For the first time, we have shown that M. pneumoniae infection can modify the allergic responses in a murine model of asthma. Our data support the hygiene hypothesis for asthma in that M. pneumoniae infection prior to allergen sensitization and challenge protected the animals from the BHR and airway inflammation seen in the control mice. On the other hand, if infection happened after allergen sensitization and challenge, BHR and airway inflammation increased.
Respiratory tract bacterial infections are common in childhood (6
), but the role of bacterial infection in asthma is still controversial. Some studies showed no association of early childhood bacterial infection and subsequent wheezing and/or asthma (4
). Other studies, however, demonstrated that endotoxin exposure during the first year of life could either minimize the risk of allergy sensitization or increase the risk of wheezing in children with a family history of allergy or asthma (9
). M. pneumoniae
is an atypical pathogenic bacterium in the human respiratory system. It is one of the common causes of community-acquired pneumonia (5
). Retrospective studies indicate that children with a previous history of M. pneumoniae
infection may have a higher incidence of asthma or wheezing (6
). These studies need to be carefully interpreted, because the exact timing of the infection and the confirmation of the pathogens might not be accurate. In the present study, we explored the effects of M. pneumoniae
infection on the pathogenesis of a murine allergic-asthma model. BHR was selected as a key parameter for the allergic response. In addition, we evaluated Th1 (IFN-γ) and Th2 (IL-4) cytokine responses and airway inflammation to elucidate the potential mechanisms behind the changes found in BHR.
In the infected-allergen-sensitized-allergen-challenged model, mycoplasma infection decreased BHR compared with saline treatment prior to allergen challenge. This reduced BHR in infected mice was accompanied by an increased Th1 and a decreased Th2 response. The numbers of BAL inflammatory cells, including eosinophils, were also decreased in the mice that were infected followed by allergen challenge. Our data support the hygiene hypothesis in that mycoplasma infection prior to allergen contact could induce a Th1 response, which is believed to be protective against the allergic response (8
). Therefore, M. pneumoniae
may be a new member of a family of infectious pathogens that could be beneficial for the prevention of asthma and other allergic diseases if the infection precedes the allergen(s).
Although respiratory infections could be linked to the acute exacerbation of asthma, the timing of the infection may be crucial to the outcome of infection in asthmatics or subjects with a family history of allergy or asthma. After we tested the hygiene hypothesis, we evaluated the effects of mycoplasma infection after allergen sensitizations and challenges were performed. We found that in our allergen-sensitized-allergen-challenged-infected model, there was a significant decrease in BHR on day 5 after allergen challenge (day 3 postinfection). From days 9 to 16 after allergen challenge, however, BHR was significantly increased. The Th1-Th2 balance in infected mice showed a trend opposite that of BHR, and this may in part explain the biphasic BHR response after infection. Generally, the pattern of Th1 and Th2 cytokine response in allergen-challenged and saline-treated mice was opposite that in allergen-challenged and infected mice. From days 5 to 16 after allergen challenge, IFN-γ increased and IL-4 decreased in saline-treated mice. This suggests that the timing after the last allergen challenge and/or infection could substantially affect the Th1 and Th2 cytokine levels in the lung, which should be considered in the interpretation of the data. In addition to the effects of Th1-Th2 balance, increased lung tissue inflammation in infected mice may also be involved in higher levels of BHR at the late time points of the experiment. These results indicate that mycoplasma infection in allergic asthma may actually be protective in the acute phase of the infection, which would challenge the traditional concept that infection always exacerbates asthma. Respiratory tract infection with M. pneumoniae in clinical patients is usually insidious. Bronchial hyporesponsiveness observed in the early phase of the infection would suggest that acute mycoplasma infection in asthma patients could not easily be identified. However, the long-term effects of the infection might be deleterious.
It is important to point out that the pattern of BHR in the allergen-sensitized-allergen-challenged-infected model is opposite that in the single M. pneumoniae
infection model without any allergen exposure, where BHR initially increased and then decreased (17
). In addition, the positivity of M. pneumoniae
in the allergen-sensitized-allergen-challenged-infected model was also lower than in the single-infection model, which showed 100% M. pneumoniae
positivity during the first week of infection. The differences in BHR, inflammatory response, and M. pneumoniae
positivity between these two studies indicate a complex interaction between the allergic inflammatory response and mycoplasma infection. The allergen-induced inflammatory milieu may also affect the activity of M. pneumoniae
in the lung.
Finally, it is worth mentioning that our present study evaluated only the interactions between a single mycoplasma infection and relatively short-term allergen challenges. Future studies need to determine the long-term effects of repeated and prolonged infections on BHR, airway inflammation, and, perhaps more importantly, airway remodeling, which are important features of asthma. This will further our understanding of asthma pathophysiology and treatment.