Dataset Information

Immune Network Modeling Predicts Specific Nasopharyngeal and Peripheral Immune Dysregulation in Otitis-Prone Children.

ABSTRACT: Acute otitis media (AOM) pathogenesis involves nasopharyngeal colonization by potential otopathogens and a viral co-infection. Stringently-defined otitis prone (sOP) children show characteristic patterns of immune dysfunction. We hypothesized that otitis proneness is largely a result of altered signaling between immune components that are otherwise competent, resulting in increased susceptibility to infection by bacterial otopathogens. To test this, we constructed a regulatory immune network model linking immune cells and signaling elements known to be involved in AOM and/or dysregulated in sOP children. The alignment of immune response mechanisms with data from in vivo and in vitro experimental observations produced 82 putative immune network models, each describing variants of immune regulatory networks consistent with available observations. Analysis of these models suggested that new measurements of serum levels of IL-4 and CXCL8 could refine competing models and resulted in the elimination of 38 of the models. Further analysis of the remaining 44 models suggested specific deviations in the predicted regulation of nasopharyngeal and peripheral immunity during response to AOM. Specifically, immune responses active in sOP children during AOM were characterized by early and constitutive activation of pro-inflammatory signaling in the nasopharynx and a Th2- and Treg-dominated profile in the periphery. We conclude that sOP children have altered regulation of key immune mediators during both health and pathogenesis. This altered regulation may be amenable to therapeutic intervention.

SUBMITTER: Morris MC

PROVIDER: S-EPMC7301607 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Immune Network Modeling Predicts Specific Nasopharyngeal and Peripheral Immune Dysregulation in Otitis-Prone Children.

Morris Matthew C MC Chapman Timothy J TJ Pichichero Michael E ME Broderick Gordon G

Frontiers in immunology 20200611

Acute otitis media (AOM) pathogenesis involves nasopharyngeal colonization by potential otopathogens and a viral co-infection. Stringently-defined otitis prone (sOP) children show characteristic patterns of immune dysfunction. We hypothesized that otitis proneness is largely a result of altered signaling between immune components that are otherwise competent, resulting in increased susceptibility to infection by bacterial otopathogens. To test this, we constructed a regulatory immune network mod ...[more]

PMID: 32595639

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Project description:Expression profiles of 22 reference Arabidopsis immunity mutants were collected using the Arabidopsis Pathoarray 464_001 (GPL3638) in order to build a network model predicting the Arabidopsis immune signaling network. Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. Here, we demonstrate that use of mRNA profiling to collect and analyze detailed descriptions of changes in the network state resulting from specific network perturbations is a powerful and economical strategy to elucidate regulatory relationships among the components of a complex signaling network. Specifically, we studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2). This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with the Pto DC3000 AvrRpt2 and used as detailed descriptions of the network states resulting from specific genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting network model accurately predicted 22 of 23 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i) the components of the network are highly interconnected; (ii) negative regulatory relationships are common between signaling sectors. One case of a novel negative regulatory relationship, between the early microbe-associated molecular pattern (MAMP)-activated sector and the salicylic acid (SA)-mediated sector, was further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a "sector-switching" network, which effectively balances two apparently conflicting demands, robustness against pathogenic perturbations and moderation of negative impacts of immune responses on plant fitness. Keywords: Responses of reference Arabidopsis immunity mutants to Pseudomonas syringae pv. tomato DC3000 carrying avrRpt2 This experiment consists of two (group00) or three (group01-04) biological replicates of each genotype (total 25 genotypes [3 are multiple mutants, which were removed for the network modeling, but were used for normalization]). For each genotype, two leaves per plant were pooled from three pots to prepare total RNA.

Dataset Information

Immune Network Modeling Predicts Specific Nasopharyngeal and Peripheral Immune Dysregulation in Otitis-Prone Children.

Publications

Immune Network Modeling Predicts Specific Nasopharyngeal and Peripheral Immune Dysregulation in Otitis-Prone Children.

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