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| Open AccessIL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube
In pelvic inflammatory disease, host immune responses to Neisseria gonorrhoeae damage Fallopian tube tissue and cause infertility. Here, Garcia et al. show that the cytokine IL-17C induces inflammatory responses, and peptidoglycan fragments reduce transcripts related to tissue integrity.
- Erin M. Garcia
- , Jonathan D. Lenz
- & Joseph P. Dillard
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Article
| Open AccessA commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response
Faecal microbiome transplant has been shown to be able to reduce Clostridioides difficile infection. Here the authors show that an intestinal commensal protozoan reduces C. difficile infection by inhibiting neutrophil recruitment and affecting arginine-ornithine metabolism.
- Huan Yang
- , Xiaoxiao Wu
- & Bing Gu
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Article
| Open AccessSecondary bone marrow graft loss after third-party virus-specific T cell infusion: Case report of a rare complication
Infusion of virus-specific T (VST) cells is used for treating drug-resistant viremia. Here the authors report, as part of the clinical trial, NCT03475212, a lethal case of unexpected bone marrow graft loss and chimerism reversal that is induced by the infusion of third-party VST intended to treat transplantation-related cytomegalovirus viremia.
- Michael D. Keller
- , Stefan A. Schattgen
- & Catherine M. Bollard
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| Open AccessPorphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis
Periodontitis is closely linked with inflammatory bowel disease (IBD) and may have overlapping characteristics. Here the authors show that a periodontal pathogen P. gingivalis promotes intestinal inflammation by affecting the microbiome metabolite linoleic acid and Th17/Treg cell balance in the intestine.
- Lu Jia
- , Yiyang Jiang
- & Yi Liu
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Article
| Open AccessExosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia
In this work, authors report on SCIMP-positive exosomes secreted by macrophages, that play a crucial anti-inflammatory role in pneumonia. Exosomal SCIMP primarily achieves bacterial clearance by the SCIMP-FPRs-neutrophils chemotaxis.
- Xiaolei Pei
- , Li Liu
- & Sizhou Feng
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Article
| Open AccessIdentifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies
Bacterial infections and sepsis are a major cause of mortality in preterm babies. Here Das and colleagues assess the paediatric immune response to bacterial infection in very preterm babies and identify blood immune markers that could improve accuracy of diagnostics to rule-out sepsis and guide antibiotic treatment.
- A. Das
- , G. Ariyakumar
- & D. L. Gibbons
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Article
| Open AccessBCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination
Bacillus Calmette-Guèrin vaccination prevents tuberculosis but some individuals control infection without immunization. Here the authors employ functional assessment of effector responses against mycobacteria to find that distinct gene expression profiles for pre-existing capacity to control and control induced by BCG vaccination.
- Krista E. van Meijgaarden
- , Wenchao Li
- & Simone A. Joosten
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| Open AccessIntegrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection
Amnesic screening methods are useful to discover host factors that are important for SARS-CoV2 infection. Here the authors use a CRISPR screen to identify three anti-viral factors, which are associated with the coagulation system, and two pro-viral candidates and then use individual genetic deletion experiments to characterise their effect.
- Jiakai Hou
- , Yanjun Wei
- & Weiyi Peng
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Article
| Open AccessPathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections
Group A streptococcus causes a wide range of human diseases and significantly contributes to morbidity and mortality worldwide. Here, Toledo et al show how streptococcus alters the structure and function of endogenous and therapeutic antibodies during infection and how this is affected by the host microenvironment.
- Alejandro Gomez Toledo
- , Eleni Bratanis
- & Johan Malmström
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Article
| Open AccessSIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions
Here, the authors used cryo-EM to explore secretory Immunoglobulin A interactions with bacterial and host receptors, uncovering unexpected binding stoichiometry and unappreciated functional consequences relevant to understanding host-pathogen interactions.
- Qianqiao Liu
- & Beth M. Stadtmueller
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Article
| Open AccessPerinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Article
| Open AccessRab41-mediated ESCRT machinery repairs membrane rupture by a bacterial toxin in xenophagy
Xenophagy targets cytosolic bacteria, but their membrane homeostatic system is not known. Here the authors show that the ESCRT machinery repairs xenophagic membrane damaged by a bacterial toxin, which is regulated by the TOM1L2–Rab41 that recruits VPS4.
- Takashi Nozawa
- , Hirotaka Toh
- & Ichiro Nakagawa
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Article
| Open AccessNAD+ metabolism is a key modulator of bacterial respiratory epithelial infections
Streptococcus pneumoniae is a common cause of lower respiratory tract infection. Here, Klabunde et al. present a transcriptomic, metabolomic and proteomic characterisation of the bronchial epithelial cell response to infection and show that NAD+ has a role in controlling bacterial replication.
- Björn Klabunde
- , André Wesener
- & Bernd Schmeck
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Article
| Open AccessBifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood
The human immune system changes with age which impacts pathogen clearance. Here, Vogel et al. probe how CD4 + T-cells from different age groups respond to bacteria and show that activation with staphylococcal antigen induces T cells to become Th1-like cells, whilst stimulation with Bifidobacterium infantis induces a regulatory phenotype.
- Katrin Vogel
- , Aditya Arra
- & Monika C. Brunner-Weinzierl
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Article
| Open AccessBile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides
Wang et al. clarify the regional heterogeneity of intestinal AMPs and identify that chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs.
- Yue Wang
- , Yanbo Yu
- & Yanqing Li
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Article
| Open AccessAntiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
Human proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce viral infectivity. Here, the authors show that SERINC3 has architecture resembling non-ATP dependent lipid transporters and induces loss of membrane asymmetry correlated with changes in envelope conformation and loss of infectivity.
- Susan A. Leonhardt
- , Michael D. Purdy
- & Mark Yeager
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Article
| Open AccessThe metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils
Neutrophil activation has been shown to rely on the pentose phosphate pathway (PPP) for NADPH generation and reactive oxygen species production. In this study, the authors identify a mechanism of neutrophil activation that is independent of the PPP but relies on the glycolytic enzyme pyruvate kinase M2 instead.
- Juliana Escher Toller-Kawahisa
- , Carlos Hiroji Hiroki
- & José Carlos Alves-Filho
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Article
| Open AccessNOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice
Maturation of interleukin-18 (IL-18) is normally mediated by activated inflammasomes in innate immune cells as an antipathogen mechanism. Here the authors show that IL-18 maturation occurs in gut epithelial cells upon encounter with Helicobacter pylorivia a noncanonical NOD1/caspase-1 pathway to maintain epithelial homoeostasis.
- L. S. Tran
- , L. Ying
- & R. L. Ferrero
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| Open AccessPathogen-specific innate immune response patterns are distinctly affected by genetic diversity
Looking at genes that are differentially responsive to pathogens depending on the genetic background may help in the identification of therapeutic targets in personalized medicine. Here, using challenge of monocytes with three pathogens the authors identified eQTL that are shared between pathogens and loci that are pathogen specific.
- Antje Häder
- , Sascha Schäuble
- & Oliver Kurzai
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Article
| Open AccessTrim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates
TRIM21 mediates intracellular antibody immunity and is exploited for targeted protein degradation using Trim-Away technology. Here, the authors dissect the ubiquitination requirements for Trim-Away, providing an explanation for how TRIM21 can target diverse substrates for degradation.
- Leo Kiss
- , Tyler Rhinesmith
- & Leo C. James
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Article
| Open AccessPolyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV
Polyamine metabolism is a determinant of T helper cell polarization. Here, Mahalingam et al analyse the metabolic and transcriptomic profile of oral mucosa from people living with HIV to demonstrate the effect of polyamine synthesis on T cell dysfunction during HIV-1 infection.
- S. S. Mahalingam
- , S. Jayaraman
- & P. Pandiyan
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Article
| Open AccessInsights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8
The multifunctional GSDMB protein is an important molecule in human immunity. Here, the authors decipher the molecular mechanisms of GSDMB targeting by the bacterial virulence factor IpaH7.8 and provide insights into GSDMB-mediated pyroptosis.
- Hang Yin
- , Jian Zheng
- & Heng Zhang
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Article
| Open AccessLysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism
Extensive lysosomal damage can result in cell death but how limited protease leakage affects cytoplasmic organelles in viable cells is not well understood. Here the authors show that limited lysosomal damage leads to changes in the mitochondrial proteome and the modulation of macrophage immunometabolism.
- Claudio Bussi
- , Tiaan Heunis
- & Maximiliano G. Gutierrez
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Article
| Open AccessStructural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns
Detection of invading bacteria is key to immunity. Here, the authors report cryo-electron microscopy structures of agonist-bound formyl peptide receptor 1 (FPR1), that reveal structural basis for recognition of bacteria-derived formyl peptides.
- Geng Chen
- , Xiankun Wang
- & Richard D. Ye
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Article
| Open AccessGolgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation
Here the authors revealed a role for the protein deacetylase SIRT2 in Golgi stress, particularly induced by bacterial infection. Shigella secrete effector proteins such as IcsB, which transfers fatty acyl groups to modify host proteins to evade host immune surveillance. The upregulated SIRT2 counteracts this function by removing the fatty acyl groups and enhancing the killing of Shigella.
- Miao Wang
- , Yugang Zhang
- & Hening Lin
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Article
| Open AccessThe intrinsically disordered protein TgIST from Toxoplasma gondii inhibits STAT1 signaling by blocking cofactor recruitment
Intrinsically disordered proteins (IDP) are pleotropic proteins with diverse functions. Here the authors show that an IDP, TgIST, from T. gondii blocks interferon-induced gene expression by binding to the STAT1 dimer interface and preventing the recruitment of co-transcriptional activators, CBP/p300, to STAT1 to inhibit expression of immunity genes.
- Zhou Huang
- , Hejun Liu
- & L. David Sibley
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Article
| Open AccessSingle-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure.
- Roy Oelen
- , Dylan H. de Vries
- & Monique G. P. van der Wijst
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Article
| Open AccessCumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host
Variants of concerns arise from SARS-CoV-2 mutations poise as severe public health threats. Here the authors chronicle SARS-CoV-2 mutations onset and immune parameters in an immunocompromised patient with continuous virus-shedding, thereby hinting potential intra-host viral evolution and escape facilitated by ineffective T cell immunity.
- Sissy Therese Sonnleitner
- , Martina Prelog
- & Gernot Walder
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Article
| Open AccessComparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants
Vaccination shows efficacy in protecting from COVID-19, but regime and dosing optimization is still ongoing. Here the authors show that BNT162b2, mRNA-1273, or their combination with ChAdOx1 induces similar antibody responses, and those receiving three doses of BNT162b2 induce neutralizing antibodies against the Omicron variant.
- Milja Belik
- , Pinja Jalkanen
- & Ilkka Julkunen
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| Open AccessThe timing of differentiation and potency of CD8 effector function is set by RNA binding proteins
RNA binding proteins (RBP) have a function in T cell activation and differentiation. Here the authors show that in the absence of two RBPs, ZFP36 and ZFP36L1, T cells acquire more rapidly superior effector capabilities, showing a limiting function for RBP in T cell activation and differentiation.
- Georg Petkau
- , Twm J. Mitchell
- & Martin Turner
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| Open AccessMechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip
Mechanical forces in lungs facilitate breathing motions. Here the authors use a microfluidic human lung alveolus chip to study influenza infection and find that mechanical forces from active chips also induce innate inflammatory responses via, at least partially, signaling from TRPV4 and RAGE, thereby implicating them as potential therapeutic targets for lung inflammation.
- Haiqing Bai
- , Longlong Si
- & Donald E. Ingber
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Article
| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessGlutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells
Follicular and marginal zone B (FoB and MZB, respectively) cells have divergent metabolic characteristics. Here the authors show that deficiency of glutamate cysteine ligase (Gclc), the enzyme for glutathione synthesis, differentially impacts FoB and MZB homeostasis, while specifically impeding FoB activation and downstream antiviral immunity.
- Davide G. Franchina
- , Henry Kurniawan
- & Dirk Brenner
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| Open AccessHuman rhinovirus promotes STING trafficking to replication organelles to promote viral replication
Evidence exists that the typically antiviral signaling mediator STING is, counterintuitively, needed for optimal human rhinovirus infection. Here the authors confirm this finding and show how human rhinovirus can reduce stored Ca2+ levels to drive this effect.
- Martha Triantafilou
- , Joshi Ramanjulu
- & Kathy Triantafilou
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| Open AccessIL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence
IL-22 induces IL-18 expression by intestinal epithelial cells. Authors show here that IL-18 is a key barrier maintenance factor during adherent-invasive E. coli invasion, inducing expression of anti-microbial genes in Paneth cells via Stat3, prompting IFNγ expression in T cells and triggering intestinal Lgr5+ stem cell expansion via Tcf4.
- Hung-Yu Chiang
- , Hsueh-Han Lu
- & Jr-Wen Shui
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Article
| Open AccessDefective humoral immunity disrupts bile acid homeostasis which promotes inflammatory disease of the small bowel
Mucosal antibodies maintain gut homeostasis, and may influence gut health through modulation of microbiota composition. Here the authors use a CD19-deficient mouse model with deficient B-cell immune responses to uncover an association between humoral immunodeficiency, dysbiosis, and perturbations to bile acid homeostasis in the gut in the context of glute-sensitive enteropathy.
- Ahmed Dawood Mohammed
- , Zahraa Mohammed
- & Jason L. Kubinak
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Article
| Open AccessDistinct kinetics of antibodies to 111 Plasmodium falciparum proteins identifies markers of recent malaria exposure
Serological markers of recent Plasmodium falciparum infection could be useful to estimate incidence. Here, the authors identify a combination of five serological markers to detect exposure to infection within the previous three months with >80% sensitivity and specificity.
- Victor Yman
- , James Tuju
- & Anna Färnert
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Article
| Open AccessCross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts
While cross-reactive immunity between human coronavirus and SARS-CoV-2 may contribute to host protection, validating evidences are still scarce. Here the authors assess a cohort of 52 donors with immediate-early contact with SARS-CoV-2 to correlate higher frequency of cross-reactive T cells with lower infection rate.
- Rhia Kundu
- , Janakan Sam Narean
- & Ajit Lalvani
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Article
| Open AccessPediatric COVID-19 patients in South Brazil show abundant viral mRNA and strong specific anti-viral responses
Children often show milder COVID-19 symptoms, but the underlying mechanistic insights are still lacking. Here the authors profile both pediatric and adult cohorts of COVID-19 patients in Brazil to find that children exhibit higher viral load but stronger and biased cellular immunity, thereby serving clues for the differential responses in children.
- Tiago Fazolo
- , Karina Lima
- & Cristina Bonorino
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Article
| Open AccessMultifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity
How the immune responses induced by SARS-CoV-2 and human coronavirus (hCoV) crosstalk is still unclear. Here the authors profile the humoral responses of prepandemic and SARS-CoV-2-infected donors to find that higher hCoV antibody titers are associated with SARS-CoV-2 negativity, and with reduced hospitalization in SARS-CoV-2 positive patients.
- Irene A. Abela
- , Chloé Pasin
- & Alexandra Trkola
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Article
| Open AccessSARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains
Mutant SARS-CoV-2 strains such as B.1.1.7 and B.1.351 have been termed variants of concerns (VoC) due to their enhanced virulence. Here the authors show, using K18-hACE2 transgenic mouse models, that these two VoCs are also more pathogenic in mice, and induce immunity and pathology distinct from those from the earlier variants.
- Peter Radvak
- , Hyung-Joon Kwon
- & Hang Xie
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Article
| Open AccessNLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly
Nlrp3 inflammasome activation requires Nek7 recruitment to drive ASC speck formation. Here the authors show how Nlrp3 phosphorylation events control this Nek7 recruitment.
- Tingting Niu
- , Charlotte De Rosny
- & Bénédicte F. Py
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Article
| Open AccessIntrathymic differentiation of natural antibody-producing plasma cells in human neonates
The thymus is known as the organ of T lymphocyte development. Here authors show that terminal B cell differentiation also takes place in the thymus of human neonates, leading to antibody production against commensal and pathogenic bacteria.
- Hector Cordero
- , Rodney G. King
- & Emmanuel Zorn
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Article
| Open AccessMetabolic requirements of NK cells during the acute response against retroviral infection
Metabolic alterations control the fate and function of immune cells in response to infections, but the function of NK cell metabolism in the context of acute viral infections is unclear. Here the authors show that acute NK cell responses to Friend retrovirus involve increased glycolysis and mitochondrial metabolism and require amino acid transport as well as iron sufficiency.
- Elisabeth Littwitz-Salomon
- , Diana Moreira
- & David K. Finlay
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Article
| Open AccessProtective humoral and cellular immune responses to SARS-CoV-2 persist up to 1 year after recovery
The quality of immune response to SARS-CoV-2 is thought to wane over time, but it is unclear how long it can persist. Here the authors show persistent immune responses in a large number of patients over the course of a 1-year follow-up from the time of recovery from COVID-19.
- Chengqian Feng
- , Jingrong Shi
- & Feng Li
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Article
| Open AccessTwo doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern
Understanding the effect of vaccination on emerging SARS-CoV-2 variants of concern is of increasing importance. Here, James et al. report that two doses of vaccination with the Pfizer-BioNTech vaccine induce more robust immune responses to the B.1.1.7 and B.1.351 SARS-CoV-2 lineages than does natural infection.
- Donal T. Skelly
- , Adam C. Harding
- & William S. James
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Article
| Open AccessDownregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.
- Noam D. Beckmann
- , Phillip H. Comella
- & Alexander W. Charney
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Article
| Open AccessNK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence
During wound healing and infection in the skin there is a hypoxic environment involving HIF-1α and NK cells. Here the authors show that NK cells through HIF-1α provide a cross-regulatory balance to provide an adequate antimicrobial defence that can inhibit subsequent wound healing.
- Michal Sobecki
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open AccessMalignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia
Vaccination is an effective strategy in suppressing COVID-19 pandemic, but rare adverse effects have been reported, including cerebral venous thrombosis. Here the authors report two cases of middle cerebral artery infarct within 9-10 days following ChAdOx1 nCov-19 vaccination that also manifest pulmonary and portal vein thrombosis.
- M. De Michele
- , M. Iacobucci
- & D. Toni