7 research outputs found

    Genetic mechanisms of critical illness in COVID-19.

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    Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

    A prenylated dsRNA sensor protects against severe COVID-19

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    Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response

    Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

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    To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1‚Äď11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

    The "morphology index" - an objective measurement of cell shae in Candida albicans.

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    The "morphology index" an objective measurement of ceil shape in Candida albicans. Louise A. Merson-Davies. The morphology of the fungus Candida albicans was characterised by measurement of cell dimensions with the aid of computerised image analysis. The dimensions were used to calculate a mathematical ratio, the morphology index, which fell in the range 1 to 4.5. Spherical yeast cells gave low Mi values, whilst true hyphal cells gave Mi values greater than 3.2. This study shows that Mi can be used reliably in the place of subjective descriptions of C. albicans morphology. The mean Mi of a cell population varied according to the growth environment and the strain of C. albicans. Mi was found to reveal a continuum of morphologies in C. albicans cells both in vitro and in vivo, with no clear relationship observed between cellular morphology and the pathogenic status of C. albicans. Chemical and cellular analyses were performed on a variety of morphological forms of C. albicans, as determined by Mi. The chitin content of C. albicans cells increased linearly with Mi, although no significant correlation was found between the activity of the polysaccharide degradation enzymes, chitinase and glucanase, and morphology. Autoradiography and analysis of cell wall expansion suggested that the apex of the cell was the main region of expansion, regardless of morphology. General wall expansion was found to be repressed in cells with Mi greater than 2. The rate of overall cell wall expansion increased linearly with Mi. Investigations with "hypha-specific" monoclonal antibodies indicated a correlation between antibody reactivity and Mi, epitope expression appeared to be induced in cells with Mi greater than 3. The linear relationship observed between some properties (polysaccharide composition and overall wall expansion) and Mi suggests that quantitative regulation mechanisms may determine cell morphology