TEF, Vol. 2 No. 1

The second annual literary anthology of students writing from Stephen F Austin State College.https://scholarworks.sfasu.edu/tef/1001/thumbnail.jp

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Seasonal variation of hydrocarbon abundances on Saturn: Comparisons of coupled ion-neutral photochemical models with Cassini UVIS, CIRS, and INMS data

International audienceThe long-lived Cassini mission provided unprecedented insight into the variation of photochemically produced species in Saturn's upper atmosphere as a function of altitude, latitude, and time. A recent analysis of stellar occultations observed in 2016-2017 by the Cassini Ultraviolet Imaging Spectrograph (UVIS) (see abstract by Z. Brown and colleagues from this meeting) has proven particularly instrumental in highlighting seasonal behavior in the upper stratosphere at pressures that are difficult to probe remotely by other methods. These observations exhibit variations with latitude that correlate with the actinic solar flux that drives photochemistry, as is expected from seasonal photochemical models, as well as highlight some unexpected behavior, such as trends in the methane homopause pressure level with latitude. To gain physical insights into the observed behavior, we have developed a time-variable photochemical model for Saturn's stratosphere and thermosphere. The model considers solar-driven coupled ion-neutral photochemistry and accounts for meridional and temporal variations in incident solar flux due to orbital and seasonal geometry, ring shadowing, and solar-cycle variations. Comparisons of the models with Cassini data (including a data set complementary to that of UVIS, consisting of Cassini Composite Infrared Spectrometer (CIRS) retrievals of hydrocarbon abundances deeper in the stratosphere) provide important clues to seasonally variable chemistry, dynamics, and haze formation in Saturn's stratosphere. The model-data comparisons confirm the importance of ion chemistry in producing benzene and polycyclic aromatic hydrocarbons in Saturn's stratosphere and point to potential missing chemistry in the model, including auroral-induced ion chemistry, and an as-yet-unidentified process that increases C2H2 production in Saturn's upper stratosphere above model predictions. We describe the model results, compare them with available spatially resolved observations, and discuss the implications. We also present low-latitude results that include the very large influx of external material, presumably from Saturn's rings, that was observed by the Cassini Ion and Neutral Mass Spectrometer (INMS) during the Grand Finale stage of the mission; we show how that incoming material affects the abundance of neutral and ionized species in Saturn's upper atmosphere. This work was supported by the NASA Solar System Workings program, grant number 80NSSC20K0462

Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity

<div><p>For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or <i>a priori</i> knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (<i>Rag1</i>, <i>Mda5</i>, <i>Mavs</i>, <i>Ifnar1</i>, <i>Ifngr1</i>, and <i>Tlr3)</i> established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection.</p></div

RdRP-induced antiviral phenotype is mediated in a MDA5-MAVS, IFNαβR-dependent manner.

<p>(A-E) Knockout mice were bred to RdRP mice and the antiviral phenotype of each cross was analyzed by immunoblotting and survival. Left, cerebrum (top panel), spinal cord (middle), and cerebellum (bottom) tissue homogenates (n = 2 uninfected mice per genotype, 1 per lane) were analyzed by immunoblotting. Right, survival curve following EMCV infection (n = 8 mice per genotype), data are representative of two independent experiments. (A) <i>IfnγR</i>^<i>-/-</i> cross. (B) <i>IfnαβR</i>^<i>-/-</i> cross. (C) <i>Tlr3</i>^<i>-/-</i> cross. (D) <i>Mda5</i>^<i>-/-</i> cross. (E) <i>Mavs</i>^<i>-/-</i> cross.</p

RdRP mice appear indistinguishable from WT controls.

<p>(A) Histological examination of WT and RdRP transgenic mice. Tissues were harvested from uninfected age-matched, sex-matched adult FVB mice (n = 2 per genotype). Histological examination was performed on formalin-fixed paraffin-embedded tissue after hematoxylin and eosin staining. (B) Gross tissue morphology. Tissues were harvested from uninfected age-matched, sex-matched adult FVB mice (n = 2 mice per genotype). (C) Kidney tissues were closely examined (40X) for signs of glomerulonephritis. (D) Sex-matched WT (n = 3) and RdRP (n = 3) mice were randomly chosen and photographed at different time points throughout their development. Mice are age-matched at postnatal (p) day 4, p15, 4 weeks (wk), 7 wk, and 12 wk. (E) Survival curve of female WT (n = 4) and RdRP (n = 4) mice in the absence of infection. (F and G) WT (F, n = 2) and RdRP mice (G, n = 4) from (E) were photographed at 20 months of age.</p

RdRP mice display highly augmented antiviral defenses.

<p>(A) Heat map of differentially expressed genes in CNS tissue. Microarray data are presented as fold change (blue = 1-fold induction; purple = 8-fold upregulation; red = ≥15-fold upregulation). WT+EMCV: expression profile of genes significantly upregulated >4-fold in spinal cords of WT FVB mice infected with EMCV (n = 2) compared with uninfected WT FVB mice (n = 2). RdRP: uninfected transgenic RdRP FVB mice (n = 3) compared with uninfected WT FVB mice (n = 3), data are representative of two independent experiments. RdRP+EMCV: RdRP FVB mice infected with EMCV (n = 2) compared with uninfected WT FVB mice (n = 2). For a complete list of upregulated genes see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005311#ppat.1005311.s006" target="_blank">S1</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005311#ppat.1005311.s008" target="_blank">S3</a> Tables. (B) mRNA levels of the prominent antiviral genes, <i>Oasl2</i>, <i>Isg15</i>, <i>Ifit1</i>, and <i>Rig-I</i>, determined by RT-PCR in cerebrum, spinal cord, and cerebellum tissues of uninfected (WT FVB or RdRP FVB) or virally-infected FVB mice (WT+EMCV or RdRP+EMCV) (n = 5 mice per group, relative to <i>Gapdh</i> mRNA, mean ± SEM). (C and D) Cerebrum, spinal cord, and cerebellum tissue homogenates (C, n = 2 mice per group, 1 per lane; D, n = 1 uninfected mouse of specified age in months per lane) were analyzed by immunoblotting using antibodies for RIG-I and ISG15. Antibody for β-ACTIN served as control. (E) RT-PCR analysis of viral titers in murine tissues two days post infection with EMCV (n = 8 mice per genotype, relative to endogenous <i>Gapdh</i> mRNA, mean ± SEM). (F) Survival curve following EMCV infection (n = 8 mice per genotype). Results are presented as a Kaplan-Meier plot and are representative of two independent experiments. * <i>P<0</i>.<i>05; ** P<0</i>.<i>01; *** P<0</i>.<i>001; **** P<0</i>.<i>0001</i>.</p

Rapid induction of antiviral ISG mRNAs following RdRP expression in human lung epithelial cells.

<p>(A) DOX-inducible RdRP A549 cell lines were generated using lentiviral vectors that inducibly co-express RdRP or RdRPΔcat and resistance to puromycin. Vector terminology: Tsin-TetON-RdRP-IRESpuro (TetON-RdRP) and Tsin-TetON-RdRPΔcat-IRESpuro (TetON-RdRPΔcat) lentiviral vectors. (B) TetON-A549 cell lysates were analyzed by immunoblotting to determine relative abundance of RdRP-HA protein (anti-HA-tag) following DOX treatment (hr). (C) mRNA levels of the prominent antiviral genes, <i>IFI27</i>, <i>OASL</i>, <i>ISG15</i>, <i>IFIT1</i>,and <i>IFNβ</i> in TetON-A549 cell lines prior to (0 hr) or after (24 and 48 hr) DOX treatment (data are mean ± SEM of three technical replicates, relative to <i>GAPDH</i> mRNA). * <i>P<0</i>.<i>05; ** P<0</i>.<i>01; *** P<0</i>.<i>001; **** P<0</i>.<i>0001</i>.</p