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

Caroline M Percopo,Michelle Ma,Helene F Rosenberg,Jamie L Redes,Ian N Moore,Mahnaz Minai,Laura S Kraemer,Eric Mai,Kirk M Druey

doi:10.3390/v12090946

Caroline M Percopo, Michelle Ma + Show 7 more

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https://doi.org/10.3390/v12090946

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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.

Highlights

Influenza infection remains among the most important of the circulating respiratory virus pathogens
In an earlier study [16], we found that repetitive administration of strict intranasal doses of a filtrate of A. alternata elicited profound eosinophil infiltration in the upper respiratory tract
Despite earlier studies documenting antiviral properties of eosinophils in the airways [17,18,19], we found that repetitive administration of A. alternata resulted in an increased rather than decreased susceptibility to the lethal sequelae of a subsequent Influenza A/H3N2 (Inf A) infection

Summary

Introduction

Influenza infection remains among the most important of the circulating respiratory virus pathogens. Vaccination against influenza has been available since the mid-1940s, the U.S. Centers for Disease Control and Prevention reports that between 9 and 45 million individuals are Viruses 2020, 12, 946; doi:10.3390/v12090946 www.mdpi.com/journal/viruses. Viruses 2020, 12, 946 infected with influenza each year, resulting in 12,000–61,000 deaths [1]. While some individuals experience mild symptoms only, others can progress to severe pneumonia and acute respiratory distress syndrome (ARDS). While there are several known pre-existing conditions that are associated with severe disease [2], we do not have a complete understanding of the factors and mechanisms promoting virulent disease and influenza-associated mortality. Fungi are ubiquitous in indoor and outdoor spaces [3]

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