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IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming.

ABSTRACT: High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups.

SUBMITTER: de Jong E

PROVIDER: S-EPMC8339879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To describe microbiota profiles considering potential influencing factors in pre-school children with recurrent respiratory tract infections (rRTIs) and to evaluate microbiota changes associated with oral bacterial lysate OM-85 treatment, we analyzed gut and nasopharynx (NP) microbiota composition in patients included in the OM-85-pediatric rRTIs (OMPeR) clinical trial (https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002705-19/IT). Relative percentage abundance was used to describe microbiota profiles in all the available biological specimens, grouped by age, atopy, and rRTIs both at inclusion (T0) and at the end of the study, after treatment with OM-85 or placebo (T1). At T0, Firmicutes and Bacteriodetes were the predominant genera in gut and Proteobacteria, Firmicutes, and Actinobacteria were the predominant genera in NP samples. Gut microbiota relative composition differed with age (<2 vs. ≥2 years) for Firmicutes, Proteobacteria, Actinobacteria (phyla) and Bifidobacterium, Ruminococcus, Lachnospiraceae (genera) (p < 0.05). Moraxella was more enriched in the NP of patients with a history of up to three RTIs. Intra-group changes in relative percentage abundance were described only for patients with gut and NP microbiota analysis available at both T0 and T1 for each study arm. In this preliminary analysis, the gut microbiota seemed more stable over the 6-month study in the OM-85 group, whose mean age was lower, as compared to the placebo group (p = 0.004). In this latter group, the relative abundance of Bacteroides decreased significantly in children ≥2 years. Some longitudinal significant differences in genera relative abundance were also detected in children of ≥2 years for NP Actinobacteria, Haemophilus, and Corynebacterium in the placebo group only. Due to the small number of patients in the different sub-populations, we could not identify significant differences in the clinical outcome and therefore no associations with microbiota changes were searched. The use of bacterial lysates might play a role in microbiota rearrangement, but further data and advanced analysis are needed to prove this in less heterogeneous populations with higher numbers of samples considering the multiple influencing factors such as delivery method, age, environment, diet, antibiotic use, and type of infections to ultimately show any associations with prevention of rRTIs.

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IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming.

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