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Alternaria alternata Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection.

ABSTRACT: Chronic inhalation of fungi and fungal components has been linked to the development of respiratory disorders, although their role with respect to the pathogenesis of acute respiratory virus infection remains unclear. Here, we evaluate inflammatory pathology induced by repetitive administration of a filtrate of the ubiquitous fungus, Alternaria alternata, and its impact on susceptibility to infection with influenza A. We showed previously that A. alternata at the nasal mucosae resulted in increased susceptibility to an otherwise sublethal inoculum of influenza A in wild-type mice. Here we demonstrate that A. alternata-induced potentiation of influenza A infection was not dependent on fungal serine protease or ribonuclease activity. Repetitive challenge with A. alternata prior to virus infection resulted proinflammatory cytokines, neutrophil recruitment, and loss of alveolar macrophages to a degree that substantially exceeded that observed in response to influenza A infection alone. Concomitant administration of immunomodulatory Lactobacillus plantarum, a strategy shown previously to limit virus-induced inflammation in the airways, blocked the exaggerated lethal response. These observations promote an improved understanding of severe influenza infection with potential clinical relevance for individuals subjected to continuous exposure to molds and fungi.

SUBMITTER: Percopo CM

PROVIDER: S-EPMC7552021 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Alternaria alternata Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection.

Percopo Caroline M CM Ma Michelle M Mai Eric E Redes Jamie L JL Kraemer Laura S LS Minai Mahnaz M Moore Ian N IN Druey Kirk M KM Rosenberg Helene F HF

Viruses 20200827 9

Chronic inhalation of fungi and fungal components has been linked to the development of respiratory disorders, although their role with respect to the pathogenesis of acute respiratory virus infection remains unclear. Here, we evaluate inflammatory pathology induced by repetitive administration of a filtrate of the ubiquitous fungus, Alternaria alternata, and its impact on susceptibility to infection with influenza A. We showed previously that A. alternata at the nasal mucosae resu ...[more]

PMID: 32867061

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Project description:BackgroundEosinophils in the nasal mucosa are an elemental feature of allergic rhinitis.ObjectiveOur objective was to explore eosinophilic inflammation and its impact on respiratory virus infection at the nasal mucosa.MethodsInflammation in the nasal mucosae of mice was evaluated in response to repetitive stimulation with strict intranasal volumes of a filtrate of Alternaria alternata. Mice were then challenged with influenza virus.ResultsRepetitive stimulation with A. alternata resulted in eosinophil recruitment to the nasal passages in association with elevated levels of IL-5, IL-13 and eotaxin-1; eosinophil recruitment was diminished in eotaxin-1-/- mice, and abolished in Rag1-/- mice. A. alternata also resulted in elevated levels of nasal wash IgA in both wild-type and eosinophil-deficient ∆dblGATA mice. Interestingly, A. alternata-treated mice responded to an influenza virus infection with profound weight loss and mortality compared to mice that received diluent alone (0% vs 100% survival, ***P < .001); the lethal response was blunted when A. alternata was heat-inactivated. Minimal differences in virus titre were detected, and eosinophils present in the nasal passages at the time of virus inoculation provided no protection against the lethal sequelae. Interestingly, nasal wash fluids from mice treated with A. alternata included more neutrophils and higher levels of pro-inflammatory mediators in response to virus challenge, among these, IL-6, a biomarker for disease severity in human influenza.Conclusions and clinical relevanceRepetitive administration of A. alternata resulted in inflammation of the nasal mucosae and unanticipated morbidity and mortality in response to subsequent challenge with influenza virus. Interestingly, and in contrast to findings in the lower airways, eosinophils recruited to the nasal passages provided no protection against lethal infection. As increased susceptibility to influenza virus among individuals with rhinitis has been the subject of several clinical reports, this model may be used for further exploration of these observations.

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Alternaria alternata Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection.

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<i>Alternaria alternata</i> Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection.

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