Abstract
Simple SummaryMacrolide treatment for Rhodococcus equi infections can result in severe adverse effects including hyperthermia and temporary anhidrosis. Despite these potentially lethal side effects, and a lack of understanding of the mechanisms causing them, macrolide drugs remain the recommended treatment for R. equi infections in foals. To better understand the molecular biology behind these adverse effects, we performed a differential gene expression study of skin biopsies of six healthy macrolide-treated foals experiencing anhidrosis. In total, 132 transcripts were significantly differentially expressed, and these genes belonged to functional ontologies relevant to sweat function. Genes involved in ubiquitination and ion-channel function were upregulated during the anhidrotic timepoint. These biological mechanisms play an important role in equine idiopathic anhidrosis and sweat gland function and warrant further investigation as potential targets for avoiding macrolide-induced temporary anhidrosis.Macrolide drugs are the treatment of choice for Rhodococcus equi infections, despite severe side-effects temporary anhidrosis as a. To better understand the molecular biology leading to macrolide induced anhidrosis, we performed skin biopsies and Quantitative Intradermal Terbutaline Sweat Tests (QITSTs) in six healthy pony-cross foals for three different timepoints during erythromycin administration—pre-treatment (baseline), during anhidrosis and post-recovery. RNA sequencing of biopsies followed by differential gene expression analysis compared both pre and post normal sweating timepoints to the erythromycin induced anhidrosis episode. After Bonferroni correction for multiple testing, 132 gene transcripts were significantly differentially expressed during the anhidrotic timepoint. Gene ontology analysis of the full differentially expressed gene set identified over-represented biological functions for ubiquitination and ion-channel function, both biologically relevant to sweat production. These same mechanisms were previously implicated in heritable equine idiopathic anhidrosis and sweat gland function and their involvement in macrolide-induced temporary anhidrosis warrants further investigation.
Highlights
IntroductionA primary cause of pneumonia in foals under six months of age, the gram-positive facultative intracellular pathogen Rhodococcus equi ( known as Prescottella equi and Rhodococcus hoagii) can be cultured from the environment on most horse farms, but incidence of clinical disease is variable [1,2,3]
The experimental period proceeded as following (Figure 1): day −3, foals and their dams brought into stalls for acclimatization; days −2, −1, 0—daily Quantitative Intradermal Terbutaline Sweat Tests (QITSTs) to establish baseline sweat capacity; days 0 to 4—oral macrolide treatment; days 5 to 10—foals remain in stalls during period of hyperthermia risk; days 10 to 39—foals and their dams taken from stalls and kept in small pasture enclosures (Figure 2); days 1, 2, 5, 9, 24, 39—QITSTs to establish the quantitative profiles for induction of, and recovery from, Animals 2021, 11, x FOR PEER REVIEW
Hypothesized involvement of ion channels and β2 -adrenergic receptors in the development of erythromycin-caused transient anhidrosis was confirmed by identification of genes relevant to these functions among those differentially expressed in this experiment
Summary
A primary cause of pneumonia in foals under six months of age, the gram-positive facultative intracellular pathogen Rhodococcus equi ( known as Prescottella equi and Rhodococcus hoagii) can be cultured from the environment on most horse farms, but incidence of clinical disease is variable [1,2,3]. The combination of the macrolide erythromycin with rifampin became the treatment of choice for R. equi pneumonia in the late 1980s and early 1990s [7]. Both erythromycin and rifampin are lipidsoluble compounds that concentrate within macrophages and neutrophils [8], enabling these drugs to penetrate caseous material and kill R. equi
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