| Salivary gland disorders (SGD) cause significant morbidity but remain an enigma. SGD includes autoimmune disorder Sjogren's syndrome (SS), and a related HIV-associated salivary gland disease (HIV-SGD), that is AIDS defining in children and increasing in the adult population. Each of these maladies is characterized by loss of exocrine function resulting from chronic immune attack directed against the salivary glands with CD4+ (SS) or CD8+ (HIV-SGD) lymphocytic infiltrates within the gland tissue. The affected individuals are disfigured by facial asymmetry and 1-10% develop malignant lymphoproliferative disease. Further, the associated xerostomia instigates caries, mucosal pathology and periodontal disease. Despite progress made toward understanding aspects of SS, critical gaps remain in understanding the pathogenesis of SGD. The long term goal of this project is to make critical strides toward understanding the etiology of SGD in order to go beyond the ineffective palliative treatment that is currently the standard of care.;The central hypothesis of this work is that viral pathogenesis is essential to the development of salivary gland disease. Results show for the first time that polyomavirus, BKV is associated with salivary gland disorders. BKV DNA and its gene products were consistently detected in HIV-SGD salivary gland biopsies and in a subset of SS patient. BKV was also detected in the peripheral blood and shed in oral fluids from HIV-SGD patients and not in control subjects. To confirm the in vivo findings an in vitro model was created whereby parotid and submandibular salivary gland cells were productively infected with BKV demonstrating each part of the viral life cycle. Salivary gland tropism was confirmed and the BKV receptor on salivary gland cells was defined. BKV transmission and pathogenesis is not well understood. Importantly, these studies suggest that BKV transmission may occur via the oral route.;Differential gene expression studies were also performed on HIV-SGD salivary gland biopsies. Among the many modulated transcripts was a novel non-coding RNA, MALAT-1, that was highly up-regulated in the disease. Further investigation of this transcript revealed that BKV infection played an important role in its regulation and we report for the first time a mechanism for MALAT-1 regulation. |
