The rockefeller university

Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (T(H)2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b(+)OX40L(+) dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate T(H)2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance. Abraham and colleagues show that a highly polarized T(H)2 bladder response to urinary tract infections promotes epithelial repair at the expense of preventing new infections and associated bladder dysfunction.

Genes with sex-biased expression in Drosophila are thought to underlie sexually dimorphic phenotypes and have been shown to possess unique evolutionary properties. However, the forces and constraints governing the evolution of sex-biased genes in the somatic tissues of Drosophila are largely unknown. By using population-scale RNA sequencing data, we show that sex-biased genes in the Drosophila brain are highly enriched on the X Chromosome and that most are biased in a species-specific manner. We show that X-linked male-biased genes, and to a lesser extent female-biased genes, are enriched for signatures of directional selection at the gene expression level. By examining the evolutionary properties of gene-flanking regions on the X Chromosome, we find evidence that adaptive cis-regulatory changes are more likely to drive the expression evolution of X-linked male-biased genes than other X-linked genes. Finally, we examine whether constraint owing to broad expression across multiple tissues and genetic constraint owing to the largely shared male and female genomes could be responsible for the observed patterns of gene expression evolution. We find that expression breadth does not constrain the directional evolution of gene expression in the brain. Additionally, we find that the shared genome between males and females imposes a substantial constraint on the expression evolution of sex-biased genes. Overall, these results significantly advance our understanding of the patterns and forces shaping the evolution of sexual dimorphism in the Drosophila brain.

Opioid use disorder (OUD) is a chronic, relapsing disease. Genetic variability, dysregulated stress system response, and history of opioid experimentation or escalating exposure all contribute to the likelihood of developing OUD, which produces complex brain changes that make it difficult to stop opioid use. Understanding the neurobiology of OUD helps nurses anticipate the behaviors of patients with OUD and approach them with empathy. Here, the authors discuss the pathophysiology of OUD, available screening tools, medical treatments, and behavioral interventions that have demonstrated efficacy in reducing substance use.

Purpose TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214. Donor B cell receptor (BCR) repertoires identified two bNAb lineages, M4008_N1 and M1214_N1, that class-switched to immunoglobulin G (IgG) and IgA. Variants of these bNAbs reconstituted as IgA demonstrated broadly neutralizing activity, and the IgA fraction of M1214 plasma conferred neutralization. M4008_N1 epitope mapping revealed a glycan-independent V3 epitope conferring tier 2 virus neutralization. A 4.86-angstrom-resolution cryogenic electron microscopy (cryo-EM) structure of M1214_N1 complexed with CH505 SOSIP revealed another elongated epitope, the V2V5 corridor, extending from V2 to V5. Overall, the VSVENV probe identified bNAb lineages with neutralizing IgG and IgA members targeting distinct sites of HIV-1 Env vulnerability.

Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 mu gml(-1) correlated with >= 99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-alpha/beta immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.

Cocaine use disorders (CUD) cause major morbidity and optimized prevention efforts are critical. It is unclear if trait impulsivity and exposure to cannabis or alcohol are associated with age trajectory of cocaine use (e.g., age of onset of heaviest use, or time of escalation), or with vulnerability to develop a CUD. This is an observational study with volunteers (>= 18 years old), from a metropolitan area. The sample (n = 1,010) included: n = 360 normal volunteers, n = 438 with cocaine dependence (CD) diagnoses, and n = 212 with other addictive diseases. Trait impulsivity was examined with BIS-11 scores. Maximal self-exposure to cannabis, alcohol, and cocaine were characterized dimensionally with Kreek-McHugh-Schluger-Kellogg (KMSK) scales. Time of escalation was defined as the interval between age of first use and age of onset of heaviest use. Onset of maximal use of cannabis (median age = 17) and alcohol (median age = 21) preceded that of cocaine (median age = 27), in volunteers with CD. Multivariate Cox regressions in volunteers with CD show that increasing self-exposure to cannabis was a predictor of earlier onset of heaviest use of cocaine. Also, more rapid time of escalation of alcohol was a predictor of more rapid time of escalation of cocaine. A multiple logistic regression shows that increasing self-exposure to cannabis or alcohol was a positive predictor of odds of CD diagnosis. Trait impulsivity and gender were not significant predictors in these multivariate analyses. This study shows that aspects of adolescent exposure to nonmedical cannabis and alcohol are predictors of early onset of CUD, and may be potentially targeted for prevention efforts.

Human papillomaviruses (HPVs) infect mucosal or cutaneous stratified epithelia. There are 5 genera and more than 200 types of HPV, each with a specific tropism and virulence. HPV infections are typically asymptomatic or result in benign tumors, which may be disseminated or persistent in rare cases, but a few oncogenic HPVs can cause cancers. This review deals with the human genetic and immunological basis of interindividual clinical variability in the course of HPV infections of the skin and mucosae. Typical epidermodysplasia verruciformis (EV) is characterized by beta-HPV-driven flat wart-like and pityriasis-like cutaneous lesions and non-melanoma skin cancers in patients with inborn errors of EVER1-EVER2-CIB1-dependent skin-intrinsic immunity. Atypical EV is associated with other infectious diseases in patients with inborn errors of T cells. Severe cutaneous or anogenital warts, including anogenital cancers, are also driven by certain alpha-, gamma-, mu or nu-HPVs in patients with inborn errors of T lymphocytes and antigen-presenting cells. The genetic basis of HPV diseases at other mucosal sites, such as oral multifocal epithelial hyperplasia or juvenile recurrent respiratory papillomatosis (JRRP), remains poorly understood. The human genetic dissection of HPV-driven lesions will clarify the molecular and cellular basis of protective immunity to HPVs, and should lead to novel diagnostic, preventive, and curative approaches in patients.

Background: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell based molecular alterations are largely unknown. Objective: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. Methods: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10x Genomics. Results: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5(+)COL18A1(+) subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3(+) dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A(+) FCER1A(+)) and tissue-resident memory T cells (CD69(+)CD103(+)). The frequencies of type 2 (IL1(3+))/type 22 (IL22(+)) T cells were higher than those of type 1 (IFNG(+)) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. Conclusion: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.