The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation.

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults.

Pneumococcal infections cause serious illness and death among older adults. The capsular polysaccharide vaccine PPSV23 and conjugated alternative PCV13 can prevent these infections; yet, underlying immunological responses and baseline predictors remain unknown. We vaccinated 39 older adults (>60 years) with PPSV23 or PCV13 and observed comparable antibody responses (day 28) and plasmablast transcriptional responses (day 10); however, the baseline predictors were distinct. Analyses of baseline flow cytometry and bulk and single-cell RNA-sequencing data revealed a baseline phenotype specifically associated with weaker PCV13 responses, which was characterized by increased expression of cytotoxicity-associated genes, increased frequencies of CD16+ natural killer cells and interleukin-17-producing helper T cells and a decreased frequency of type 1 helper T cells. Men displayed this phenotype more robustly and mounted weaker PCV13 responses than women. Baseline expression levels of a distinct gene set predicted PPSV23 responses. This pneumococcal precision vaccinology study in older adults uncovered distinct baseline predictors that might transform vaccination strategies and initiate novel interventions.

Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

TIMely connections: APOE4, aging, and Alzheimer's.

How do APOE4 and aging, two of the strongest risk factors for late-onset Alzheimer's disease (AD), promote disease progression? In this issue of Immunity, Millet et al. examine microglia in AD mice bearing different APOE alleles at distinct ages and identify a conserved exhausted-like microglial state enriched in very elderly and APOE4 AD brains.

An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains.

The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-ß clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

This article presents global cancer statistics by world region for the year 2022 based on updated estimates from the International Agency for Research on Cancer (IARC). There were close to 20 million new cases of cancer in the year 2022 (including nonmelanoma skin cancers [NMSCs]) alongside 9.7 million deaths from cancer (including NMSC). The estimates suggest that approximately one in five men or women develop cancer in a lifetime, whereas around one in nine men and one in 12 women die from it. Lung cancer was the most frequently diagnosed cancer in 2022, responsible for almost 2.5 million new cases, or one in eight cancers worldwide (12.4% of all cancers globally), followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%). Lung cancer was also the leading cause of cancer death, with an estimated 1.8 million deaths (18.7%), followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach (6.8%) cancers. Breast cancer and lung cancer were the most frequent cancers in women and men, respectively (both cases and deaths). Incidence rates (including NMSC) varied from four-fold to five-fold across world regions, from over 500 in Australia/New Zealand (507.9 per 100,000) to under 100 in Western Africa (97.1 per 100,000) among men, and from over 400 in Australia/New Zealand (410.5 per 100,000) to close to 100 in South-Central Asia (103.3 per 100,000) among women. The authors examine the geographic variability across 20 world regions for the 10 leading cancer types, discussing recent trends, the underlying determinants, and the prospects for global cancer prevention and control. With demographics-based predictions indicating that the number of new cases of cancer will reach 35 million by 2050, investments in prevention, including the targeting of key risk factors for cancer (including smoking, overweight and obesity, and infection), could avert millions of future cancer diagnoses and save many lives worldwide, bringing huge economic as well as societal dividends to countries over the forthcoming decades.

Global population profile of tropical cyclone exposure from 2002 to 2019.

Tropical cyclones have far-reaching impacts on livelihoods and population health that often persist years after the event1-4. Characterizing the demographic and socioeconomic profile and the vulnerabilities of exposed populations is essential to assess health and other risks associated with future tropical cyclone events5. Estimates of exposure to tropical cyclones are often regional rather than global6 and do not consider population vulnerabilities7. Here we combine spatially resolved annual demographic estimates with tropical cyclone wind fields estimates to construct a global profile of the populations exposed to tropical cyclones between 2002 and 2019. We find that approximately 560 million people are exposed yearly and that the number of people exposed has increased across all cyclone intensities over the study period. The age distribution of those exposed has shifted away from children (less than 5 years old) and towards older people (more than 60 years old) in recent years compared with the early 2000s. Populations exposed to tropical cyclones are more socioeconomically deprived than those unexposed within the same country, and this relationship is more pronounced for people exposed to higher-intensity storms. By characterizing the patterns and vulnerabilities of exposed populations, our results can help identify mitigation strategies and assess the global burden and future risks of tropical cyclones.

Semantic encoding during language comprehension at single-cell resolution.

From sequences of speech sounds1,2 or letters3, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing4-12, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a fine-scale cortical representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Moreover, rather than responding to the words as fixed memory representations, their activities were highly dynamic, reflecting the words' meanings based on their specific sentence contexts and independent of their phonetic form. Collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real time during speech and how they tracked the sentences in which they appeared. We also show how they encoded the hierarchical structure of these meaning representations and how these representations mapped onto the cell population. Together, these findings reveal a finely detailed cortical organization of semantic representations at the neuron scale in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.

Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

Single-cell multiplex chromatin and RNA interactions in ageing human brain.

Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA1-3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells4-7. Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and RNA-chromatin associations within individual nuclei. When applied to 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types and states. We observed that nuclei exhibiting fewer short-range chromatin interactions were correlated with both an 'older' transcriptomic signature and Alzheimer's disease pathology. Furthermore, the cell type exhibiting chromatin contacts between cis expression quantitative trait loci and a promoter tends to be that in which these cis expression quantitative trait loci specifically affect the expression of their target gene. In addition, female cortical cells exhibit highly heterogeneous interactions between XIST non-coding RNA and chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploration of chromatin architecture and transcription at cellular resolution in complex tissues.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.

Single-cell multiregion dissection of Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1-3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.

A concerted neuron-astrocyte program declines in ageing and schizophrenia.

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

An enterococcal phage-derived enzyme suppresses graft-versus-host disease.

Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT)1-6. However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD7-10. Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD.

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity.

Inflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%-33% depending on the study). This proportion is increased in the youngest subsets, which is diagnosed prior to the age of 2. To date, there are approximately 80 monogenic causes of VEOIBD that have been identified and published. Many of these monogenic causes are inborn errors of immunity yet the majority of VEOIBD patients do not have an identifiable genetic cause for their disease. In this review, we will focus on the clinical presentation, evaluation, and monogenic categories which have been associated with VEOIBD including (1) Epithelial cell defects (2) Adaptive immune defects, (3) Innate Immune/Bacterial Clearance and Recognition defects, and (4) Hyperinflammatory and autoinflammatory disorders. We will highlight differential diagnosis of VEOIBD presentations, as well as evaluation and treatment, which will be helpful for those who study and care for VEOIBD patients outside of the pediatric gastroenterology field. This is a fast-moving field of research which has grown significantly based on knowledge that we gain from our patients. These scientific findings have identified novel mucosal biology pathways and will continue to inform our understanding of gastrointestinal biology.

Human autoantibodies neutralizing type I IFNs: From 1981 to 2023.

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID-19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto-Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto-Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto-Abs, focusing particularly on their known causes and consequences.

The genetic landscape of age-related hearing loss.

Age-related hearing loss (ARHL) is a prevalent concern in the elderly population. Recent genome-wide and phenome-wide association studies (GWASs and PheWASs) have delved into the identification of causative variants and the understanding of pleiotropy, highlighting the polygenic intricacies of this complex condition. While recent large-scale GWASs have pinpointed significant SNPs and risk variants associated with ARHL, the detailed mechanisms, encompassing both genetic and epigenetic modifications, remain to be fully elucidated. This review presents the latest advances in association studies, integrating findings from both human studies and model organisms. By juxtaposing historical perspectives with contemporary genomics, we aim to catalyze innovative research and foster the development of novel therapeutic strategies for ARHL.