https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61380-3.pdf

Role of viral respiratory infections in asthma and asthma exacerbations

About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact might confer protection against the development of allergic illnesses. The so-called hygiene hypothesis has ever since undergone numerous more or less subtle modifications by various researchers in the fields of epidemiology, clinical science, and immunology. Three major tracts have developed exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and the effect of both on underlying responses of the innate and adaptive immunity. To date, a truly unifying concept has not yet emerged, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures becomes apparent. These influences are discussed as determinants for a number of complex allergic illnesses in this review, while we attempt to pay attention to the importance of different phenotypes, namely of the asthma syndrome. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future.

https://www.jacionline.org/article/S0091-6749(06)00645-2/pdf

The many faces of the hygiene hypothesis.

Viral respiratory infections can predispose to the development of asthma by mechanisms that are presently undetermined. Using a murine model of respiratory syncytial virus (RSV) infection, acute infection is associated with airway hyperresponsiveness as well as enhanced responses to subsequent sensitization to allergen. We demonstrate that acute viral infection results in increased airway responsiveness to inhaled methacholine and pulmonary neutrophilic and eosinophilic inflammation. This response is associated with predominant production of Th-1-type cytokines in peribronchial lymph node cells in vitro. Mice sensitized to ovalbumin via the airways after RSV infection developed increased airway responsiveness to methacholine and pulmonary eosinophilic and neutrophilic inflammation, associated with the predominant production of Th-2-type cytokines. Treatment of the mice with anti-IL-5 antibody abolished airway hyperresponsiveness and eosinophilic but not neutrophilic inflammation in both acutely infected mice and mice sensitized after infection. We conclude that RSV infection results in airway hyperresponsiveness in the acute phase and leads to changes in immune function that can enhance the effects of airway sensitization to antigen after infection. In both situations, airway hyperresponsiveness is closely associated with pulmonary eosinophilic inflammation. This model provides a means for further analyzing the influence of viral respiratory infections on airway sensitization and the development of altered airway responsiveness.

/pdf/respiratory-syncytial-virus-infection-results-in-airway-1qbbmzixa2.pdf

Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen.

Virus-induced Airway Hyperresponsiveness and Asthma

The purpose of this study was to explore whether repeated exposure to aerosolized ovalbumin (OVA) in the context of local expression of GM-CSF can initiate a Th2-driven, eosinophilic inflammation in the airways. On day -1, Balb/c mice were infected intranasally with an adenovirus construct expressing GM-CSF (Ad/GM-CSF). From day 0 to day 9 mice were exposed daily to an OVA aerosol. Mice exposed to OVA alone did not show any evidence of airway inflammation. Mice receiving both Ad/GM-CSF and aerosolized OVA exhibited marked airway inflammation characterized by eosinophilia and goblet cell hyperplasia. Migration of eosinophils into the airway was preceded by a rise in IL-5 and IL-4. Both IL-5 and class II MHC were critically required to generate airway eosinophilia. After resolution, airway eosinophilia was reconstituted after a single OVA exposure. Flow cytometric analysis of dispersed lung cells revealed an increase in macrophages and dendritic cells expressing B7.1 and B7.2, and expansion of activated (CD69-expressing) CD4 and CD8 T cells in mice exposed to OVA and Ad/GM-CSF. Our data indicate that expression of GM-CSF in the airway compartment increases local antigen presentation capacity, and concomitantly facilitates the development of an antigen-specific, eosinophilic inflammatory response to an otherwise innocuous antigen.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/4000/4160/JCI9804160.pdf

GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice.

An IgE antibody specific to ovalbumin was produced when C3H mice were first infected with influenza A virus before challenge with the aerosolized antigen. No antibody could be detected in those animals without preceding viral infection. Antigen inhalation immediately after virus infection could not induce the IgE antibody. A time lag of at least 2 days was required to sensitize the infected mice with inhaled antigen. The study revealed that allergic sensitization could be elicited only during the acute stage of the infection, but not in the convalescent stage. We concluded therefore that the inflammation of respiratory mucous membrane might allow inhaled antigens to penetrate the barrier, resulting in reaginic antibody production that has the capacity to serve as an allergic response.

T Takishima

Papers

Effect of influenza virus infection on allergic sensitization to aerosolized ovalbumin in mice.