Distorted TCR repertoires define multisystem inflammatory syndrome in children

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with severe (n=12) or mild (n=8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n=8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of severely ill children are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines severity of disease in children.

Migration without interbreeding: evolutionary history of a highly selfing Mediterranean grass inferred from whole genomes

Whole genome sequences and coalescence theory allow the study of plant evolution in unprecedented detail. In this study we extend the genomic resources for the wild Mediterranean grass Brachypodium distachyon to investigate the scale of population structure and its underlying history at whole-genome resolution. The analysis of 196 accessions, spanning the Mediterranean from Iberia to Iraq, shows that the interplay of high selfing and seed dispersal rates has shaped genetic structure. At the continental scale, evolution in B. distachyon is characterized by the independent expansion of three lineages during the Upper Pleistocene. Today, these lineages may occur in sympatry yet do not interbreed. At the local scale, dispersal and selfing interact to maintain high genotypic diversity. Our study lays a foundation for the study of microevolution in B. distachyon and identifies adaptive phenotypic plasticity and frequency-dependent selection as key themes to be addressed with this model system.

The diverging evolutionary history of opsin genes in Diptera

Opsin receptors mediate the visual process in animals and their evolutionary history can provide precious hints on the ecological factors that underpin their diversification. Here we mined the genomes of more than 60 Dipteran species and reconstructed the evolution of their opsin genes in a phylogenetic framework. Our phylogenies indicate that dipterans possess an ancestral set of five core opsins which have undergone several lineage-specific events including an independent expansion of low wavelength opsins in flies and mosquitoes and numerous family specific duplications and losses. Molecular evolutionary studies indicate that gene turnover rate, overall mutation rate, and site-specific selective pressure are higher in Anopheles than in Drosophila; we found signs of positive selection in both lineages, including events possibly associated with their peculiar behaviour. Our findings indicate an extremely variable pattern of opsin evolution in dipterans, showcasing how two similarly aged radiations - Anopheles and Drosophila - can be characterized by contrasting dynamics in the evolution of this gene family.

Transposon-mediated telomere destabilization: a driver of genome evolution in the blast fungus

The fungus Magnaporthe oryzae causes devastating diseases of crops, including rice and wheat, and in various grasses. Strains from ryegrasses have highly unstable chromosome ends that undergo frequent rearrangements, and this has been associated with the presence of retrotransposons (Magnaporthe oryzae Telomeric Retrotransposons—MoTeRs) inserted in the telomeres. The objective of the present study was to determine the mechanisms by which MoTeRs promote telomere instability. Targeted cloning, mapping, and sequencing of parental and novel telomeric restriction fragments (TRFs), along with MinION sequencing of genomic DNA allowed us to document the precise molecular alterations underlying 109 newly-formed TRFs. These included truncations of subterminal rDNA sequences; acquisition of MoTeR insertions by ‘plain’ telomeres; insertion of the MAGGY retrotransposons into MoTeR arrays; MoTeR-independent expansion and contraction of subtelomeric tandem repeats; and a variety of rearrangements initiated through breaks in interstitial telomere tracts that are generated during MoTeR integration. Overall, we estimate that alterations occurred in approximately sixty percent of chromosomes (one in three telomeres) analyzed. Most importantly, we describe an entirely new mechanism by which transposons can promote genomic alterations at exceptionally high frequencies, and in a manner that can promote genome evolution while minimizing collateral damage to overall chromosome architecture and function.

Model independent expansion history from supernovae: Cosmology versus systematics

We examine the Pantheon supernovae distance data compilation in a model independent analysis to test the validity of cosmic history reconstructions beyond the concordance ΛCDM cosmology. Strong deviations are allowed by the data at z ≳ 1 in the reconstructed Hubble parameter, Om diagnostic, and dark energy equation of state. We explore three interpretations: 1) possibility of the true cosmology being far from ΛCDM, 2) supernovae property evolution, and 3) survey selection effects. The strong (and theoretically problematic) deviations at z ≳ 1 vanish and good consistency with ΛCDM is found with a simple Malmquist-like linear correction. The adjusted data is robust against the model independent iterative smoothing reconstruction. However, we caution that while by eye the original deviation from ΛCDM is striking, χ2 tests do not show the extra linear correction parameter is statistically significant, and a model-independent Gaussian Process regression does not find significant evidence for the need for correction at high-redshifts.

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell–dependent and –independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

TLR9-mediated inflammation drives a Ccr2-independent peripheral monocytosis through enhanced extramedullary monocytopoiesis

Monocytes are innate immune cells that interact with their environment through the expression of pattern recognition receptors, including Toll-like receptors (TLRs). Both monocytes and TLRs are implicated in driving persistent inflammation in autoimmune diseases. However, cell-intrinsic mechanisms to control inflammation, including TLR tolerance, are thought to limit inflammatory responses in the face of repeated TLR activation, leaving it unclear how chronic TLR-mediated inflammation is maintained in vivo. Herein, we used a well-characterized model of systemic inflammation to determine the mechanisms allowing sustained TLR9 responses to develop in vivo. Monocytes were identified as the main TLR9-responsive cell and accumulated in peripherally inflamed tissues during TLR9-driven inflammation. Intriguingly, canonical mechanisms controlling monocyte production and localization were altered during the systemic inflammatory response, as accumulation of monocytes in the liver and spleen developed in the absence of dramatic increases in bone marrow monocyte progenitors and was independent of chemokine (C-C motif) receptor 2 (Ccr2). Instead, TLR9-driven inflammation induced a Ccr2-independent expansion of functionally enhanced extramedullary myeloid progenitors that correlated with the peripheral accumulation of monocytes in both wild-type and Ccr2−/− mice. Our data implicate inflammation-induced extramedullary monocytopoiesis as a peripheral source of newly produced TLR9 responsive monocytes capable of sustaining chronic TLR9 responses in vivo. These findings help to explain how chronic TLR-mediated inflammation may be perpetuated in autoimmune diseases and increase our understanding of how monocytes are produced and positioned during systemic inflammatory responses.