Cai, L. P. | Search bioRxiv

bioRxiv2021

Long-term effects of wildfire smoke exposure during early-life on the nasal epigenome in rhesus macaques

BackgroundWildfire smoke is responsible for around 20% of all particulate emissions in the U.S. and affects millions of people worldwide. Children are especially vulnerable, as ambient air pollution exposure during early childhood is associated with reduced lung function. Most studies, however, have focused on the short-term impacts of wildfire smoke exposures. We aimed to identify long-term baseline epigenetic changes associated with early-life exposure to wildfire smoke. We collected nasal epithelium samples for whole genome bisulfite sequencing (WGBS) from two groups of adult female rhesus macaques: one group born just before the 2008 California wildfire season and exposed to wildfire smoke during early-life (n = 8), and the other group born in 2009 with no wildfire smoke exposure during early-life (n = 14). RNA-sequencing was also performed on a subset of these samples. ResultsWe identified 3370 differentially methylated regions (DMRs) (difference in methylation [≥] 5% empirical p < 0.05) and 1 differentially expressed gene (FLOT2) (FDR< 0.05, fold of change [≥] 1.2). The DMRs were annotated to genes significantly enriched for synaptogenesis signaling, protein kinase A signaling, and a variety of immune processes, and some DMRs significantly correlated with gene expression differences. DMRs were also significantly enriched within regions of bivalent chromatin (top odds ratio = 1.46, q-value < 3 x 10-6) that often silence key developmental genes while keeping them poised for activation in pluripotent cells. ConclusionsThese data suggest that early-life exposure to wildfire smoke leads to long-term changes in the methylome over genes impacting the nervous and immune systems, but follow-up studies will be required to test whether these changes influence transcription following an immune/respiratory challenge.

genomics↗

bioRxiv2018

CagY-dependent regulation of type IV secretion in Helicobacter pylori is associated with alterations in integrin binding

Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4+ T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human 5{beta}1 integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to 5{beta}1 integrin. Using a cell-free microfluidic assay, we found that H. pylori binding to 5{beta}1 integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed when H. pylori is in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to 5{beta}1 integrin. Bacteria with variant cagY alleles that reduced T4SS function showed comparable reduction in binding to 5{beta}1 integrin, though CagY was still expressed on the bacterial surface. We speculate that cagY-dependent modulation of H. pylori T4SS function is mediated by alterations in binding to 5{beta}1 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection.\n\nIMPORTANCEInfection with H. pylori can cause peptic ulcers, and is the most important risk factor for gastric cancer, the third most common cause of cancer death worldwide. The major H. pylori virulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We previously showed that recombination in CagY, an essential T4SS component, modulates the function of the T4SS. Here we found that these recombination events produce parallel changes in specific binding to 5{beta}1 integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. We propose that CagY-dependent binding to 5{beta}1 integrin acts like a molecular rheostat that alters T4SS function and modulates the host immune response to promote persistent infection.

microbiology↗