Commensal Fungi in Asthma

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): The human intestine is home to more than 100 trillion microbes (the microbiota) that are becoming increasingly recognized an integral component of our normal physiology. A critical function of the microbiota is to facilitate proper development and maturation of the immune system; the goal of which is to ensure protective responses against pathogens while limiting responses directed at our own tissues and innocuous agents like allergens. Asthma is a chronic inflammatory disease of the airways that is largely caused by inappropriate activation of the immune system in response to ubiquitous allergens like dust mites, and is becoming increasing prevalent in the United States. There is growing evidence that the increased incidence of allergic diseases like asthma in westernized countries is associated with a reduced exposure to microbial stimuli in the environment, as well as with lifestyle-induced alterations in the microbial communities that reside in the body. The intestinal microbiota is comprised largely of bacteria, however also harbors fungi, viruses, and archea that undoubtedly have significant biological functions. Importantly, the overgrowth of intestinal fungi, which is commonly observed following broad-spectrum antibiotic use in humans, predisposes mice towards development of severe asthma-like allergic airway disease. However, it is not known if the normal presence of commensal fungi under homeostatic conditions can influence disease. Our preliminary data show that depletion of commensal fungi in mice surprisingly leads to exacerbated development of allergic airway disease, implicating an important protective role for these organisms in the steady state. On the other hand, overgrowth of intestinal fungi also led to more severe allergic disease, suggesting that there is a need for maintaining a healthy balance of commensal fungi in the gut to properly tune the systemic immune response. The experiments proposed will define the mechanisms by which both of these seemingly opposing conditions of fungal imbalance impacts the immune system to promote allergic disease. The overall hypothesis is that intestinal fungi, under homeostatic conditions, are important for maintaining a healthy balance of Th1/Th2/Th17 immune polarization, and that this is disrupted following fungal depletion. We further hypothesize that pathological overgrowth of fungi results in secondary microbial dysbiosis that promotes further immune imbalances to drive exacerbated allergic airway disease. We will address these questions in two aims. In the first aim we will determine if innate immune recognition of commensal fungi by the ß-glucan receptor Dectin-1 is important for providing basal Th17 immune polarization signals to antagonize Th2 differentiation and subsequent development of allergic airway disease. In the second aim we will utilize high-throughput sequencing to characterize the changes that occur in fungal and bacterial populations in the intestine following antifungal treatment, and in response to fungal overgrowth. Together these studies will provide a wealth of information on dynamic effects that commensal fungi have on immune system function, and furthermore will provide a more comprehensive understanding of the interactions that occur between commensal bacteria and fungi in health and disease.