The precise environmental causes of asthma and related allergic diseases have not been established with confidence, but both human and experimental evidence increasingly links allergic airway diseases to fungal exposure and airway infection (15
). To experimentally address the possible contribution of common environmental fungi to allergic disease, we analyzed 12 common fungal species from 8 genera, isolated from the houses of asthmatic children, for the ability to induce allergic disease in mice. Although prior studies suggested that inhaled fungal conidia do not induce immune reactions (3
), our results clearly demonstrate that the ability to induce a strong Th2-mediated mucosal immune response is common, if not universal, among typical household fungi, further substantiating a possible host-pathogen environmental link not only to allergic asthma but potentially also to chronic rhinosinusitis and other allergic syndromes (31
). We further demonstrated that an inevitable consequence of having an excessive mucosal fungal burden is local tissue invasion and widespread dissemination, especially to the brain, accompanied by immune phenotype switching, thereby demonstrating for the first time that T cell immune responses to fungi exist along a continuum and are conidium dose dependent. However, fungus-specific factors are not the sole determinants of dissemination, as we have formally demonstrated for the first time that mucosal T helper cells are crucial for containing fungal infection and preventing invasion and dissemination.
Prior fungal conidium inhalation research has focused on rodent models in which typical exposures exceed 1 × 107 A. fumigatus
). These exposures surpass the minimum A. fumigatus
challenge doses required to induce allergic lung disease by over 3 orders of magnitude and, where studied, typically produce invasive fungal disease and pathology devoid of allergic features. Although type 2 immunity was not reported in association with invasive disease, strong type 1 responses, which were absent in our studies, with the exception of invasive C. lunata
and high doses of A. fumigatus
conidia, were observed. In contrast, relatively low C. lunata
and A. fumigatus
conidium doses induced strictly type 2 responses and allergic lung disease. Thus, in contrast to prior studies involving very large exposure doses, we have shown that the typical response to low-grade airway mucosal exposure to fungal conidia is allergic inflammation accompanied by typical markers of Th2 cell-dependent airway obstruction, i.e., airway hyperreactivity and goblet cell metaplasia.
At conidium challenge doses that induced predominantly Th2 cell and allergic responses, no or minimal evidence of lung invasion, distant dissemination, or other morbidity (i.e., weight loss, altered behavior, etc.) was observed. However, all Rag1−/−
mice exposed to comparable A. fumigatus
conidium doses manifested gross dissemination of infection to the brain, with profound morbidity (). Thus, although Th2 cytokines are believed to impair the normally protective Th1 immune response and inhibit infection control (10
), our data demonstrate that the Th2-based allergic response is not merely the typical murine response to low-grade airway mucosal fungal infection but also is linked to protection against fungal invasion and dissemination. Moreover, T cells alone are required adaptive immune cells, as we could demonstrate no role for B cells or antibodies in protection against fungal infection in this context. Nonetheless, even highly polarized Th2 responses against fungal infection are accompanied to some degree by both type 1 and type 17 cytokines and chemokines ( and ). Future studies are therefore required to determine separately the contributions of type 1, type 2, and type 17 cytokines to optimal fungal infection control at the airway mucosa.
An apparent paradox of allergic type 2 immunity in response to fungal airway infection is that it is associated with both protective (i.e., facilitating organism removal and preventing dissemination) and detrimental (i.e., asthma-like airway obstructive disease) outcomes. Our study demonstrates, however, that allergic lung disease with airway obstruction is a far less morbid alternative to invasive/disseminated disease that is the inevitable consequence of overwhelming infection. Systemic dissemination was inevitably accompanied by brain involvement that resulted in ataxia, rapid weight loss, and, ultimately, death (data not shown). ABPA is linked to locally invasive fungal airway infection (47
), which in turn may be the cause of irreversible bronchiectasis that is a characteristic feature of the severest forms of this condition (2
). Moreover, deep cutaneous and central nervous system fungal infections have rarely been documented for subjects whose only significant medical condition was asthma (9
). We therefore postulate that the potentially protective role of the type 2 immune response, potentially in conjunction with type 1 and 17 responses, against mucosal fungal infection represents a highly specific mechanism to prevent the disastrous consequences arising from invasion of the lung parenchyma and dissemination of airway fungi.
Although our experiments have revealed the importance of T cells in preventing fungal dissemination at high infectious challenge doses, the importance of innate immune neutrophils, eosinophils, and macrophages should not be discounted. T cells are most likely of greatest relevance when the fungal infectious burden is relatively high, as demonstrated by Rag1−/− mice, which tolerated relatively low A. fumigatus infectious burdens (<0.5 × 106 conidia/day) with minimal or no morbidity (data not shown). Thus, innate immunity alone is sufficient to successfully cope with low-grade fungal airway infections that continuously arise through routine inhalational exposures, and T cells likely assume critically important protective roles only in the settings of high infectious burdens and innate immune cell dysfunction.
Patients with asthma are at risk for developing several life-threatening complications, including status asthmaticus (profound airway obstruction often requiring mechanical ventilatory assistance) (18
), steroid resistance (1
), ABPA (48
), Churg-Strauss syndrome (allergic granulomatosis and angiitis) (22
), eosinophilic pneumonia, and disseminated fungal disease. Of these conditions, only ABPA is obviously linked to airway fungal infection. However, given the nearly universal propensity of fungi to cause airway infection and allergic lung disease, as shown here, the possibility exists that all of these complications are related at least in part to underlying, preexisting fungal mucosal infection. Severe, steroid-resistant asthma is a particular concern, as the patient subset with this manifestation accounts for the majority of asthma-related health care expenditures (6
). Our demonstration that control of airway fungal infection is strongly T cell associated raises further concerns regarding current asthma therapy, which is based on administration of immunosuppressive corticosteroids that suppress T cell function and that, while clearly beneficial for treatment of asthma, are also contraindicated in the setting of any infectious disease. Thus, our findings urgently call for clarification of the precise role played by fungal infection and the most appropriate use of corticosteroids and alternative therapies such as antifungal antibiotics for treatment of asthma (16