Abstract
Abstract Mannheimia haemolytica (MH) is a common commensal bacteria found in the nasopharynx of healthy cattle, and its colonization is generally well controlled by innate and adaptive immune defenses. Following immunological stressors, MH can migrate into the lungs and develop into lower respiratory tract infections or pneumonia. These infections are often exacerbated by infiltrating cytotoxic leukocytes and excessive inflammation. IL-17A is thought to play an integral part in MH pathogenesis by driving inflammatory pathways, invoking neutrophilia, and modulating innate immune defenses. Therefore, to better understand the immune-induced tissue damage that follows MH infection, this study employed the use of an IL-17A inhibitor, ursolic acid (UA), and determined its impact on immune responses and disease severity. Two independent experiments were performed using 4 week old Holstein calves; each of these studies challenged a non-treated group (UA−/MH+; n = 8) and a prophylactic UA treated group (UA+/MH+; n=8). Serum samples, whole blood, and nasal swabs were collected throughout the course of both studies, with bronchoalveolar lavage fluid and lung tissue sections collected at necropsy. UA treated calves had reduced lung pathology and bacterial loads in the lungs compared to control calves. Subsequent analysis of lung tissue confirmed UA treatment modulated host immune responses, including decreased expression of the inflammatory mediators IL-6, IL-17, and STAT3; furthermore, expression of innate defense molecules, such as antimicrobial peptides, mucins, and metalloproteases, was altered. Taken together, these results outline a mechanistic role for IL-17A-mediated immunity to contribute to the pathogenesis of MH infection.
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