Daily Respiratory Research Analysis

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease with poorly understood pathogenesis. Here, we identify reduced lysine β-hydroxybutyrylation (Kbhb) of the focal adhesion protein Zyxin in bleomycin (BLM)-induced pulmonary fibrosis in mice. In a BLM-induced mouse model, we observe a significant reduction in lung tissue Kbhb levels, while β-hydroxybutyrate (β-OHB) supplementation restores Kbhb modification, there by mitigating fibrosis. Transcriptome profiling suggests that β-OHB exerts anti-fibrotic effects by modulating the PI3K/AKT pathway. Proteomic analysis further reveals a decrease in Kbhb modification at the K263 site of Zyxin in IPF mice. In vivo experiments demonstrate that Zyxin knockout or β-OHB treatment markedly alleviates fibrotic pathology and reduces collagen deposition as well as mouse mortality. This study is the first to elucidate the mechanism by which Zyxin Kbhb modification suppresses pulmonary fibrosis via the PI3K/AKT pathway, offering a novel metabolic modification-based therapeutic strategy for IPF.

Respiratory syncytial virus (RSV) infection poses a considerable disease burden worldwide. Although multiple studies have estimated the short-term effects of ambient temperature on mortality and morbidity, the burden of RSV attributable to temperature is poorly characterized. This nationwide study aimed to quantify the total burden of RSV infection in Japan attributable to non-optimum ambient temperature conditions, and to partition this burden into contributions from low and high temperatures and from moderate and extreme components of non-optimum temperature. We collected weekly time-series data on the number of reported RSV cases and meteorological variables (mean temperature, relative humidity, wind speed, and sunshine duration) for all 47 Japanese prefectures from 2006 to 2019. An extended two-stage approach was used: First, a time-stratified case-crossover design fitted with conditional quasi-Poisson regression was used to estimate prefecture-specific associations. Second, multivariate random-effects meta-analysis was used to obtain pooled estimates. The number of attributable cases were estimated for temperatures above and below the optimum minimum morbidity temperature (MMT) and further categorized as moderate or extreme using the 2.5th and 97.5th percentiles as cutpoints. Data on 1,227,012 RSV cases reported during the study period were analyzed. The pooled exposure-response relationship between temperature and RSV incidence was U-shaped, with a higher RSV incidence at both low and high temperature levels. In most prefectures the MMT was between the 40th to 50th percentiles of the local temperature distribution. Overall, 21.32% (95% empirical confidence interval [eCI] 18.93% to 22.78%) of cases were attributable to non-optimum temperature, with marked geographic heterogeneity: from 8.24% (95% eCI: - 9.06-21.12%) in Akita, to 32.63% (95% eCI: 27.86-41.78%) in Kagoshima. A greater share of temperature-attributable cases was due to moderate high temperatures (12.27%, 95% eCI: 10.95-13.19%) than to low temperatures (9.05%, 95% eCI: 7.12-10.36%), whereas the contributions of extremely high and extremely low temperatures were relatively small. High weekly mean ambient temperatures over lag 0-3 weeks were associated with a substantial attributable risk of RSV infection. Public health efforts to reduce the RSV burden should take ambient temperature into account, paying particular attention to the impact of sustained, moderately warm conditions.

Coronaviruses and influenza A viruses are major respiratory pathogens with pandemic potential. Using pigs as a translational large-animal model, we compare the virulence, pathogenesis, and immune responses to porcine respiratory coronavirus (PRCV) and pandemic H1N1 2009 influenza virus (pH1N1). Here we show that PRCV induces higher viral load and prolonged viral shedding, stronger systemic and mucosal T cell activation, expansion of memory B cells, and distinct nasal microbiome changes. In contrast, pH1N1 results in rapid neutralising antibody production, robust Tfh and germinal centre B cell responses, and broader early nasal microbial diversity. Transcriptional responses to PRCV and pH1N1 infection start with the activation of shared interferon-stimulated genes but later diverge as pathways involving stromal-immune interactions and vascular integrity shapes lung pathology and subsequent immune responses. These findings demonstrate fundamental differences in coronavirus and influenza virus-host interactions and establish the pig as a powerful comparative model for studying respiratory virus pathogenesis and immunity.