastard P, Gervais A, Danjou W, Aubrun F, Roumieu F, Josset L, Labaune JM, Bal A, Simon B, Casanova JL, Lina B, Picaud JC, Dupont C, Huissoud C, Bitker L
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Virological and clinical features of acute respiratory failure associated with COVID-19 in pregnancy: a case-control study

CRITICAL CARE AND RESUSCITATION 2022 SEP; 24(3):242-250
Objective: Pregnancy is a risk factor for acute respiratory failure (ARF) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We hypothesised that SARS-CoV-2 viral load in the respiratory tract might be higher in pregnant intensive care unit (ICU) patients with ARF than in non-pregnant ICU patients with ARF as a consequence of immunological adaptation during pregnancy. Design: Single-centre, retrospective observational case- control study. Setting: Adult level 3 ICU in a French university hospital. Participants: Eligible participants were adults with ARF associated with coronavirus disease 2019 (COVID-19) pneumonia. Main outcome measure: The primary endpoint of the study was viral load in pregnant and non-pregnant patients. Results: 251 patients were included in the study, including 17 pregnant patients. Median gestational age at ICU admission amounted to 28 + 3/7 weeks (interquartile range [IQR], 26 + 1/7 to 31 + 5/7 weeks). Twelve patients (71%) had an emergency caesarean delivery due to maternal respiratory failure. Pregnancy was independently associated with higher viral load (-4.6 +/- 1.9 cycle threshold; P < 0.05). No clustering or over-represented mutations were noted regarding SARS-CoV-2 sequences of pregnant women. Emergency caesarean delivery was independently associated with a modest but significant improvement in arterial oxygenation, amounting to 32 +/- 12 mmHg in patients needing invasive mechanical ventilation. ICU mortality was significantly lower in pregnant patients (0 v 35%; P < 0.05). Age, Simplified Acute Physiology Score (SAPS) II score, and acute respiratory distress syndrome were independent risk factors for ICU mortality, while pregnancy status and virological variables were not. Conclusions: Viral load was substantially higher in pregnant ICU patients with COVID-19 and ARF compared with non-pregnant ICU patients with COVID-19 and ARF. Pregnancy was not independently associated with ICU mortality after adjustment for age and disease severity.
Wang ZJ, Zhou PC, Muecksch F, Cho ALC, Ben Tanfous T, Canis M, Witte L, Johnson B, Raspe R, Schmidt F, Bednarski E, Da Silva J, Ramos V, Zong S, Turroja M, Millard KG, Yao KH, Shimeliovich I, Dizon J, Kaczynska A, Jankovic M, Gazumyan A, Oliveira TY, Caskey M, Gaebler C, Bieniasz PD, Hatziioannou T, Nussenzweig MC
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Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans

JOURNAL OF EXPERIMENTAL MEDICINE 2022 SEP 23; 219(12):? Article e20221006
Wang et al. analyze memory B cell and antibody responses in SARS-CoV-2 mRNA vaccines to breakthrough infections with Delta or Omicron BA.1 variants. Breakthrough infection after two or three doses of mRNA vaccination was comparable to three doses of vaccination in eliciting broad and potent memory B cells. The findings provide insights on broad and strain-specific memory responses after mRNA vaccination with Wuhan-Hu-1. Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
Daza-Cajigal V, Albuquerque AS, Young DF, Ciancanelli MJ, Moulding D, Angulo I, Jeanne-Julien V, Rosain J, Minskaia E, Casanova JL, Boisson-Dupuis S, Bustamante J, Randall RE, McHugh TD, Thrasher AJ, Burns SO
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Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria

FRONTIERS IN IMMUNOLOGY 2022 SEP 9; 13(?):? Article 888427
Purpose Janus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-alpha/beta and IFN-gamma), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control. Methods We investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA. Results Partial JAK1 deficiency impairs IFN-gamma -dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-alpha responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts. Conclusion Our data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-gamma responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-alpha responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.
Silva KDA, Nunes JPS, Andrieux P, Brochet P, Almeida RR, Takara ACKK, Pereira NB, Abel L, Cobat A, Zaniratto RCF, Levy D, Bydlowski SP, Cecconello I, Seguro FCBD, Kalil J, Chevillard C, Cunha-Neto E
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Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-gamma Stimulus

BIOMEDICINES 2022 SEP; 10(9):? Article 2215
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 8 million people, and around 1/3 develop chronic cardiac (CCC) or digestive disease (megaesophagus/megacolon), while the majority remain asymptomatic, in the indeterminate form of Chagas disease (ASY). Most CCC cases in families with multiple Chagas disease patients carry damaging mutations in mitochondrial genes. We searched for exonic mutations associated to chagasic megaesophagus (CME) in genes essential to mitochondrial processes. We performed whole exome sequencing of 13 CME and 45 ASY patients. We found the damaging variant MRPS18B 688C > G P230A, in five out of the 13 CME patients (one of them being homozygous; 38.4%), while the variant appeared in one out of 45 ASY patients (2.2%). We analyzed the interferon (IFN)-gamma-induced nitro-oxidative stress and mitochondrial function of EBV-transformed lymphoblastoid cell lines. We found the CME carriers of the mutation displayed increased levels of nitrite and nitrated proteins; in addition, the homozygous (G/G) CME patient also showed increased mitochondrial superoxide and reduced levels of ATP production. The results suggest that pathogenic mitochondrial mutations may contribute to cytokine-induced nitro-oxidative stress and mitochondrial dysfunction. We hypothesize that, in mutation carriers, IFN-gamma produced in the esophageal myenteric plexus might cause nitro-oxidative stress and mitochondrial dysfunction in neurons, contributing to megaesophagus.
Rapaport F, Seier K, Neelamraju Y, Hassane D, Baslan T, Gildea DT, Haddox S, Lee T, Murdock HM, Sheridan C, Thurmond A, Wang L, Carroll M, Cripe LD, Fernandez H, Mason CE, Paietta E, Roboz GJ, Sun ZX, Tallman MS, Zhang YM, Gonen M, Levine R, Melnick AM, Kleppe M, Garrett-Bakelman FE
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Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group's clinical trial E3999

BLOOD CANCER JOURNAL 2022 SEP 23; 12(9):? Article 137
Du J, Vandavasi VG, Molloy KR, Yang H, Massenburg LN, Singh A, Kwansa AL, Yingling YG, O'Neill H, Chait BT, Kumar M, Nixon BT
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Evidence for Plant-Conserved Region Mediated Trimeric CESAs in Plant Cellulose Synthase Complexes br

BIOMACROMOLECULES 2022 SEP 12; 23(9):3663-3677
Higher plants synthesize cellulose using membrane bound, six-lobed cellulose synthase complexes, each lobe containing trimeric cellulose synthases (CESAs). Although molecular biology reports support heteromeric trimers composed of different isoforms, a homomeric trimer was reported for in vitro studies of the catalytic domain of CESA1 of Arabidopsis (AtCESA1CatD) and confirmed in cryoEM structures of fulllength CESA8 and CESA7 of poplar and cotton, respectively. In both structures, a small portion of the plant-conserved region (PCR) forms the only contacts between catalytic domains of the monomers. We report inter-subunit lysine-crosslinks that localize to the small P-CR, negative-stain EM structure, and modeling data for homotrimers of AtCESA1CatD. Molecular dynamics simulations for AtCESA1CatD trimers based on the CESA8 cryoEM structure were stable and dependent upon a small set of residue contacts. The results suggest that homomeric CESA trimers may be important for the synthesis of primary and secondary cell walls and identify key residues for future mutagenic studies.
Poulton NC, Azadian ZA, DeJesus MA, Rock JM
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Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 2022 SEP 20; 66(9):?
Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB. One promising drug target in Mtb is the arabinogalactan biosynthetic enzyme DprE1, and there have been over a dozen unique chemical scaffolds identified which inhibit the activity of this protein. Among the most promising lead compounds are the benzothiazinones BTZ043 and PBTZ169, both of which are currently in or have completed phase IIa clinical trials. Due to the potential clinical utility of these drugs, we sought to identify potential synergistic interactions and new mechanisms of resistance using a genome-scale CRISPRi chemical-genetic screen with PBTZ169. We found that knockdown of rv0678, the negative regulator of the mmpS5/L5 drug efflux pump, confers resistance to PBTZ169. Mutations in rv0678 are the most common form of resistance to bedaquiline and there is already abundant evidence of these mutations emerging in bedaquiline-treated patients. We confirmed that rv0678 mutations from clinical isolates confer low level cross-resistance to BTZ043 and PBTZ169. While it is yet unclear whether rv0678 mutations would render benzothiazinones ineffective in treating TB, these results highlight the importance of monitoring for clinically prevalent rv0678 mutations during ongoing BTZ043 and PBTZ169 clinical trials.
Zhao HT, Lee J, Chen J
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The hemolysin A secretion system is a multi-engine pump containing three ABC transporters

CELL 2022 SEP 1; 185(18):3329-+
Type 1 secretion systems (T1SSs) are widespread in pathogenic Gram-negative bacteria, extruding protein substrates following synthesis of the entire polypeptide. The Escherichia coli hemolysin A secretion system has long been considered a prototype in structural and mechanistic studies of T1SSs. Three membrane pro-teins-an inner membrane ABC transporter HlyB, an adaptor protein HlyD, and an outer membrane porin TolC-are required for secretion. However, the stoichiometry and structure of the complex are unknown. Here, cryo-electron microscopy (cryo-EM) structures determined in two conformations reveal that the inner membrane complex is a hetero-dodecameric assembly comprising three HlyB homodimers and six HlyD subunits. Functional studies indicate that oligomerization of HlyB and HlyD is essential for protein secretion and that polypeptides translocate through a canonical ABC transporter pathway in HlyB. Our data suggest that T1SSs entail three ABC transporters, one that functions as a protein channel and two that allosterically power the translocation process.
Waidmann EN, Koyano KW, Hong JJ, Russ BE, Leopold DA
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Local features drive identity responses in macaque anterior face patches

NATURE COMMUNICATIONS 2022 SEP 23; 13(1):? Article 5592
Anterior face patches in the macaque have been assumed to represent face identity in a holistic manner. Here the authors show that the neural encoding of face identity in the anterior medial and anterior fundus face patches are instead driven principally by local features. Humans and other primates recognize one another in part based on unique structural details of the face, including both local features and their spatial configuration within the head and body. Visual analysis of the face is supported by specialized regions of the primate cerebral cortex, which in macaques are commonly known as face patches. Here we ask whether the responses of neurons in anterior face patches, thought to encode face identity, are more strongly driven by local or holistic facial structure. We created stimuli consisting of recombinant photorealistic images of macaques, where we interchanged the eyes, mouth, head, and body between individuals. Unexpectedly, neurons in the anterior medial (AM) and anterior fundus (AF) face patches were predominantly tuned to local facial features, with minimal neural selectivity for feature combinations. These findings indicate that the high-level structural encoding of face identity rests upon populations of neurons specialized for local features.
Weymar GHJ, Bar -On Y, Oliveira TY, Gaebler C, Ramos V, Hartweger H, Breton G, Caskey M, Cohn LB, Jankovic M, Nussenzweig MC
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Distinct gene expression by expanded clones of quiescent memory CD4(+) T cells harboring intact latent HIV-1 proviruses

CELL REPORTS 2022 SEP 6; 40(10):? Article 111311
Antiretroviral therapy controls, but does not cure, HIV-1 infection due to a reservoir of rare CD4(+) T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here, we report a strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single-cell transcriptomic analysis of 1,050 CD4(+) T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis reveals that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, granzymes A and K, cystatin F, LYAR, and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4(+) T cell population, opening possibilities for eradication.