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In the present studies, the assessment of how viral exacerbation of asthmatic responses with and without pulmonary steroid treatment alters the microbiome in conjunction with immune responses presents striking data. The overall findings identify that although steroid treatment of allergic animals diminished the severity of the respiratory syncytial virus (RSV)-induced exacerbation of airway function and mucus hypersecretion, there were local increases in IL-17 expression. Analysis of the lung and gut microbiome suggested that there are differences in RSV exacerbation that are further altered by fluticasone (FLUT) treatment. Using metagenomic inference software, PICRUSt2, we were able to predict that the metabolite profile produced by the changed gut microbiome was significantly different with multiple metabolic pathways and associated with specific treatments with or without FLUT. Importantly, measuring plasma metabolites in an unbiased manner, our data indicate that there are significant changes associated with chronic allergen exposure, RSV exacerbation, and FLUT treatment that are reflective of responses to the disease and treatment. In addition, the changes in metabolites appeared to have contributions from both host and microbial pathways. To understand if airway steroids on their own altered lung and gut microbiome along with host responses to RSV infection, naïve animals were treated with lung FLUT before RSV infection. The naïve animals treated with FLUT before RSV infection demonstrated enhanced disease that corresponded to an altered microbiome and the related PICRUSt2 metagenomic inference analysis. Altogether, these findings set the foundation for identifying important correlations of severe viral exacerbated allergic disease with microbiome changes and the relationship of host metabolome with a potential for early life pulmonary steroid influence on subsequent viral-induced disease. NEW & NOTEWORTHY: These studies outline a novel finding that airway treatment with fluticasone, a commonly used inhaled steroid, has significant effects on not only the local lung environment but also on the mucosal microbiome, which may have significant disease implications. The findings further provide data to support that pulmonary viral exacerbations of asthma with or without steroid treatment alter the lung and gut microbiome, which have an impact on the circulating metabolome that likely alters the trajectory of disease progression. [ABSTRACT FROM AUTHOR]

Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive of altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation in RSV-infected DC. Real-time cell metabolic analysis demonstrated increased glycolysis in PARP1-/- DC after RSV infection, confirming a role for PARP1 in regulating DC metabolism. Our data show that enzymatic inhibition or genomic ablation of PARP1 resulted in increased ifnb1, il12, and il27 in RSV-infected DC which, together, promote a more appropriate anti-viral environment. PARP1-/- mice and PARP1-inhibitor-treated mice were protected against RSV-induced immunopathology including airway inflammation, Th2 cytokine production, and mucus hypersecretion. However, delayed treatment with PARP1 inhibitor in RSV-infected mice provided only partial protection, suggesting that PARP1 is most important during the earlier innate immune stage of RSV infection. [ABSTRACT FROM AUTHOR]

Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults.

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8(-/)- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo.

Author(s): Kei E Fujimura [1]; Alexandra R Sitarik [2]; Suzanne Havstad [2]; Din L Lin [1]; Sophia Levan [1]; Douglas Fadrosh [1]; Ariane R Panzer [1]; Brandon LaMere [1]; Elze [...]