Acute, but Not Resolved, Influenza A Infection Enhances Susceptibility to House Dust Mite-Induced Allergic Disease

Abstract

The impact of respiratory viral infections on the emergence of the asthmatic phenotype is a subject of intense investigation. Most experimental studies addressing this issue have used the inert Ag OVA with controversial results. We examined the consequences of exposure to a low dose of the common aeroallergen house dust mite (HDM) during the course of an influenza A infection. First, we delineated the kinetics of the immune-inflammatory response in the lung of mice following intranasal infection with influenza A/PR8/34. Our data demonstrate a peak response during the first 10 days, with considerable albeit not complete resolution at day 39 postinfection (p.i.). At day 7 p.i., mice were exposed, intranasally, to HDM for 10 consecutive days. We observed significantly enhanced eosinophilic inflammation, an expansion in Th2 cells, enhanced HDM-specific IgE and IgG1 responses and increased mucous production. Furthermore, lung mononuclear cells produced enhanced IFN-␥ and IL-5, unchanged IL-13, and reduced IL-4. These immunologic and structural changes lead to marked lung dysfunction. This allergic phenotype occurs at a time when there is a preferential increase in plasmacytoid dendritic cells over myeloid dendritic cells, activated CD8؉ T cells, and increased IFN-␥ production, all of which have been proposed to inhibit allergic responses. In contrast, the inflammatory response elicited by HDM was reduced when exposure occurred during the resolution phase (day 40 p.i.). Interestingly, this was not associated with a reduction in sensitization. Thus, the proinflammatory environment established during an acute influenza A infection enhances Th2-polarized immunity to a low dose of HDM and precipitates marked lung dysfunction.

Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights

“…Thus, priming of the immune environment of the lung through environmental coexposures may shift HDM responsiveness and, thus, increase the susceptibility to develop allergic sensitization and, eventually, allergic asthma. The research we report in this article is based on a previous study in which we described a distinctive asthmatic phenotype in mice exposed to a low concentration of HDM (5 mg daily) in the context of an acute influenza infection (7). In this model, exposure to HDM alone elicits minimal allergic sensitization and airway eosinophilia and, importantly, does not alter lung function.…”

“…Consistent with our previous report of increased expression of proinflammatory cytokines and the accumulation of neutrophils, DCs, and monocytes into the lung of mice during the acute phase of the response (7), influenza infection at day 10 postinfection regulated the expression of a substantial number of chemokines and their receptors involved in the recruitment of various leukocytes, such as monocytes, macrophages, DCs' Th cells, eosinophils, and mast cells (Table III). The cytokine gene profile elicited by influenza reflects its potent Th1 cell-promoting effects, with strong induction of members of the type I IFN family, as well as proinflammatory cytokines, such as TNF-a and several members of the IL-1 family of proteins, including IL-1b, IL-18bp and, notably, IL-33 (7,28) (Table IV). Interestingly, IL-33 was shown to amplify both Th1-and Th2-type responses by targeting mast cells, basophils, and Th2 cells, as well as NK and NK T cells, hence suggesting an important role in asthma pathogenesis (29).…”

“…In this regard, there is abundant evidence in humans of an association between viral infections and the expression of asthma (5,6). In mice, we previously reported that exposure to a concentration of HDM, which by itself elicits negligible airway inflammation and no changes in lung function, results in a phenotype characterized by robust allergic airway inflammation, enhanced mucus production, and marked lung dysfunction in the context of an acute influenza A virus (Flu) infection (7).…”

Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

“…To assess IAV neutralization by mucosal S-IgA, Madin-Darby canine kidney (MDCK) cells were incubated with mixtures of IAV and S-IgA purified from NWs and BALF, as described previously (1). The S-IgA from NWs and BALF was purified with the Kaptiv-AE IgA affinity column according to the protocol provided by the manufacturer (Tecnogen S.p.A., Piacenza, Italy).…”

Dust Mite Allergen Der F 8 Promotes Th2 Polarization via Modulating Chromatin Structure at the TIM4 Gene Locus in Dendritic Cells

“…In line with previous studies [20,21], we created a DME-specific airway allergy mouse model without an extra adjuvant. A significant finding in the present study is that the capacity of inducing the specific Th2 polarization in the airway was significantly attenuated with the Der f 8-null DME, pinpointing the importance of Der f 8 in the allergy-induction capacity of dust mite.…”