{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T04:15:01Z","timestamp":1744863301656,"version":"3.40.4"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL145396"],"award-info":[{"award-number":["R01 HL145396"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA270792"],"award-info":[{"award-number":["R01 CA270792"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32 HL007106"],"award-info":[{"award-number":["T32 HL007106"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Streptococcus pneumoniae<\/jats:italic> is the leading cause of community-acquired pneumonia. Mertk is a receptor tyrosine kinase and a member of the TAM family. It serves as an efferocytosis receptor involved in the recognition and removal of apoptotic debris by phagocytic cells, dampening the inflammatory response. Here we show that at 24h post-inoculation with <jats:italic>S. pneumoniae<\/jats:italic>, <jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice generated through homologous recombination and backcrossed (HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice) have fewer bacteria present in their pneumonic lung than wild type mice. This enhanced clearance was not observed in <jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice generated by CRISPR technology. The enhanced clearance of HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice was associated with fewer neutrophils and more IFN\u03b3 in the bronchoalveolar lavage, but was not prevented by a neutralizing IFN\u03b3 antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus, suggesting that they are primed for an inflammatory response. HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice similarly had enhanced host defense pathways in <jats:italic>S. pneumoniae-<\/jats:italic>stimulated alveolar macrophages <jats:italic>in vitro<\/jats:italic> and in pneumonic lung tissue. However, HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> alveolar macrophages demonstrated no defect in phagocytosis and acidification <jats:italic>in vivo<\/jats:italic>, and genes and gene sets describing phagocytic pathways were not enriched, suggesting that the enhanced clearance may be through alterations in the lung microenvironment. HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice are reported to have a long 129P2 DNA insert (~645 genes) in chromosome 2 adjacent to Mertk, as well as other alterations at multiple sites. Thus, while Mertk deficiency may contribute to the enhanced bacterial clearance, it is not solely responsible, because the phenotype is not seen in the CRISPR-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice. The 129P2 DNA insert in the HRB-<jats:italic>Mertk<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice must be mediating at least some of this phenotype. Understanding the mechanistic differences and the means by which this 129P2 DNA insert enhances bacterial clearance remains critically important.<\/jats:p>","DOI":"10.1371\/journal.pone.0320660","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T17:45:12Z","timestamp":1744825512000},"page":"e0320660","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Host responses to S. pneumoniae in wild type and Mertk mutant mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Matthew K.","family":"McPeek","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7960-9043","authenticated-orcid":true,"given":"Yitong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Dang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. Shelton","family":"Earp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2638-3321","authenticated-orcid":true,"given":"Claire M.","family":"Doerschuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"issue":"2","key":"pone.0320660.ref001","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1164\/rccm.201801-0139WS","article-title":"Future Research Directions in Pneumonia. NHLBI Working Group Report","volume":"198","author":"CS Dela Cruz","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"issue":"3","key":"pone.0320660.ref002","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1152\/physrev.00032.2017","article-title":"Integrative Physiology of Pneumonia","volume":"98","author":"LJ Quinton","year":"2018","journal-title":"Physiol Rev"},{"issue":"5","key":"pone.0320660.ref003","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1097\/MCC.0000000000000756","article-title":"Nosocomial pneumonia diagnosis revisited","volume":"26","author":"D Koulenti","year":"2020","journal-title":"Curr Opin Crit Care"},{"issue":"3","key":"pone.0320660.ref004","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/MCP.0000000000000671","article-title":"Update in adult community-acquired pneumonia: key points from the new American Thoracic Society\/Infectious Diseases Society of America 2019 guideline","volume":"26","author":"JP Metlay","year":"2020","journal-title":"Curr Opin Pulm Med"},{"key":"pone.0320660.ref005","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.3389\/fimmu.2020.01722","article-title":"Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury","volume":"11","author":"V Kumar","year":"2020","journal-title":"Front Immunol"},{"key":"pone.0320660.ref006","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev-physiol-021014-071937","article-title":"Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling","volume":"77","author":"LJ Quinton","year":"2015","journal-title":"Annu Rev Physiol"},{"issue":"9","key":"pone.0320660.ref007","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1164\/rccm.201206-1063PP","article-title":"Respiratory infection and the impact of pulmonary immunity on lung health and disease","volume":"186","author":"JP Mizgerd","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"pone.0320660.ref008","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s41479-023-00106-8","article-title":"Innate immune responses in pneumonia","volume":"15","author":"FT Korkmaz","year":"2023","journal-title":"Pneumonia (Nathan)"},{"issue":"1","key":"pone.0320660.ref009","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"D Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"4","key":"pone.0320660.ref010","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1111\/j.1462-5822.2011.01746.x","article-title":"Recognition of Streptococcus pneumoniae by the innate immune system","volume":"14","author":"U Koppe","year":"2012","journal-title":"Cell Microbiol"},{"issue":"6","key":"pone.0320660.ref011","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1165\/rcmb.2020-0311OC","article-title":"TBK1 Is Required for Host Defense Functions Distinct from Type I IFN Expression and Myeloid Cell Recruitment in Murine Streptococcus pneumoniae Pneumonia","volume":"66","author":"RS Hagan","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"pone.0320660.ref012","doi-asserted-by":"crossref","first-page":"929483","DOI":"10.3389\/fcimb.2022.929483","article-title":"Streptococcus pneumoniae interactions with the complement system","volume":"12","author":"E Gil","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"issue":"12","key":"pone.0320660.ref013","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrc3847","article-title":"The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer","volume":"14","author":"DK Graham","year":"2014","journal-title":"Nat Rev Cancer"},{"issue":"11","key":"pone.0320660.ref014","doi-asserted-by":"crossref","first-page":"a009076","DOI":"10.1101\/cshperspect.a009076","article-title":"Biology of the TAM receptors","volume":"5","author":"G Lemke","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"pone.0320660.ref015","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-immunol-032414-112103","article-title":"TAM receptor signaling in immune homeostasis","volume":"33","author":"CV Rothlin","year":"2015","journal-title":"Annu Rev Immunol"},{"key":"pone.0320660.ref016","doi-asserted-by":"crossref","first-page":"e03385","DOI":"10.7554\/eLife.03385","article-title":"Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities","volume":"3","author":"ED Lew","year":"2014","journal-title":"Elife"},{"issue":"2","key":"pone.0320660.ref017","doi-asserted-by":"crossref","first-page":"e1646","DOI":"10.1038\/cddis.2015.18","article-title":"Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells","volume":"6","author":"I Dransfield","year":"2015","journal-title":"Cell Death Dis"},{"issue":"9","key":"pone.0320660.ref018","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1084\/jem.20101157","article-title":"Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums","volume":"207","author":"KS Ravichandran","year":"2010","journal-title":"J Exp Med"},{"issue":"6834","key":"pone.0320660.ref019","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/35075603","article-title":"Phagocytosis and clearance of apoptotic cells is mediated by MER","volume":"411","author":"RS Scott","year":"2001","journal-title":"Nature"},{"issue":"12","key":"pone.0320660.ref020","doi-asserted-by":"crossref","first-page":"e1005723","DOI":"10.1371\/journal.pgen.1005723","article-title":"Tyro3 Modulates Mertk-Associated Retinal Degeneration","volume":"11","author":"D Vollrath","year":"2015","journal-title":"PLoS Genet"},{"key":"pone.0320660.ref021","doi-asserted-by":"crossref","first-page":"e80530","DOI":"10.7554\/eLife.80530","article-title":"Tissue-specific modifier alleles determine Mertk loss-of-function traits","volume":"11","author":"YT Akalu","year":"2022","journal-title":"Elife"},{"issue":"6","key":"pone.0320660.ref022","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.4049\/jimmunol.162.6.3498","article-title":"A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock","volume":"162","author":"TD Camenisch","year":"1999","journal-title":"J Immunol"},{"key":"pone.0320660.ref023","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.3389\/fimmu.2019.01864","article-title":"In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection","volume":"10","author":"N Sharma-Chawla","year":"2019","journal-title":"Front Immunol"},{"issue":"3","key":"pone.0320660.ref024","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.micinf.2006.12.003","article-title":"Role of interferon-gamma in Valpha14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs","volume":"9","author":"M Nakamatsu","year":"2007","journal-title":"Microbes Infect"},{"issue":"1","key":"pone.0320660.ref025","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"},{"issue":"3","key":"pone.0320660.ref026","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"M Pertea","year":"2015","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pone.0320660.ref027","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"voom: Precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"CW Law","year":"2014","journal-title":"Genome Biol"},{"issue":"7","key":"pone.0320660.ref028","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"43","key":"pone.0320660.ref029","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"A Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0320660.ref030","volume-title":"Fast gene set enrichment analysis 2016","author":"G Korotkevich"},{"issue":"1","key":"pone.0320660.ref031","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"M Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"pone.0320660.ref032","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-4939-6783-4_11","article-title":"Functional Interaction Network Construction and Analysis for Disease Discovery","volume":"1558","author":"G Wu","year":"2017","journal-title":"Methods Mol Biol"},{"issue":"1","key":"pone.0320660.ref033","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12859-015-0611-3","article-title":"InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams","volume":"16","author":"H Heberle","year":"2015","journal-title":"BMC Bioinformatics"},{"issue":"18","key":"pone.0320660.ref034","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Z Gu","year":"2016","journal-title":"Bioinformatics"},{"issue":"4","key":"pone.0320660.ref035","first-page":"656","article-title":"BLAT--the BLAST-like alignment tool","volume":"12","author":"WJ Kent","year":"2002","journal-title":"Genome Res"},{"issue":"Database issue","key":"pone.0320660.ref036","first-page":"D493-6","article-title":"The UCSC Table Browser data retrieval tool","volume":"32","author":"D Karolchik","year":"2004","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0320660.ref037","doi-asserted-by":"crossref","first-page":"L41","DOI":"10.1152\/ajplung.00039.2024","article-title":"Leukocyte kinetics and bacterial clearance during Streptococcus pneumoniae pneumonia and contributions of ICAM-1","volume":"328","author":"MK McPeek","year":"2025","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"9","key":"pone.0320660.ref038","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1158\/2326-6066.CIR-23-0666","article-title":"MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming","volume":"12","author":"EY Zewdie","year":"2024","journal-title":"Cancer Immunol Res"},{"issue":"9","key":"pone.0320660.ref039","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41577-019-0167-y","article-title":"How macrophages deal with death","volume":"19","author":"G Lemke","year":"2019","journal-title":"Nat Rev Immunol"},{"issue":"5","key":"pone.0320660.ref040","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/mi.2014.129","article-title":"The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung","volume":"8","author":"T Fujimori","year":"2015","journal-title":"Mucosal Immunol"},{"issue":"1","key":"pone.0320660.ref041","doi-asserted-by":"crossref","first-page":"L69","DOI":"10.1152\/ajplung.00058.2017","article-title":"Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK","volume":"314","author":"MP Mohning","year":"2018","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"1","key":"pone.0320660.ref042","doi-asserted-by":"crossref","first-page":"110-125.e11","DOI":"10.1016\/j.cell.2020.08.020","article-title":"Patrolling Alveolar Macrophages Conceal Bacteria from the Immune System to Maintain Homeostasis","volume":"183","author":"AS Neupane","year":"2020","journal-title":"Cell"},{"issue":"2","key":"pone.0320660.ref043","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nri3600","article-title":"Alveolar macrophages: plasticity in a tissue-specific context","volume":"14","author":"T Hussell","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"pone.0320660.ref044","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.molimm.2016.06.016","article-title":"Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K\/Akt and SOCS3","volume":"76","author":"B Zhang","year":"2016","journal-title":"Mol Immunol"},{"issue":"5","key":"pone.0320660.ref045","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1189\/jlb.0909610","article-title":"TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes\/macrophages","volume":"87","author":"F Alciato","year":"2010","journal-title":"J Leukoc Biol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0320660","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T17:45:28Z","timestamp":1744825528000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0320660"}},"subtitle":[],"editor":[{"given":"James P.","family":"Maloney","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0320660","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,16]]}}}