{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T06:39:02Z","timestamp":1778827142469,"version":"3.51.4"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["2021-68014-34144"],"award-info":[{"award-number":["2021-68014-34144"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["1014680"],"award-info":[{"award-number":["1014680"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["NI21AHDRXXXXG028"],"award-info":[{"award-number":["NI21AHDRXXXXG028"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Bovine respiratory disease (BRD) is a leading cause of calf morbidity and mortality, and prevalence remains high despite current management practices. Differential gene expression (DGE) provides detailed insight into individual immune responses and can illuminate enriched pathways and biomarkers that contribute to disease susceptibility and outcomes. The aims of this study were to investigate differences in peripheral leukocyte gene expression in Holstein preweaned heifer calves 1) with and without BRD, and 2) across weeks of age. Calves were enrolled for this short-term longitudinal study on two commercial dairies in Washington State. Calves were assessed every two weeks throughout the pre-weaning period using clinical respiratory scoring (CRS) and thoracic ultrasonography (TUS), and blood samples were collected. Calves were selected that were either healthy (n = 10) or had BRD diagnosed by CRS (n = 7), TUS (n = 6), or both (n = 6) in weeks 5 or 7 of life). Three consecutive time point samples were analyzed for each BRD calf consisting of PRE, ONSET, and POST samples. Nineteen genes of interest were selected based on previous gene expression studies in cattle: <jats:italic>ALOX15<\/jats:italic>, <jats:italic>BPI<\/jats:italic>, <jats:italic>CATHL6<\/jats:italic>, <jats:italic>CXCL8<\/jats:italic>, <jats:italic>DHX58<\/jats:italic>, <jats:italic>GZMB<\/jats:italic>, <jats:italic>HPGD<\/jats:italic>, <jats:italic>IFNG<\/jats:italic>, <jats:italic>IL17D<\/jats:italic>, <jats:italic>IL1R2<\/jats:italic>, <jats:italic>ISG15<\/jats:italic>, <jats:italic>LCN2<\/jats:italic>, <jats:italic>LIF<\/jats:italic>, <jats:italic>MX1<\/jats:italic>, <jats:italic>OAS2<\/jats:italic>, <jats:italic>PGLYRP1<\/jats:italic>, <jats:italic>S100A8<\/jats:italic>, <jats:italic>SELP<\/jats:italic>, and <jats:italic>TNF<\/jats:italic>. Comparisons were made between age and disease time point matched BRD and healthy calves as well as between calf weeks of age. No DGE was observed between diseased and healthy calves; however, DGE was observed between calf weeks of age regardless of disease state. Developmental differences in leukocyte gene expression, phenotype, and functionality make pre-weaned calves immunologically distinct from mature cattle, and early life shifts in calf leukocyte populations likely contribute to the age-related gene expression differences we observed. Age overshadows disease impacts to influence gene expression in young calves, and immune development progresses upon a common trajectory regardless of disease during the preweaning period.<\/jats:p>","DOI":"10.1371\/journal.pone.0285876","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T17:50:39Z","timestamp":1684259439000},"page":"e0285876","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Differential gene expression in peripheral leukocytes of pre-weaned Holstein heifer calves with respiratory disease"],"prefix":"10.1371","volume":"18","author":[{"given":"Lily A.","family":"Elder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holly R.","family":"Hinnant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris M.","family":"Mandella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel A.","family":"Claus-Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay M.","family":"Parrish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovana S.","family":"Slanzon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8085-5302","authenticated-orcid":true,"given":"Craig S.","family":"McConnel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"pone.0285876.ref001","unstructured":"USDA. Feedlot 2011 Part IV: Health and Health Management on U.S. Feedlots with a Capacity of 1,000 or More Head. Fort Collins, CO, USA; 2013 Sep pp. 18\u201327. Report No.: 638.0913."},{"key":"pone.0285876.ref002","unstructured":"USDA. Dairy 2014: Health and Management Practices on U.S. Dairy Operations, 2014. Fort Collins, CO, USA; 2018 Feb pp. 35\u201336. Report No.: 696.0218."},{"key":"pone.0285876.ref003","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.tvjl.2003.08.004","article-title":"Animal welfare implications of neonatal mortality and morbidity in farm animals","volume":"168","author":"DJ Mellor","year":"2004","journal-title":"Vet J"},{"key":"pone.0285876.ref004","first-page":"1095","article-title":"The epidemiology of bovine respiratory disease: what is the evidence for predisposing factors?","volume":"51","author":"JD Taylor","year":"2010","journal-title":"Can Vet J"},{"key":"pone.0285876.ref005","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0749-0720(15)30303-0","article-title":"Dairy calf pneumonia","volume":"13","author":"TR Ames","year":"1997","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref006","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cvfa.2006.03.009","article-title":"Bovine respiratory disease: pathogenesis, clinical signs, and treatment in lightweight calves","volume":"22","author":"M. Apley","year":"2006","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref007","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.cvfa.2020.03.006","article-title":"Bovine respiratory disease vaccination against viral pathogens: modified-live versus inactivated antigen vaccines, intranasal versus parenteral, what is the evidence?","volume":"36","author":"MF Chamorro","year":"2020","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref008","doi-asserted-by":"crossref","first-page":"11723","DOI":"10.3168\/jds.2019-18044","article-title":"Randomized clinical trial to assess the effect of antibiotic therapy on health and growth of preweaned dairy calves diagnosed with respiratory disease using respiratory scoring and lung ultrasound","volume":"103","author":"ES Binversie","year":"2020","journal-title":"J Dairy Sci"},{"key":"pone.0285876.ref009","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cvfa.2010.03.004","article-title":"Control, management, and prevention of bovine respiratory disease in dairy calves and cows","volume":"26","author":"PJ Gorden","year":"2010","journal-title":"Vet Clin Food Anim Pract"},{"key":"pone.0285876.ref010","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.cvfa.2020.03.009","article-title":"Bovine respiratory disease: looking back and looking forward, what do we see?","volume":"36","author":"RA Smith","year":"2020","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref011","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cvfa.2020.03.003","article-title":"Host tolerance to infection with the bacteria that cause bovine respiratory disease","volume":"36","author":"LL Bassel","year":"2020","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref012","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.micpath.2003.12.002","article-title":"Protective effect of dexamethasone in experimental bovine pneumonic mannheimiosis","volume":"36","author":"C Malazdrewich","year":"2004","journal-title":"Microb Pathog"},{"key":"pone.0285876.ref013","doi-asserted-by":"crossref","first-page":"11165","DOI":"10.3168\/jds.2021-20207","article-title":"Diagnosis of respiratory disease in preweaned dairy calves using sequential thoracic ultrasonography and clinical respiratory scoring: temporal transitions and association with growth rates","volume":"104","author":"V Rhodes","year":"2021","journal-title":"J Dairy Sci"},{"key":"pone.0285876.ref014","doi-asserted-by":"crossref","first-page":"e0227507","DOI":"10.1371\/journal.pone.0227507","article-title":"Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease","volume":"15","author":"MA Scott","year":"2020","journal-title":"PloS One"},{"key":"pone.0285876.ref015","doi-asserted-by":"crossref","first-page":"e0250758","DOI":"10.1371\/journal.pone.0250758","article-title":"Comprehensive at-arrival transcriptomic analysis of post-weaned beef cattle uncovers type I interferon and antiviral mechanisms associated with bovine respiratory disease mortality","volume":"16","author":"MA Scott","year":"2021","journal-title":"PloS One"},{"key":"pone.0285876.ref016","doi-asserted-by":"crossref","first-page":"e0131459","DOI":"10.1371\/journal.pone.0131459","article-title":"Immunological response to single pathogen challenge with agents of the bovine respiratory disease complex: an RNA-sequence analysis of the bronchial lymph node transcriptome","volume":"10","author":"PC Tizioto","year":"2015","journal-title":"PloS One"},{"key":"pone.0285876.ref017","doi-asserted-by":"crossref","first-page":"14736","DOI":"10.1038\/s41598-019-51094-z","article-title":"Experimental challenge with bovine respiratory syncytial virus in dairy calves: bronchial lymph node transcriptome response","volume":"9","author":"D Johnston","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0285876.ref018","doi-asserted-by":"crossref","first-page":"9392","DOI":"10.1038\/s41598-021-88878-1","article-title":"Messenger RNA biomarkers of bovine respiratory syncytial virus infection in the whole blood of dairy calves","volume":"11","author":"D Johnston","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0285876.ref019","doi-asserted-by":"crossref","first-page":"627623","DOI":"10.3389\/fgene.2021.627623","article-title":"Whole-blood transcriptome analysis of feedlot cattle with and without bovine respiratory disease","volume":"12","author":"J Jiminez","year":"2021","journal-title":"Front Genet"},{"key":"pone.0285876.ref020","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1186\/s13104-018-3900-x","article-title":"Complete blood count data and leukocyte expression of cytokine genes and cytokine receptor genes associated with bovine respiratory disease in calves","volume":"11","author":"AK Lindholm-Perry","year":"2018","journal-title":"BMC Res Notes"},{"key":"pone.0285876.ref021","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.1016\/j.ygeno.2020.07.014","article-title":"Longitudinal blood transcriptomic analysis to identify molecular regulatory patterns of bovine respiratory disease in beef cattle","volume":"112","author":"H-Z Sun","year":"2020","journal-title":"Genomics"},{"key":"pone.0285876.ref022","doi-asserted-by":"crossref","first-page":"e30244","DOI":"10.1371\/journal.pone.0030244","article-title":"Characterization and comparison of the leukocyte transcriptomes of three cattle breeds","volume":"7","author":"W Huang","year":"2012","journal-title":"PloS One"},{"key":"pone.0285876.ref023","doi-asserted-by":"crossref","first-page":"e0159707","DOI":"10.1371\/journal.pone.0159707","article-title":"Characterisation of the whole blood mRNA transcriptome in Holstein-Friesian and Jersey calves in response to gradual weaning","volume":"11","author":"D Johnston","year":"2016","journal-title":"PloS One"},{"key":"pone.0285876.ref024","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.2119\/molmed.2011.00169","article-title":"The influence of developmental age on the early transcriptomic response of children with septic shock","volume":"17","author":"JL Wynn","year":"2011","journal-title":"Mol Med"},{"key":"pone.0285876.ref025","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.cell.2018.06.045","article-title":"Stereotypic immune system development in newborn children","volume":"174","author":"A Olin","year":"2018","journal-title":"Cell"},{"key":"pone.0285876.ref026","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1186\/s12864-018-5050-x","article-title":"Prioritizing candidate genes post-GWAS using multiple sources of data for mastitis resistance in dairy cattle","volume":"19","author":"Z Cai","year":"2018","journal-title":"BMC Genomics"},{"key":"pone.0285876.ref027","doi-asserted-by":"crossref","first-page":"358","DOI":"10.4236\/ojas.2015.54040","article-title":"Combining genome wide association studies and differential gene expression data analyses identifies candidate genes affecting mastitis caused by two different pathogens in the dairy cow","volume":"5","author":"X Chen","year":"2015","journal-title":"Open J Anim Sci"},{"key":"pone.0285876.ref028","doi-asserted-by":"crossref","first-page":"784","DOI":"10.15232\/aas.2020-02092","article-title":"Transcriptomic analysis of peripheral leukocytes in dairy cows with and without evidence of metritis and associated early postpartum disease","volume":"36","author":"C McConnel","year":"2020","journal-title":"Appl Anim Sci"},{"key":"pone.0285876.ref029","doi-asserted-by":"crossref","first-page":"559279","DOI":"10.3389\/fvets.2020.559279","article-title":"A Fixed Cohort Field Study of Gene Expression in Circulating Leukocytes From Dairy Cows With and Without Mastitis","volume":"7","author":"CS McConnel","year":"2020","journal-title":"Front Vet Sci"},{"key":"pone.0285876.ref030","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.vetimm.2006.02.006","article-title":"Differential expression of genes encoding CD30L and P-selectin in cattle with Johne\u2019s disease: progress toward a diagnostic gene expression signature","volume":"112","author":"K Skovgaard","year":"2006","journal-title":"Vet Immunol Immunopathol"},{"key":"pone.0285876.ref031","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.cvfa.2007.10.003","article-title":"Disease Management of Dairy Calves and Heifers","volume":"24","author":"SM McGuirk","year":"2008","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref032","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cvfa.2015.09.001","article-title":"On-farm use of ultrasonography for bovine respiratory disease","volume":"32","author":"TL Ollivett","year":"2016","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0285876.ref033","first-page":"e151","article-title":"NanoStringDiff: a novel statistical method for differential expression analysis based on NanoString nCounter data","volume":"44","author":"H Wang","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pone.0285876.ref034","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1471-2199-7-3","article-title":"The RIN: an RNA integrity number for assigning integrity values to RNA measurements","volume":"7","author":"A Schroeder","year":"2006","journal-title":"BMC Mol Biol"},{"key":"pone.0285876.ref035","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.prevetmed.2015.02.018","article-title":"Bayesian estimation of the accuracy of the calf respiratory scoring chart and ultrasonography for the diagnosis of bovine respiratory disease in pre-weaned dairy calves","volume":"119","author":"S Buczinski","year":"2015","journal-title":"Prev Vet Med"},{"key":"pone.0285876.ref036","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.vetimm.2006.04.001","article-title":"Lymphocyte subpopulations and neutrophil function in calves during the first 6 months of life","volume":"113","author":"AH Kampen","year":"2006","journal-title":"Vet Immunol Immunopathol"},{"key":"pone.0285876.ref037","doi-asserted-by":"crossref","first-page":"110417","DOI":"10.1016\/j.vetimm.2022.110417","article-title":"Flow cytometry panels for immunophenotyping dairy cattle peripheral blood leukocytes","volume":"248","author":"S Casaro","year":"2022","journal-title":"Vet Immunol Immunopathol"},{"key":"pone.0285876.ref038","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.3389\/fimmu.2018.03011","article-title":"Bovine neonatal monocytes display phenotypic differences compared with adults after challenge with the infectious abortifacient agent Neospora caninum","volume":"9","author":"P Sharma","year":"2018","journal-title":"Front Immunol"},{"key":"pone.0285876.ref039","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nri.2015.4","article-title":"Specialized pro-resolving mediators: endogenous regulators of infection and inflammation","volume":"16","author":"MC Basil","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"pone.0285876.ref040","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.bbalip.2010.08.002","article-title":"Specialized pro-resolving lipid mediators in the inflammatory response: An update","volume":"1801","author":"G Bannenberg","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"pone.0285876.ref041","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/s41418-020-00652-4","article-title":"Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation","volume":"28","author":"RG Snodgrass","year":"2021","journal-title":"Cell Death Differ"},{"key":"pone.0285876.ref042","doi-asserted-by":"crossref","first-page":"1010039","DOI":"10.3389\/fvets.2022.1010039","article-title":"Impact of preweaning vaccination on host gene expression and antibody titers in healthy beef calves","volume":"9","author":"MA Scott","year":"2022","journal-title":"Front Vet Sci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0285876","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T17:51:34Z","timestamp":1684259494000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0285876"}},"subtitle":[],"editor":[{"given":"Angel","family":"Abuelo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0285876","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]}}}