Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021.

We present a global analysis of the spread of recently emerged SARS-CoV-2 variants and estimate changes in effective reproduction numbers at country-specific level using sequence data from GISAID. Nearly all investigated countries demonstrated rapid replacement of previously circulating lineages by the World Health Organization-designated variants of concern, with estimated transmissibility increases of 29% (95% CI: 24-33), 25% (95% CI: 20-30), 38% (95% CI: 29-48) and 97% (95% CI: 76-117), respectively, for B.1.1.7, B.1.351, P.1 and B.1.617.2

Serotonergic chemosensory neurons modify the <i>C. elegans</i> immune response by regulating G-protein signaling in epithelial cells

The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food

The impact of genetic variation on IFITM3 related influenza virus restriction

The IFITM3 protein is a prominent restriction factor of influenza virus that has been shown to antagonise the cellular entry of influenza virus. In 2012, the minor allele of a synonymous SNP in IFITM3, known as rs12252 (major T, minor C), was shown to be associated with severe influenza virus infection. Numerous studies have corroborated this association, showing clear links between the C allele and increased risk of severe influenza virus infection in East Asian and European populations. It was hypothesised that the observed effects of rs12252-C were related to aberrant splicing of IFITM3, causing an isoform coding for an N-terminally truncated variant of the protein. More recently, additional IFITM3-associated genetic risk factors for severe influenza virus infection have also been uncovered. In this thesis, we investigated the molecular mechanisms of rs12252. In chapter 3, we show that the IFITM3 splicing profile is consistently dominated by the canonical isoform, and that truncated isoforms are produced at extremely low levels regardless of rs12252 genotype. In chapter 4, we investigated associations between rs12252 and expression of IFITM3 at mRNA and protein level, using in vitro systems and healthy donors. We show that rs12252 is an expression Quantitative Trait Locus (eQTL) for IFITM3, and its activity is potentially tissue dependent. We also uncovered potential effects of this SNP on blood transcriptional signature. Next, in chapter 5, we identified two novel eQTLs for IFITM3, which may be risk variants for severe influenza virus infection. Finally, in chapter 6, we analysed the association between rs12252 and severe influenza infection using several model systems. These findings uncovered potential associations between rs12252 and differential interferon signalling, although further experimentation is required to confirm this.</p

IFITM3: How genetics influence influenza infection demographically

The role of host genetics in influenza infection is unclear despite decades of interest. Confounding factors such as age, sex, ethnicity and environmental factors have made it difficult to assess the role of genetics without influence. In recent years a single nucleotide polymorphism, interferon-induced transmembrane protein 3 (IFITM3) rs12252, has been shown to alter the severity of influenza infection in Asian populations. In this review we investigate this polymorphism as well as several others suggested to alter the host's defence against influenza infection. In addition, we highlight the open questions surrounding the viral restriction protein IFITM3 with the hope that by answering some of these questions we can elucidate the mechanism of IFITM3 viral restriction and therefore how this restriction is altered due to the rs12252 polymorphism. Keywords: IFITM3, Influenza, IAV, Viral infection, Viral contro

The serotonin biosynthetic enzyme TPH-1 is required in chemosensory neurons to inhibit the Dar phenotype and decrease pathogen clearance rates.

<p>Adult <i>tph-1(mg280)</i> or <i>tph-1(n4622)</i> animals lacking the serotonin biosynthetic enzyme TPH-1 were infected on lawns contaminated with 10% <i>M. nematophilum</i>. The percentage of <i>tph-1(mg280)</i> and <i>tph-1(n4622)</i> progeny with the Dar phenotype was indistinguishable from wild type (A). When animals were infected on lawns contaminated with 0.05% <i>M. nematophilum</i> the Dar phenotype was increased from 60.3% in wild type animals to 92.1% in <i>tph-1(mg280)</i> and 83.0% in <i>tph-1(n4622)</i> (A). This increase could be rescued by treatment with exogenous 5-HT (A) or expression of TPH-1 cDNA in ADF, but not NSM, neurons (B). <i>tph-1(mg280)</i> and <i>tph-1(n4622)</i> animals cleared SYTO13 labeled pathogen more quickly than wild type animals consistent with a role for TPH-1 in suppressing the immune response (C). This phenotype was rescued by 5-HT treatment (C) or expression of a TPH-1 cDNA in both ADF and NSM neurons or ADF neurons alone but not by expression in NSM alone (D). * indicates significance relative to wild type. § indicates significance relative to untreated mutant control (C) or <i>tph-1(mg280)</i> (D) (see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003787#s4" target="_blank">materials and methods</a> for details of statistical analysis).</p

Serotonin synthesis in chemosensory neurons inhibits the immune response by altering rectal epithelial G-protein signaling.

<p>In response to environmental cues, such as the presence or absence of food, serotonin, released from ADF chemosensory neurons acts, directly or indirectly, to regulate GOA-1(Gαo) signaling in the rectal epithelium. This signaling suppresses the Dar phenotype that forms part of the innate immune response and limits the rate of pathogen clearance from the rectal opening.</p

Increased expression of TPH-1 in ADF chemosensory neurons is caused by reduced contact with contaminated bacterial lawns.

<p>Wild type and <i>egl-30(ad805)</i> animals carrying an integrated <i>tph-1p</i>::DSRED transgene were infected with <i>M. nematophilum</i> or an avirulent form of <i>M. nematophilum</i> using standard (small lawn) or “big lawn” assay conditions. The mean <i>tph-1p</i>::DSRED fluorescence in ADF neurons was quantified. Expression of <i>tph-1p</i>::DSRED was significantly increased when wild type animals were grown on small lawns contaminated with virulent <i>M. nematophilum</i>. This increase in expression was not observed under conditions when animals were unable to leave the bacterial lawn; in <i>egl-30(ad805)</i> animals or when wild type animals were infected on “big lawns”.</p

Exogenous serotonin inhibits the Dar phenotype and decreases pathogen clearance rates.

<p>Adult wild type animals were exposed to <i>M. nematophilum</i> on plates containing exogenous serotonin and the Dar phenotype was scored in their progeny. Treatment with 3.8 mg/ml 5-HT caused a 35% decrease in the number of Dar animals following <i>M. nematophilum</i> infection using standard assay conditions (small lawn) (A). A similar decrease was observed when assay conditions were modified so that animals were unable to avoid the pathogen (big lawn) (A). The Dar phenotype was still decreased when wild type animals were infected in the presence of exogenous serotonin during development, at L1 or L2/3 stage, or 10–18 hours prior to adulthood, at L3/4 stage (B). Similar amounts of <i>M. nematophilum</i> bacteria, labelled using the nucleic acid stain SYTO13, still attached to the anal opening following serotonin treatment (C, D and E) (the rectal opening is indicated with an arrow head in C and D). SYTO13 labeled <i>M. nematophilum</i> was cleared from the anal opening of wild type animals and less than 50% of animals were colonized 90 minutes after transfer to plates without food (F). Treatment of infected animals with 3.8 mg/ml 5-HT significantly decreased the clearance of labeled pathogen from the anal opening (F).</p

Rectal epithelial EGL-10 acts downstream of serotonin to modify the immune response and affect pathogen clearance.

<p>Treatment of wild type animals with 3.8/ml 5-HT caused a decrease in the number of Dar animals following infection with <i>M. nematophilum</i> (A) and decreased the clearance of SYTO13 labeled pathogen from the rectal opening (B). Serotonin was unable to decrease the percentage of Dar animals (A) or the rate of pathogen clearance (B) when EGL-10 cDNA was overexpressed in the rectal epithelium of wild type animals suggesting that GOA-1(Gáo) signaling in the rectal epithelium is required for serotonin to suppress the immune response. Animals lacking <i>tph-1</i> have wild type levels of Dar response on lawns contaminated with 10% <i>M. nematophilum</i> (A) but are more able to clear pathogen infections than wild type (C). Conversely activation of GOA-1(Gáo) using <i>egl-10</i> loss-of-function mutants results in a decrease in the percentage of Dar animals (A) and infections clear more slowly than wild type animals (C). To determine whether GOA-1(Gáo) acts downstream of serotonin we combined <i>egl-10(n692)</i> with <i>tph-1(mg280)</i> or <i>tph-1(n4622)</i>. The percentage of Dar animals (A) and the rate of pathogen clearance was indistinguishable between <i>egl-10(n692)</i> and these double mutants (C). Thus GOA-1(Gáo) signaling acts downstream of serotonin synthesis to suppress the immune response to <i>M. nematophilum</i> infection.</p