Oral bacteria in the occluded arteries of patients with Buerger disease

ObjectiveRecent studies have suggested that infectious organisms play a role in vascular diseases. In this study, to explore a possible link between oral infection and Buerger disease, we investigated whether oral (periodontal) bacteria were present in occluded arteries removed from patients with characteristic Buerger disease.MethodsFourteen male patients with a smoking history who had developed characteristics of Buerger disease before the age of 50 years were included in this study. Occluded arteries, including superficial femoral (n = 4), popliteal (n = 2), anterior tibial (n = 4), and posterior tibial (n = 4) arteries, were removed and studied. A periodontist performed a periodontal examination on each patient and collected dental plaque and saliva samples from them at the same time. The polymerase chain reaction method was applied to detect whether seven species of periodontal bacteria—Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Campylobacter rectus, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Prevotella nigrescens—were present in the occluded arteries and oral samples. In addition, arterial specimens from seven control patients were examined by polymerase chain reaction analysis.ResultsDNA of oral bacteria was detected in 13 of 14 arterial samples and all oral samples of patients with Buerger disease. Treponema denticola was found in 12 arterial and all oral samples. Campylobacter rectus, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis, and Prevotella nigrescens were found in 14% to 43% of the arterial samples and 71% to 100% of the oral samples. A pathologic examination revealed that arterial specimens showed the characteristics of an intermediate-chronic-stage or chronic-stage lesion of Buerger disease. All 14 patients with Buerger disease had moderate to severe periodontitis. None of the control arterial samples was positive for periodontal bacteria.ConclusionsThis is the first study to identify oral microorganisms in the lesions of Buerger disease. Our findings suggest a possible etiologic link between Buerger disease and chronic infections such as oral bacterial infections

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Reduced Expression of Laminin α3 and α5 Chains in Non‐small Cell Lung Cancers

The basement membrane is considered to act as a barrier which hinders cancer cells from invading the surrounding stroma. In order to assess changes in essential components during neoplasia in the lung, we immunohistochemically studied distribution patterns of laminins α3 and α5 in 40 adeno‐carcinomas and 8 squamous cell carcinomas. The α5 chain was generally preserved at the periphery, frequently disrupted in foci with alveolar collapse and absent in foci of fibroblastic proliferation within adenocarcinomas. Fragmentation and absence of laminin α3 chain were more prominent than for α5 chain. Laminin α3 chain was partially fragmented or absent in peripheral areas of adenocarcinomas, being significantly different from α5 chain. Non‐small cell lung cancers with reduced α5 chain showed a tendency for greater lymph node metastasis. In cultured normal air way epithelial cells, both laminin α3 and α5 chains were found to be expressed by northern analysis. Eleven of the twelve cultured lung cancer cell lines did not express a3 chain and expression of α5 chain was reduced in three. Quantitative RT‐PCR analysis also demonstrated expression of laminin α3 chain in adenocarcinoma tissues to be significantly lower than in normal lung tissues. These results suggest that expression of laminin a chains is often reduced in lung cancer cells and this might contribute to basement membrane fragmentation and subsequent proliferation of stromal elements, as well as play some role in the process of cancer cell invasion