The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections

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 (M...

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Autores principales:	Jamison R. Slate, Bradley O. Chriswell, Robert E. Briggs, Jodi L. McGill
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Mannheimia haemolytica bovine respiratory disease complex innate immunity inflammation interleukin-17A immunomodulation Veterinary medicine SF600-1100
Acceso en línea:	https://doaj.org/article/e4fa7f8df8474ddcbcaf66779689a079
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spelling	oai:doaj.org-article:e4fa7f8df8474ddcbcaf66779689a0792021-11-18T09:32:43ZThe Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections2297-176910.3389/fvets.2021.782872https://doaj.org/article/e4fa7f8df8474ddcbcaf66779689a0792021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fvets.2021.782872/fullhttps://doaj.org/toc/2297-1769Bovine 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.Jamison R. SlateBradley O. ChriswellRobert E. BriggsJodi L. McGillFrontiers Media S.A.articleMannheimia haemolyticabovine respiratory disease complexinnate immunityinflammationinterleukin-17AimmunomodulationVeterinary medicineSF600-1100ENFrontiers in Veterinary Science, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mannheimia haemolytica bovine respiratory disease complex innate immunity inflammation interleukin-17A immunomodulation Veterinary medicine SF600-1100
spellingShingle	Mannheimia haemolytica bovine respiratory disease complex innate immunity inflammation interleukin-17A immunomodulation Veterinary medicine SF600-1100 Jamison R. Slate Bradley O. Chriswell Robert E. Briggs Jodi L. McGill The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
description	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.
format	article
author	Jamison R. Slate Bradley O. Chriswell Robert E. Briggs Jodi L. McGill
author_facet	Jamison R. Slate Bradley O. Chriswell Robert E. Briggs Jodi L. McGill
author_sort	Jamison R. Slate
title	The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
title_short	The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
title_full	The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
title_fullStr	The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
title_full_unstemmed	The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections
title_sort	effects of ursolic acid treatment on immunopathogenesis following mannheimia haemolytica infections
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e4fa7f8df8474ddcbcaf66779689a079
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The Effects of Ursolic Acid Treatment on Immunopathogenesis Following Mannheimia haemolytica Infections

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