Abstract
Bovine respiratory disease complex (BRDC) is a costly economic and health burden for the dairy and feedlot cattle industries. BRDC is a multifactorial disease, often involving viral and bacterial pathogens, which makes it difficult to effectively treat or vaccinate against. Mannheimia haemolytica (MH) are common commensal bacteria found in the nasopharynx of healthy cattle; however, following environmental and immunological stressors, these bacteria can rapidly proliferate and spread to the lower respiratory tract, giving rise to pneumonic disease. Severe MH infections are often characterized by leukocyte infiltration and dysregulated inflammatory responses in the lungs. IL-17A is thought to play a key role in this inflammatory response by inducing neutrophilia, activating innate and adaptive immune cells, and further exacerbating lung congestion. Herein, we used a small molecule inhibitor, ursolic acid (UA), to suppress IL-17A production and to determine the downstream impact on the immune response and disease severity following MH infection in calves. We hypothesized that altering IL-17A signaling during MH infections may have therapeutic effects by reducing immune-mediated lung inflammation and improving disease outcome. Two independent studies were performed (Study 1 = 32 animals and Study 2 = 16 animals) using 4-week-old male Holstein calves, which were divided into 4 treatment group including: (1) non-treated and non-challenged, (2) non-treated and MH-challenged, (3) UA-treated and non-challenged, and (4) UA-treated and MH-challenged. Based on the combined studies, we observed a tendency (p = 0.0605) toward reduced bacterial burdens in the lungs of UA-treated animals, but did not note a significant difference in gross (p = 0.3343) or microscopic (p = 0.1917) pathology scores in the lungs. UA treatment altered the inflammatory environment in the lung tissues following MH infection, reducing the expression of IL-17A (p = 0.0870), inflammatory IL-6 (p = 0.0209), and STAT3 (p = 0.0205) compared to controls. This reduction in IL-17A signaling also appeared to alter the downstream expression of genes associated with innate defenses (BAC5, DEFB1, and MUC5AC) and lung remodeling (MMP9 and TIMP-1). Taken together, these results support our hypothesis that IL-17A signaling may contribute to lung immunopathology following MH infections, and further understanding of this inflammatory pathway could expand therapeutic intervention strategies for managing BRDC.
Highlights
Bovine respiratory disease complex (BRDC) is a leading cause of morbidity and mortality within the North American feedlot [1] and dairy [2] industries, and its economic burden is estimated to cost in excess of 1 billion dollars annually due to increased labor and production-loss expenses [3, 4]
Mannheimia haemolytica (MH) is a common commensal bacteria found in the nasopharynx of healthy cattle, where its proliferation is generally limited by other commensal flora and the host’s immune system [3, 4]
These data show that ursolic acid (UA) treatment can effectively reduce IL-17A production at concentrations that are not cytotoxic to bovine lymphocytes in vitro
Summary
Bovine respiratory disease complex (BRDC) is a leading cause of morbidity and mortality within the North American feedlot [1] and dairy [2] industries, and its economic burden is estimated to cost in excess of 1 billion dollars annually due to increased labor and production-loss expenses [3, 4]. Current vaccinations strategies are limited in their efficacy [5], and BRDC is often difficult to treat because it is a multifactorial disease. These infections typically involve a combination of environmental and host factors, as well as multiple viral and bacterial pathogens. Following immunological stressors or a primary viral infection, MH can migrate deeper into the lower respiratory tract, eventually culminating in severe bacterial pneumonia [4]. BRDC is a syndrome involving multiple viral and bacterial pathogens, MH is often the most prevalent bacteria isolated from pneumonic bovine lungs, and it is considered the principal bacterial agent involved in BRDC [6]. Severe MH infections are often characterized by fibrinous exudate and an accumulation of activated macrophages and neutrophils, which further contribute to lung congestion through inflammatory cytokine signaling and excretion of cytotoxic compounds [6, 7]
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