Author ORCID Identifier

https://orcid.org/0000-0003-1063-5723

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Agriculture, Food and Environment

Department

Veterinary Science

First Advisor

Dr. Martin K. Nielsen

Abstract

Cyathostomins are ubiquitous parasites in equids. In rare cases, cyathostomins lead to a generalized typhlocolitis and death. In healthy horses, local reactions are noted to the mucosal larvae; however, the mechanisms and importance of these reactions have not been elucidated. It has been hypothesized that anthelmintics can alter these reactions. Currently, three drug classes are approved for use in horses against cyathostomins; while all products target the adults, only two products are labeled as larvicidal. Adulticidal therapy is implicated in triggering the typhlocolitis, however, current evidence is contradictory. There is also conjecture that the larvicidal drugs can increase the risk for adverse inflammatory reactions; however, there has been limited investigation into possible mechanisms. One component of the local mucosal response is goblet cell hyperplasia (GCH), but its exact role in cyathostomin infections is unknown. We hypothesize that GCH in horses plays an important role with expulsion of the worms following treatment.

Two studies were conducted to elucidate the local and systemic immune response following larvicidal treatment based on histology, immunohistochemistry, and gene expression. In the first study, ponies with naturally acquired cyathostomin infections were allocated into three groups: fenbendazole-treated (FBZ), moxidectin-treated (MOX), and untreated control. Whole blood was collected weekly and tissue samples from the large intestine were collected at the 2- and 5-weeks post treatment (WPT) necropsies. Samples were evaluated for proinflammatory, anti-inflammatory and local mucosal responses. There were few significant differences between the three groups; however, there were significant correlations between luminal worm burdens, GCH, and goblet cell gene expression (MUC2, r= -0.2358 and RELM- β, r= -0.2261). This study identified the potential for seasonal turnover and expulsion of worms, where GCH score was lower at 2 WPT than 5 WPT across all groups (p< 0.001), and not associated with treatment.

The second study aimed at evaluating and comparing a larvicidal treatment with a non-larvicidal treatment belonging to the same anthelmintic class to classify the local and systemic immune response following larvicidal treatment based on histology, immunohistochemistry, and gene expression. Horses with naturally acquired cyathostomin infections were allocated into three groups: Ivermectin (IVM)/praziquantel-treated, MOX/praziquantel-treated, and untreated control. Whole blood was collected weekly and tissue samples from the large intestine were collected at the 2 and 5 WPT necropsies. Samples were evaluated for proinflammatory, anti-inflammatory and local mucosal responses, as above. MOX treatment was associated with lower GCH than the control and IVM treatment groups, and the IVM treated group had lower GCH than the control horses (p< 0.0376). There were statistically significant positive associations between mucosal worm burdens and goblet cell hyperplasia and associated gene expression (GCH scores p< 0.001, MUC2 p< 0.001, RELM-β< 0.001). Higher GCH was associated with higher worm burdens across all groups and was higher at 2 WPT than 5 WPT.

Overall, these studies demonstrate that treatment with an anthelmintic, both larvicidal and non-larvicidal, in healthy horses does not significantly change the proinflammatory or anti-inflammatory response. In fact, it may decrease the local mucosal response in horses, due to the decrease in worm burdens. Cyathostomins induce a proinflammatory response within the host tissue, while the encysted larvae may also induce an anti-inflammatory response as well. These studies demonstrate that that GCH is implicated in worm expulsion. This could further impact what we know of infections and how we interpret the disease complex.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.160

Funding Information

15EQRGPARA01, Zoetis, LLC 2015

18ERGPAR-01-01, Zoetis, LLC 2018

19ERGPAR-01-01, Zoetis, LLC 2019

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