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Multipopulational transcriptome analysis of post-weaned beef cattle at arrival further validates candidate biomarkers for predicting clinical bovine respiratory disease.

ABSTRACT: Bovine respiratory disease (BRD) remains the leading infectious disease in post-weaned beef cattle. The objective of this investigation was to contrast the at-arrival blood transcriptomes from cattle derived from two distinct populations that developed BRD in the 28 days following arrival versus cattle that did not. Forty-eight blood samples from two populations were selected for mRNA sequencing based on even distribution of development (n = 24) or lack of (n = 24) clinical BRD within 28 days following arrival; cattle which developed BRD were further stratified into BRD severity cohorts based on frequency of antimicrobial treatment: treated once (treated_1) or treated twice or more and/or died (treated_2+). Sequenced reads (~ 50 M/sample, 150 bp paired-end) were aligned to the ARS-UCD1.2 bovine genome assembly. One hundred and thirty-two unique differentially expressed genes (DEGs) were identified between groups stratified by disease severity (healthy, n = 24; treated_1, n = 13; treated_2+, n = 11) with edgeR (FDR ≤ 0.05). Differentially expressed genes in treated_1 relative to both healthy and treated_2+ were predicted to increase neutrophil activation, cellular cornification/keratinization, and antimicrobial peptide production. Differentially expressed genes in treated_2+ relative to both healthy and treated_1 were predicted to increase alternative complement activation, decrease leukocyte activity, and increase nitric oxide production. Receiver operating characteristic (ROC) curves generated from expression data for six DEGs identified in our current and previous studies (MARCO, CFB, MCF2L, ALOX15, LOC100335828 (aka CD200R1), and SLC18A2) demonstrated good-to-excellent (AUC: 0.800-0.899; ≥ 0.900) predictability for classifying disease occurrence and severity. This investigation identifies candidate biomarkers and functional mechanisms in at arrival blood that predicted development and severity of BRD.

SUBMITTER: Scott MA

PROVIDER: S-EPMC8669006 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite decades of extensive research, bovine respiratory disease (BRD) remains the most devastating disease in beef cattle production. Establishing a clinical diagnosis often relies upon visual detection of non-specific signs, leading to low diagnostic accuracy. Thus, post-weaned beef cattle are often metaphylactically administered antimicrobials at facility arrival, which poses concerns regarding antimicrobial stewardship and resistance. Additionally, there is a lack of high-quality research that addresses the gene-by-environment interactions that underlie why some cattle that develop BRD die while others survive. Therefore, it is necessary to decipher the underlying host genomic factors associated with BRD mortality versus survival to help determine BRD risk and severity. Using transcriptomic analysis of at-arrival whole blood samples from cattle that died of BRD, as compared to those that developed signs of BRD but lived (n = 3 DEAD, n = 3 ALIVE), we identified differentially expressed genes (DEGs) and associated pathways in cattle that died of BRD. Additionally, we evaluated unmapped reads, which are often overlooked within transcriptomic experiments.Results69 DEGs (FDR<0.10) were identified between ALIVE and DEAD cohorts. Several DEGs possess immunological and proinflammatory function and associations with TLR4 and IL6. Biological processes, pathways, and disease phenotype associations related to type-I interferon production and antiviral defense were enriched in DEAD cattle at arrival. Unmapped reads aligned primarily to various ungulate assemblies, but failed to align to viral assemblies.ConclusionThis study further revealed increased proinflammatory immunological mechanisms in cattle that develop BRD. DEGs upregulated in DEAD cattle were predominantly involved in innate immune pathways typically associated with antiviral defense, although no viral genes were identified within unmapped reads. Our findings provide genomic targets for further analysis in cattle at highest risk of BRD, suggesting that mechanisms related to type I interferons and antiviral defense may be indicative of viral respiratory disease at arrival and contribute to eventual BRD mortality.

Project description:BackgroundBovine coronavirus (BCV) is associated with respiratory infections in cattle of all ages; however, a temporal study to evaluate the effect of BCV immunity on virus shedding and bovine respiratory disease (BRD) incidence in pre-weaned beef calves has not been reported. Thus, we report here a prospective study in three herds of crossbred beef calves (n = 817) with endemic BCV. Serial blood samples for measurement of serum anti-BCV antibody titers and nasal swabs for detection of BCV and other common viral and bacterial BRD pathogens were collected from all calves or subsets of calves at predetermined times from birth through weaning. The calves were monitored for BRD and those that developed signs of respiratory disease were sampled for diagnostic testing. To discover additional risk factors that could have influenced BRD development, sequence analysis of the BCV strain(s) circulating in each herd, and the prevalence of common opportunistic bacterial pathogens in the upper respiratory tract of sick and apparently healthy cattle were also evaluated.ResultsTwo hundred forty-eight of the 817 study calves (30.4%) were treated for BRD prior to weaning; 246 of those were from a single herd involved in two outbreaks of BRD leading to mass treatment of all calves in that group. Molecular diagnostic testing found BCV and Histophilus somni in nasal swabs taken at the time of BRD treatment. Between herd analyses revealed anti-BCV serum antibody abundance did not associate with the incidence of BRD or BCV shedding, though these measurements may have been hindered by the long periods between sample collections. Analysis of the BCV spike gene hypervariable region revealed four polymorphisms in 15 isolates from the three herds, making strain variation unlikely to account for differences in treatment rates between herds. Persistent or recurrent shedding episodes of BCV occurred in some animals treated for BRD.ConclusionCo-detection of BCV and H. somni at the time of the disease outbreak suggests that these pathogens contributed to disease pathogenesis. Developing appropriate control measures for respiratory BCV infections may help decrease the incidence of pre-weaning BRD. The role of antibodies in protection must still be further defined.

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Multipopulational transcriptome analysis of post-weaned beef cattle at arrival further validates candidate biomarkers for predicting clinical bovine respiratory disease.

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