Activating transcription factor 5 (ATF5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice.

Intestinal tuft cells, a chemosensory cell type in mucosal epithelia that secrete interleukin (IL)-25, play a pivotal role in type 2 immune responses triggered by parasitic infections. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2) to secrete IL-13, which, in turn, acts on intestinal stem or transient amplifying cells to expand tuft cells themselves and mucus-secreting goblet cells. However, the molecular mechanisms of tuft cell differentiation under type 2 immune responses remain unclear. The present study investigated the effects of the deletion of activating transcription factor 5 (ATF5) on the type 2 immune response triggered by succinate (a metabolite of parasites) in mice. ATF5 mRNAs were expressed in the small intestine, and the loss of the ATF5 gene did not affect the gross morphology of the tissue or the basal differentiation of epithelial cell subtypes. Succinate induced marked increases in tuft and goblet cell numbers in the ATF5-deficient ileum. Tuft cells in the ATF5-deficient ileum are assumed to be a subtype of intestinal tuft cells (Tuft-2 cells) marked by the transcription factor Spib. Exogenous IL-25 induced similar increases in tuft and goblet cell numbers in wild-type and ATF5-deficient ilea. IL-13 at a submaximal dose enhanced tuft cell differentiation more in ATF5-deficient than in wild-type intestinal organoids. These results indicate that the loss of ATF5 enhanced the tuft cell-ILC2 type 2 immune response circuit by promoting tuft cell differentiation in the small intestine, suggesting its novel regulatory role in immune responses against parasitic infections.

Modeling the Impact of Ensitrelvir on SARS-CoV-2 Dynamics and Its Application for Assessment of Transmission Mitigation of Patients with COVID-19.

INTRODUCTION: Mathematical modeling can provide quantitative understanding of the viral dynamics and viral reduction effects of drugs and enable simulations of the dynamics in various scenarios. In this study, a drug effect model of ensitrelvir was developed to describe the viral reduction effect. Using the model, we also estimated the impact of treatment with ensitrelvir on the reduction in the number of infected patients at the population level in Japan. METHODS: The drug effect model of ensitrelvir was developed based on a viral dynamic model for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a population pharmacokinetic model of ensitrelvir using 10,477 samples of viral load from 1447 patients with coronavirus disease 2019 (COVID-19) in a phase 2/3 study. It was assumed that the drug effect on SARS-CoV-2 promoted the viral clearance depending on the free plasma concentrations. We estimated the impact of ensitrelvir treatment on the reduction in the number of infected patients at the population level in Japan using the susceptible-infectious-recovered-susceptible (SIRS) model including transmission mitigation. RESULTS: The viral reduction effect of ensitrelvir was characterized as a promotion of viral clearance depending on the plasma ensitrelvir concentrations using the Emax model. The maximum reduction effect was considered to depend on the time from symptom onset to treatment. The maximum transmission mitigation effect was observed when treatment was initiated within 12-24 h of symptom onset, and secondary infections could be reduced by administering ensitrelvir as soon as possible after symptom onset. CONCLUSION: The viral reduction by ensitrelvir could be characterized based on the viral dynamics, and the dynamics could be estimated using the drug effect model. Furthermore, the drug effect on population level transmission based on the dynamics could be estimated. Thus, the simulation could be conducted for various conditions.

Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial.

BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

Origin and evolutionary history of domestic chickens inferred from a large population study of Thai red junglefowl and indigenous chickens.

In this study, we aimed to elucidate the origin of domestic chickens and their evolutionary history over the course of their domestication. We conducted a large-scale genetic study using mitochondrial DNA D-loop sequences and 28 microsatellite DNA markers to investigate the diversity of 298 wild progenitor red junglefowl (Gallus gallus) across two subspecies (G. g. gallus and G. g. spadiceus) from 12 populations and 138 chickens from 10 chicken breeds indigenous to Thailand. Twenty-nine D-loop sequence haplotypes were newly identified: 14 and 17 for Thai indigenous chickens and red junglefowl, respectively. Bayesian clustering analysis with microsatellite markers also revealed high genetic diversity in the red junglefowl populations. These results suggest that the ancestral populations of Thai indigenous chickens were large, and that a part of the red junglefowl population gene pool was not involved in the domestication process. In addition, some haplogroups that are distributed in other countries of Southeast Asia were not observed in either the red junglefowls or the indigenous chickens examined in the present study, suggesting that chicken domestication occurred independently across multiple regions in Southeast Asia.

Geographic Origin and Genetic Characteristics of Japanese Indigenous Chickens Inferred from Mitochondrial D-Loop Region and Microsatellite DNA Markers.

Japanese indigenous chickens have a long breeding history, possibly beginning 2000 years ago. Genetic characterization of Japanese indigenous chickens has been performed using mitochondrial D-loop region and microsatellite DNA markers. Their phylogenetic relationships with chickens worldwide and genetic variation within breeds have not yet been examined. In this study, the genetic characteristics of 38 Japanese indigenous chicken breeds were assessed by phylogenetic analyses of mitochondrial D-loop sequences compared with those of indigenous chicken breeds overseas. To evaluate the genetic relationships among Japanese indigenous chicken breeds, a STRUCTURE analysis was conducted using 27 microsatellite DNA markers. D-loop sequences of Japanese indigenous chickens were classified into five major haplogroups, A-E, among 15 haplogroups found in chickens worldwide. The haplogroup composition suggested that Japanese indigenous chickens originated mainly from China, with some originating from Southeast Asia. The STRUCTURE analyses revealed that Japanese indigenous chickens are genetically differentiated from chickens overseas; Japanese indigenous chicken breeds possess distinctive genetic characteristics, and Jidori breeds, which have been reared in various regions of Japan for a long time, are genetically close to each other. These results provide new insights into the history of chickens around Asia in addition to novel genetic data for the conservation of Japanese indigenous chickens.

Molecular cytogenetic characterization of repetitive sequences comprising centromeric heterochromatin in three Anseriformes species.

The highly repetitive DNA sequence of centromeric heterochromatin is an effective molecular cytogenetic marker for investigating genomic compartmentalization between macrochromosomes and microchromosomes in birds. We isolated four repetitive sequence families of centromeric heterochromatin from three Anseriformes species, viz., domestic duck (Anas platyrhynchos, APL), bean goose (Anser fabalis, AFA), and whooper swan (Cygnus cygnus, CCY), and characterized the sequences by molecular cytogenetic approach. The 190-bp APL-HaeIII and 101-bp AFA-HinfI-S sequences were localized in almost all chromosomes of A. platyrhynchos and A. fabalis, respectively. However, the 192-bp AFA-HinfI-L and 290-bp CCY-ApaI sequences were distributed in almost all microchromosomes of A. fabalis and in approximately 10 microchromosomes of C. cygnus, respectively. APL-HaeIII, AFA-HinfI-L, and CCY-ApaI showed partial sequence homology with the chicken nuclear-membrane-associated (CNM) repeat families, which were localized primarily to the centromeric regions of microchromosomes in Galliformes, suggesting that ancestral sequences of the CNM repeat families are observed in the common ancestors of Anseriformes and Galliformes. These results collectively provide the possibility that homogenization of centromeric heterochromatin occurred between microchromosomes in Anseriformes and Galliformes; however, homogenization between macrochromosomes and microchromosomes also occurred in some centromeric repetitive sequences.