Biology subjects

Imai, N.

Publications and source records attributed to Imai, N..

7 recordsLinked to original sources

bioRxiv2022

Immunological landscape of human lymph nodes during ex vivo measles virus infection

In humans, lymph nodes are the primary site of measles virus (MeV) replication. To understand the immunological events that occur at this site, we infected human lymphoid tissue explants using a pathogenic strain of MeV that expresses GFP. We found that MeV infected between 5-15% of cells across donors. Using single cell RNA-Seq (scRNA-Seq) and flow cytometry, we found that while most of the 29 cell populations identified in the lymphoid culture were susceptible to MeV, there was a broad preferential infection of B cells and reduced infection of T cells. Further subsetting of T cells revealed that this reduction may be driven by the decreased infection of naive T cells. Transcriptional changes in infected B cells were dominated by an interferon stimulated gene (ISG) signature. To determine which of these ISGs were most substantial, we evaluated the proteome of MeV-infected Raji cells by mass spectrometry. We found that IFIT1, IFIT2, IFIT3, ISG15, CXCL10, MX2, and XAF1 proteins were the most highly induced, and positively correlated with their expression in the transcriptome. These data provide insight into the immunological events that occur in lymph nodes during infection and may lead to the development of therapeutic interventions.

immunology↗

bioRxiv2021

Suppression of Fatty Acid Oxidation by Thioesterase Superfamily Member 2 in Skeletal Muscle Promotes Hepatic Steatosis and Insulin Resistance

Thioesterase superfamily member 2 (Them2) is highly expressed in oxidative tissues where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/-) are protected against diet-induced obesity, insulin resistance and hepatic steatosis, liver-specific Them2-/- mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle (S-Them2-/-), cardiac muscle (C-Them2-/-) or adipose tissue (A-Them2-/-). When fed a high-fat diet, S-Them2-/- but not C-Them2-/- or A-Them2-/- mice exhibited reduced weight gain. Only S-Them2-/- mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis in S-Them2-/- mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.

molecular biology↗

bioRxiv2020

Thioesterase Superfamily Member 1 Undergoes Stimulus-coupled Reorganization to Regulate Metabolism

In brown adipose tissue, cold exposure promotes thermogenesis, in large part by increasing mitochondrial {beta}-oxidation of lipid droplet-derived fatty acids. This process is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is highly upregulated by cold ambient temperatures. Them1 reduces fatty acid availability for {beta}-oxidation in mitochondria and limits thermogenesis by cellular mechanisms that are not well defined. We show that Them1 regulates metabolism by undergoing marked intracellular conformational changes that occur in response to {beta}-adrenergic stimulation. Mechanistically, Them1 formed puncta that were localized near LD and mitochondria in an immortalized brown adipose cell line. In response to stimulation by norepinephrine, Them1 was phosphorylated by PKC{beta} at S15, which specifically inhibited puncta formation and resulted in a diffuse intracellular localization. This change in Them1 localization also occurred after stimulation in vivo. Puncta formation activated Them1 metabolic activity in vitro, as evidenced by suppression of oxygen consumption following {beta}-adrenergic stimulation. We show by correlative light and electron microscopy that puncta are biomolecular condensates (also known as membraneless organelles) that typically form by phase separation. Them1 contains one intrinsically disordered region at the N-terminus with multiple interacting motifs that is frequently observed in phase-separating proteins. Phosphorylation, which is known to disrupt phase separation and aggregation, results in a diffuse Them1 localization. Our data thus establish that Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 thus provides fine-tuning of thermogenesis and energy expenditure.

cell biology↗

bioRxiv2020

Allosteric regulation of Thioesterase Superfamily Member 1 by free fatty acids and lysophosphatidylcholine

Non-shivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally upregulated in brown adipose tissue upon cold exposure and suppresses thermogenesis to conserve energy reserves. Them1 hydrolyzes long-chain fatty acyl-CoAs, preventing their use as fuel for thermogenesis. Them1 contains a C-terminal StAR-related lipid transfer domain (StarD) with unknown ligand or function. By complementary biophysical approaches, we show that StarD binds to long-chain fatty acids, products of Them1s enzymatic reaction, as well lysophosphatidylcholine (LPC), which activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the StarD and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the StarD functions to localize Them1 near lipid droplets. These findings define the role of the StarD as a lipid sensor that allosterically regulates Them1 activity and localization.

biochemistry↗

bioRxiv2018

Spatiotemporal Variability in Dengue Transmission Intensity in Jakarta, Indonesia

BackgroundApproximately 70% of the global burden of dengue disease occurs on the Asian continent, where many large urban centres provide optimal environments for sustained endemic transmission and periodic epidemic cycles. Jakarta, the capital of Indonesia, is a densely populated megacity with hyperendemic dengue transmission. Characterization of the spatiotemporal distribution of dengue transmission intensity is of key importance for optimal implementation of novel control and prevention programmes, including vaccination. In this paper we use mathematical models to provide the first detailed description of spatial and temporal variability in dengue transmission in Jakarta.\n\nMethodology/Principal FindingsWe applied catalytic models in a Bayesian framework to age-stratified dengue case notification data to estimate dengue force of infection and reporting probabilities in 42 subdistricts of Jakarta. The model was fit to yearly and average annual data covering a 10- year period between 2008 and 2017. We estimated a long-term average annual transmission intensity of 13.0% (95%CrI: 12.9-13.1%) per year in Jakarta province, ranging from 9.0% (95%CrI: 7.7-10.3%) to 16.4% (95%CrI: 15.3-17.4%) across subdistricts. Annual average transmission intensity in Jakarta province during the 10-year period ranged from 1.2% (95%CrI: 1.1-1.3%) in 2017 to 12.4% (95%CrI: 12.1-12.8%) in 2016.\n\nConclusions/SignificanceWhile the absolute number of dengue case notifications cannot be relied upon as a measure of endemicity, the age-distribution of reported dengue cases provides valuable insights into the underlying nature of transmission. Our estimates from yearly and average annual case notification data represent the first detailed estimates of dengue transmission intensity in Jakartas subdistricts, which will be important to consider when assessing the population-level impact and cost-effectiveness of potential control and prevention programmes in Jakarta province, such as the controlled release of Wolbachia-carrying mosquitoes and vaccination.

epidemiology↗

bioRxiv2017

Targeting Vaccinations for the Licensed Dengue Vaccine: Considerations for Serosurvey Design

ObjectiveWHO recommends countries consider dengue vaccination in geographic settings only where epidemiological data indicate a high burden of disease. In defining target populations, WHO recommend that prior infection with any dengue serotype should be >70% seroprevalence. Here we address considerations for serosurvey design in the context of the newly licensed CYD-TDV vaccine.\n\nMethodsTo explore how the design of seroprevalence surveys (age range, survey size) would affect estimates of the force of infection, for every combination of age range, total survey size, transmission setting, and test sensitivity/specificity, 100 age-specific seroprevalence surveys were simulated using a beta-binomial distribution and a simple catalytic model. The transmission intensity was then re-estimated using a Metropolis-Hastings Markov Chain Monte-Carlo algorithm.\n\nFindingsSampling from a wide age range led to more accurate estimates than having a larger sample size. This finding was consistent across all transmission settings. The optimal age range to sample from differed by transmission intensity, with younger and older ages being important in high and low transmission settings respectively. The optimum test sensitivity and specificity given an imperfect test also differed by transmission setting with high sensitivity being important in high transmission settings and high specificity important in low transmission settings.\n\nConclusionsWhen assessing the suitability for vaccination by seroprevalence surveys, countries should ensure that an appropriate age range is sampled, taking into account epidemiological evidence about the local burden of dengue.

epidemiology↗

bioRxiv2017

International risk of yellow fever spread from the ongoing outbreak in Brazil

The largest Yellow Fever (YF) outbreak in a decade in Latin America is underway in the Southeast of Brazil. In this article we provide a quantitative assessment of the risk of travel-related international spread of YF. We argue that mitigating the risk of imported YF cases seeding local transmission requires heightened surveillance in the southern United States, Latin America (especially Argentina, Chile and Uruguay) and Europe (especially Portugal, Spain, Italy and Germany).

epidemiology↗