The global scale of Covid-19 has constrained academics from conducting much person-facing research. Reactively, trend is increasing for digital-based methodologies capturing already existing online ...data. Scholars often 'scrape' user-postings from internet forums using coding algorithms and text capture tools, before analysing data, drawing conclusions and publishing findings. The online social news aggregation and discussion website Reddit is a particularly rich source of data for researchers. The public nature of Reddit materials may suggest rationale for user-data to be replicated, analysed and archived; indefinitely and in multiple locations, for scholarly research. However, this position overlooks several key ethical considerations. This paper presents an overview and explanation of Reddit, followed by an exploration of studies that use Reddit-acquired data. Arising ethical issues are discussed, and solutions to salient dilemmas presented. This is to enhance awareness of potential problems and improve protections for those whose data is unknowingly used for research.
One of the hallmarks of the vertebrate adaptive immune system is the prolific expansion of individual cell clones that encounter their cognate antigen. More recently, however, there is growing ...evidence for the clonal expansion of innate lymphocytes, particularly in the context of pathogen challenge. Clonal expansion not only serves to amplify the number of specific lymphocytes to mount a robust protective response to the pathogen at hand but also results in selection and differentiation of the responding lymphocytes to generate a multitude of cell fates. Here, we summarize the evidence for clonal expansion in innate lymphocytes, which has primarily been observed in natural killer (NK) cells responding to cytomegalovirus infection, and consider the requirements for such a response in NK cells in light of those for T cells. Furthermore, we discuss multiple aspects of heterogeneity that both contribute to and result from the fundamental immunological process of clonal expansion, highlighting the parallels between innate and adaptive lymphocytes, with a particular focus on NK cells and CD8
T cells.
Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Whether tissue-resident lymphocytes confer early antiviral immunity at local sites of primary ...infection prior to the initiation of circulating responses is not well understood. Furthermore, the kinetics of initial antiviral responses at sites of infection remain unclear. Here, we show that tissue-resident type 1 innate lymphoid cells (ILC1) serve an essential early role in host immunity through rapid production of interferon (IFN)-γ following viral infection. Ablation of Zfp683-dependent liver ILC1 lead to increased viral load in the presence of intact adaptive and innate immune cells critical for mouse cytomegalovirus (MCMV) clearance. Swift production of interleukin (IL)-12 by tissue-resident XCR1+ conventional dendritic cells (cDC1) promoted ILC1 production of IFN-γ in a STAT4-dependent manner to limit early viral burden. Thus, ILC1 contribute an essential role in viral immunosurveillance at sites of initial infection in response to local cDC1-derived proinflammatory cytokines.
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•ILC1 represent the major early source of IFN-γ in virally infected tissues•ILC1-derived IFN-γ limits early MCMV replication in primary infected tissues•Crosstalk between cDC1 and ILC1 populations mediate initial local control of virus•ILC1 display enhanced responsiveness to IL-12 compared to other lymphocytes
Innate lymphoid cells have a non-redundant role as initial responders to viral infections.
Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a ...property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.
Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate ...transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α
NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.
To determine whether hydrogen peroxide vapor (HPV) decontamination can reduce environmental contamination with and nosocomial transmission of Clostridium difficile.
A prospective before-after ...intervention study.
A hospital affected by an epidemic strain of C. difficile.
Intensive HPV decontamination of 5 high-incidence wards followed by hospital-wide decontamination of rooms vacated by patients with C. difficile-associated disease (CDAD). The preintervention period was June 2004 through March 2005, and the intervention period was June 2005 through March 2006.
Eleven (25.6%) of 43 cultures of samples collected by sponge from surfaces before HPV decontamination yielded C. difficile, compared with 0 of 37 cultures of samples obtained after HPV decontamination (P < .001). On 5 high-incidence wards, the incidence of nosocomial CDAD was significantly lower during the intervention period than during the preintervention period (1.28 vs 2.28 cases per 1,000 patient-days; P = .047). The hospital-wide CDAD incidence was lower during the intervention period than during the preintervention period (0.84 vs 1.36 cases per 1,000 patient-days; P = .26). In an analysis limited to months in which the epidemic strain was present during both the preintervention and the intervention periods, CDAD incidence was significantly lower during the intervention period than during the preintervention period (0.88 vs 1.89 cases per 1,000 patient-days; P = .047).
HPV decontamination was efficacious in eradicating C. difficile from contaminated surfaces. Further studies of the impact of HPV decontamination on nosocomial transmission of C. difficile are warranted.
Natural killer (NK) cells are innate lymphocytes that display features of adaptive immunity during viral infection. Biallelic mutations in IRF8 have been reported to cause familial NK cell deficiency ...and susceptibility to severe viral infection in humans; however, the precise role of this transcription factor in regulating NK cell function remains unknown. Here, we show that cell-intrinsic IRF8 was required for NK-cell-mediated protection against mouse cytomegalovirus infection. During viral exposure, NK cells upregulated IRF8 through interleukin-12 (IL-12) signaling and the transcription factor STAT4, which promoted epigenetic remodeling of the Irf8 locus. Moreover, IRF8 facilitated the proliferative burst of virus-specific NK cells by promoting expression of cell-cycle genes and directly controlling Zbtb32, a master regulator of virus-driven NK cell proliferation. These findings identify the function and cell-type-specific regulation of IRF8 in NK-cell-mediated antiviral immunity and provide a mechanistic understanding of viral susceptibility in patients with IRF8 mutations.
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•IRF8 is required for NK-cell-mediated protection against MCMV•Rapid NK cell upregulation of IRF8 during MCMV infection is STAT4 dependent•IRF8 is essential for MCMV-specific NK cell expansion•IRF8 supports NK cell proliferation by directly regulating Zbtb32
The link between human IRF8 mutations and immunodeficiency is poorly understood. Adams et al. demonstrate that IRF8 is required for NK-cell-mediated antiviral immunity by promoting proliferation of virus-specific NK cells.
Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal ...Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.
Innate lymphoid cells (ILCs) function to protect epithelial barriers against pathogens and maintain tissue homeostasis in both barrier and non-barrier tissues. Here, utilizing Eomes reporter mice, we ...identify a subset of adipose group 1 ILC (ILC1) and demonstrate a role for these cells in metabolic disease. Adipose ILC1s were dependent on the transcription factors Nfil3 and T-bet but phenotypically and functionally distinct from adipose mature natural killer (NK) and immature NK cells. Analysis of parabiotic mice revealed that adipose ILC1s maintained long-term tissue residency. Diet-induced obesity drove early production of interleukin (IL)-12 in adipose tissue depots and led to the selective proliferation and accumulation of adipose-resident ILC1s in a manner dependent on the IL-12 receptor and STAT4. ILC1-derived interferon-γ was necessary and sufficient to drive proinflammatory macrophage polarization to promote obesity-associated insulin resistance. Thus, adipose-resident ILC1s contribute to obesity-related pathology in response to dysregulated local proinflammatory cytokine production.
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•Adipose ILC1s represent a stable population distinct from immature and mature NK cells•Adipose ILC1s, but not mature NK cells, are tissue resident•Adipose ILC1 IFN-γ contributes to M1 macrophage polarization and insulin resistance•IL-12 and STAT4 drive proliferation and accumulation of adipose ILC1 during obesity
Here, Sun and colleagues demonstrate that adipose group 1 innate lymphoid cells (ILCs) contain distinct populations of immature and mature NK cells and tissue-resident ILC1. Adipose-resident ILC1s selectively accumulate in the adipose depots following diet-induced obesity and produce IFN-γ in response to IL-12 production to contribute toward M1 macrophage polarization and insulin resistance.
The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model accounts for hematopoiesis in ...transplant settings, its applicability to steady-state hematopoiesis remains to be clarified. Here, we used inducible clonal DNA barcoding of endogenous adult HSCs to trace their contribution to major hematopoietic cell lineages in unmanipulated animals. While the majority of barcodes were unique to a single lineage, we also observed frequent barcode sharing between multiple lineages, specifically between lymphocytes and myeloid cells. These results suggest that both single-lineage and multilineage contributions by HSCs collectively drive continuous hematopoiesis, and highlight a close relationship of myeloid and lymphoid development.
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