Virginia Bioinformatics Institute and Virginia Tech biological sciences associate professor Chris Lawrence is teaming up with Mayo Clinic on a $2.4 million project funded by the National Institute of Allergy and Infectious Diseases (NIAID). The work could help researchers develop treatments, diagnostic tools, and preventative measures for patients suffering from chronic rhinosinusitis (CRS).
CRS is a debilitating chronic airway disease that results in up to 18?22 million clinical cases per year and at least 30 million courses of antibiotic treatment (National Center for Health Statistics). CRS can produce inflammation of the lining of the nasal sinus. In some cases, this is followed by thickening of sinus mucosa and the formation of polyps or growths in the nasal cavity. Even with aggressive medical and surgical therapies, a significant number of patients with CRS have persistent or recurrent problems associated with the disease. The goal of the five-year project, entitled “The Pathogenesis of Chronic Rhinosinusitis,” is to positively impact treatment, clinical decisions, and medical care costs involving CRS, as well as develop a better understanding of the mechanisms of the disease.
Dr. Chris Lawrence, associate professor at VBI, stated: “Several years ago researchers at Mayo, including clinical assistant professor Jens Ponikau, who is now at the University at Buffalo School of Medicine & Biomedical Sciences, and Hirohito Kita, professor of Immunology and the director of the Allergic Diseases Laboratory at Mayo, discovered that lymphocytes including T-cells from a significant percentage of CRS patients have an overzealous inflammatory immune response to antigens derived from common airborne fungi. The most exaggerated and statistically significant response by far was to Alternaria alternata antigens. Our research group along with VBI professor Brett Tyler has been sequencing the Alternaria brassicicola genome in collaboration with Washington University School of Medicine and developing functional genomics technologies for Alternaria research. It made sense to use the A. brassicicola genome resources, our bioinformatics infrastructure, and our molecular techniques to aid in the identification of the fungal products from the closely related species A. alternata that trigger the response in CRS patients. Since then, we have also started to amass genome data from A. alternata. The Mayo group had already performed a lot of work to characterize the fungal-associated immune responses in CRS patients. However, identifying the specific fungal antigens and other proteins contributing to the pathology of the disorder has proved elusive.”
The new project will involve a transdisciplinary team of immunologists, allergy physicians, otorhinolaryngology surgeons, and genomic scientists. Principal Investigator Hirohito Kita, professor of medicine at the Mayo Medical and Graduate Schools, will lead the project at Mayo Clinic, while Lawrence will head the work at VBI in collaboration with VBI assistant professor Dharmendar Rathore. The VBI team will produce a set of recombinant fungal proteins that will be used to dissect the different molecular steps involved in the development and progression of CRS. The VBI researchers will also create a series of fungal knockout mutants for specific genes that will be evaluated in in vitro and in vivo immunological assays during the course of the project.
Dr. Kita commented: “Certain molds in the environment, especially Alternaria, are also risk factors for bronchial asthma and CRS. When extracts of Alternaria were tested in the laboratory with immune cells from CRS patients, chemical signals, called cytokines, were produced that indicated damaging inflammatory changes of these cells. Several clinical trials also suggest that nasal washing with anti-fungal agents improve clinical symptoms and inflammation in many CRS patients. These pieces of evidence give us clues that CRS patients may be overly reactive to Alternaria and that removal of this fungus may cure the disease in a significant number of patients.” He added: “The new grant project will explore more precisely which products of Alternaria are the culprits and how we can provide better treatment for patients with this difficult disease.”