Influenza A Virus Infection Inhibits the Efficient Recruitment of Th2 Cells into the Airways and the Development of Airway Eosinophilia

Abstract

Most infections with respiratory viruses induce Th1 responses characterized by the generation of Th1 and CD8+ T cells secreting IFN-γ, which in turn have been shown to inhibit the development of Th2 cells. Therefore, it could be expected that respiratory viral infections mediate protection against asthma. However, the opposite seems to be true, because viral infections are often associated with the exacerbation of asthma. For this reason, we investigated what effect an influenza A (flu) virus infection has on the development of asthma. We found that flu infection 1, 3, 6, or 9 wk before allergen airway challenge resulted in a strong suppression of allergen-induced airway eosinophilia. This effect was associated with strongly reduced numbers of Th2 cells in the airways and was not observed in IFN-γ- or IL-12 p35-deficient mice. Mice infected with flu virus and immunized with OVA showed decreased IL-5 and increased IFN-γ, eotaxin/CC chemokine ligand (CCL)11, RANTES/CCL5, and monocyte chemoattractant protein-1/CCL2 levels in the bronchoalveolar lavage fluid, and increased airway hyperreactivity compared with OVA-immunized mice. These results suggest that the flu virus infection reduced airway eosinophilia by inducing Th1 responses, which lead to the inefficient recruitment of Th2 cells into the airways. However, OVA-specific IgE and IgG1 serum levels, blood eosinophilia, and goblet cell metaplasia in the lung were not reduced by the flu infection. Flu virus infection also directly induced AHR and goblet cell metaplasia. Taken together, our results show that flu virus infections can induce, exacerbate, and suppress features of asthmatic disease in mice.

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

“…To assess for the possibility that the bilirubin-induced reduction in eosinophil accumulation is due to altered chemotactic signaling, we measured the concentration of eotaxin, a chemokine responsible for eosinophil migration (39), in lung lavage fluid. Consistent with the findings of other investigators (40), eotaxin levels increase following OVA challenge, but are unaffected by bilirubin administration (Fig. 13A).…”

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

“…Our findings may appear to contrast with those of Wohlleben et al (29) showing that, in a conventional OVA model, a prior flu infection inhibited airway eosinophilia and Th2 cell recruitment and that these effects were dependent on IFN-␥. However, the timing of viral and allergen exposures were fundamentally different from those used in our study.…”

“…It should be noted that, in the absence of exogenous adjuvants, mucosal exposure to OVA leads to the induction of tolerance and, in this regard, Tsitoura et al (26) clearly demonstrated that a concurrent flu infection is able to prevent the induction of tolerance. In addition, others have shown that a flu infection can either enhance or suppress allergic responses, interestingly both effects being mediated by IFN-␥ (28,29). The controversial and, in some instances, even contradictory nature of these and other data in OVA-based systems intimate that models of allergic asthma that require the introduction of Ag into the peritoneal cavity along with chemical adjuvants to elicit productive immunity are limited.…”

“…However, the timing of viral and allergen exposures were fundamentally different from those used in our study. Indeed, Wohlleben et al (29) examined already sensitized mice that were subsequently infected with influenza A 1-9 wk before OVA challenge. Hence, this study examined the impact of a flu infection on OVA-specific recall responses rather than on mucosal allergic sensitization.…”

Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity

“…For example, infection with human rhinovirus in children before 3 years of age increases the later risk of developing asthma (8), while other respiratory viral infections appear to protect against the later development of asthma (9)(10)(11)(12)(13)(14). However, in older individuals with established asthma, respiratory viral infection, particularly with influenza A virus, almost always triggers acute symptoms of asthma (15)(16)(17).…”