{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T20:46:38Z","timestamp":1793738798842,"version":"4.6.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI156293, AI159347, AI139449"],"award-info":[{"award-number":["AI156293, AI159347, AI139449"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The increased susceptibility of neonates to specific pathogens has previously been attributed to an underdeveloped immune system. More recent data suggest neonates have effective protection against most pathogens but are particularly susceptible to those that target immune functions specific to neonates. <jats:italic>Bordetella pertussis<\/jats:italic> (<jats:italic>Bp<\/jats:italic>), the causative agent of \u201cwhooping cough\u201d, causes more serious disease in infants attributed to its production of pertussis toxin (PTx), although the neonate-specific immune functions it targets remain unknown. Problematically, the rapid development of adult immunity in mice has confounded our ability to study interactions of the neonatal immune system and its components, such as virtual memory T cells which are prominent prior to the maturation of the thymus. Here, we examine the rapid change in susceptibility of young mice and define a period from five- to eight-days-old during which mice are much more susceptible to <jats:italic>Bp<\/jats:italic> than mice even a couple days older. These more narrowly defined \u201cneonatal\u201d mice display significantly increased susceptibility to wild type <jats:italic>Bp<\/jats:italic> but very rapidly and effectively respond to and control <jats:italic>Bp<\/jats:italic> lacking PTx, more rapidly even than adult mice. Thus, PTx efficiently blocks some very effective form(s) of neonatal protective immunity, potentially providing a tool to better understand the neonatal immune system. The rapid clearance of the PTx mutant correlates with the early accumulation of neutrophils and T cells and suggests a role for PTx in disrupting their accumulation. These results demonstrate a striking age-dependent response to <jats:italic>Bp<\/jats:italic>, define an early age of extreme susceptibility to <jats:italic>Bp<\/jats:italic>, and demonstrate that the neonatal response can be more efficient than the adult response in eliminating bacteria from the lungs, but these neonatal functions are substantially blocked by PTx. This refined definition of \u201cneonatal\u201d mice may be useful in the study of other pathogens that primarily infect neonates, and PTx may prove a particularly valuable tool for probing the poorly understood neonatal immune system.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1125794","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T07:04:02Z","timestamp":1675839842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis"],"prefix":"10.3389","volume":"14","author":[{"given":"Colleen J.","family":"Sedney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Caulfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylan K.","family":"Dewan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uriel","family":"Blas-Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiya","family":"Callender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy R.","family":"Manley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T.","family":"Harvill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60522-4","article-title":"Assessment of the 2010 global measles mortality reduction goal: Results from a model of surveillance data","volume":"379","author":"Simons","year":"2012","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60206-1","article-title":"Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: A systematic review and meta-analysis","volume":"375","author":"Nair","year":"2010","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30390-0","article-title":"An update of the global burden of pertussis in children younger than 5 years: A modelling study","volume":"17","author":"Yeung","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2014.942288","article-title":"Immune responses in neonates","volume":"10","author":"Basha","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-091319-083608.Neonatal","article-title":"Neonatal T cells: A reinterpretation","volume":"176","author":"Rudd","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700742","article-title":"Erythroid suppressor cells compromise neonatal immune response against bordetella pertussis","volume":"199","author":"Dunsmore","year":"2017","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/mi.2012.54","article-title":"Immunity to the respiratory pathogen bordetella pertussis","volume":"5","author":"Higgs","year":"2012","journal-title":"Mucosal Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90748-4","article-title":"Toward a layered immune system","volume":"59","author":"Herzenberg","year":"1989","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.cell.2018.05.029","article-title":"Developmental origin governs CD8+ T cell fate decisions during infection","volume":"174","author":"Smith","year":"2018","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102213","article-title":"Derivation and maintenance of virtual memory CD8 T cells","volume":"188","author":"Akue","year":"2012","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4467","article-title":"Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation","volume":"24","author":"He","year":"2018","journal-title":"Nat Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature12675","article-title":"Immunosuppressive CD71 + erythroid cells compromise neonatal host defence against infection","volume":"504","author":"Elahi","year":"2013","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307572110","article-title":"Virtual memory CD8 T cells display unique functional properties","volume":"110","author":"Lee","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081829","article-title":"The antigen-specific CD8 + T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion","volume":"206","author":"Lee","year":"2009","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501867","article-title":"The neonatal CD8 + T cell repertoire rapidly diversifies during persistent viral infection","volume":"196","author":"Haluszczak","year":"2016","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.abj0789","article-title":"Infant T cells are developmentally adapted for robust lung immune responses through enhanced T cell receptor signaling","volume":"6","author":"Venturi","year":"2016","journal-title":"Sci Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.immuni.2018.07.011","article-title":"Lung \u03b3\u03b4 T cells mediate protective responses during neonatal influenza infection that are associated with type 2 immunity","volume":"49","author":"Thapa","year":"2018","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2016.00141","article-title":"Rapid CD8+ function is critical for protection of neonatal mice from an extracellular bacterial enteropathogen","volume":"4","author":"Siefker","year":"2017","journal-title":"Front Pediatr"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05492-y","article-title":"A mouse model reproducing the pathophysiology of neonatal group b streptococcal infection","volume":"9","author":"Siefker","year":"2018","journal-title":"Nat Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00723","article-title":"Use of a neonatal-mouse model to characterize vaccines and strategies for overcoming the high susceptibility and severity of pertussis in early life","volume":"11","author":"Martin Aispuro","year":"2020","journal-title":"Front Microbiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.7.3521-3528.2002","article-title":"Immunogenicity and protective efficacy of neonatal vaccination against bordetella pertussis in a murine model: Evidence for early control of pertussis","volume":"70","author":"Martin Aispuro","year":"2002","journal-title":"Infect Immun"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/IAI.00355-17","article-title":"Fatal pertussis in the neonatal mouse model is associated with pertussis toxin-mediated pathology beyond the airways","volume":"85","author":"Scanlon","year":"2017","journal-title":"Infect Immun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1097\/01.inf.0000160911.65632.e1","article-title":"Health burden of pertussis in infants and children","volume":"24","author":"Greenberg","year":"2005","journal-title":"Pediatr Infect Dis J"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2012-302968","article-title":"Strategies to control pertussis in infants","volume":"98","author":"Amirthalingam","year":"2013","journal-title":"Arch Dis Child"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00808-12","article-title":"Pertussis toxin exacerbates and prolongs airway inflammatory responses during bordetella pertussis infection","volume":"80","author":"Connelly","year":"2012","journal-title":"Infect Immun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/toxins3070884","article-title":"Gi\/o protein-dependent and -independent actions of pertussis toxin (ptx)","volume":"3","author":"Mangmool","year":"2011","journal-title":"Toxins (Basel)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00414-07","article-title":"Pertussis toxin utilizes proximal components of the T-cell receptor complex to initiate signal transduction events in T cells","volume":"75","author":"Schneider","year":"2007","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803114","article-title":"Pertussis toxin signals through the TCR to initiate cross-desensitization of the chemokine receptor CXCR4","volume":"182","author":"Schneider","year":"2009","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24609","article-title":"Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of bordetella pertussis","volume":"115","author":"Kirimanjeswara","year":"2005","journal-title":"J Clin Invest"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/iai.67.11.6109-6118.1999","article-title":"Pregenomic comparative analysis between bordetella bronchiseptica RB50 and bordetella pertussis tohama I in murine models of respiratory tract infection","volume":"67","author":"Harvill","year":"1999","journal-title":"Infect Immun"},{"key":"B31","doi-asserted-by":"crossref","unstructured":"PizzaM\n          Mutants of pertussis toxin suitable for vaccine development and rino rappuoli published by : American association for the advancement of science1989","DOI":"10.1126\/science.2683073"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.6.3350-3358.2004","article-title":"Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by bordetella pertussis and identification of an immunodominant lipoprotein","volume":"72","author":"Carbonetti","year":"2004","journal-title":"Infect Immun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646632","article-title":"Guidelines for the use of flow cytometry and cell sorting in immunological studies","volume":"47","author":"Carbonetti","year":"2017","journal-title":"Eur J Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12277","article-title":"Similar but different: Virtual memory CD8 T cells as a memory-like cell population","volume":"97","author":"Hussain","year":"2019","journal-title":"Immunol Cell Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0067401","article-title":"T-Bet and eomes regulate the balance between the Effector\/Central memory T cells versus memory stem like T cells","volume":"8","author":"Hussain","year":"2013","journal-title":"PloS One"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0086MA","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung","volume":"49","author":"v. Misharin","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01077","article-title":"Outgrowing the immaturity myth: The cost of defending from neonatal infectious disease","volume":"9","author":"Harbeson","year":"2018","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"crossref","unstructured":"ZhaoJ\n            Dong KimK\n            YangX\n            AuhS\n            FuY-X\n            TangH\n          Hyper innate responses in neonates lead to increased morbidity and mortality after infection2008","DOI":"10.1073\/pnas.0800152105"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2004.02313.x","article-title":"Immature anti-inflammatory response in neonates","volume":"135","author":"Schultz","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0107071","article-title":"Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages","volume":"82","author":"Chelvarajan","year":"2007","journal-title":"J Leukoc Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2017.00023","article-title":"Age-appropriate functions and dysfunctions of the neonatal neutrophil","volume":"5","author":"Lawrence","year":"2017","journal-title":"Front Pediatr"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms21228626","article-title":"Hiding in plain sight: Virtually unrecognizable memory phenotype CD8+ T cells","volume":"21","author":"Thiele","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0662-0","article-title":"Forget \u201cME\u201d not virtual memory cells","volume":"21","author":"Daniels","year":"","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15252\/embj.201899883","article-title":"The virtuous self-tolerance of virtual memory T cells","volume":"37","author":"Truckenbrod","year":"2018","journal-title":"EMBO J"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abg9433","article-title":"Virtual memory T cells orchestrate extralymphoid responses conducive to resident memory","volume":"6","author":"Hou","year":"2021","journal-title":"Sci Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401661","article-title":"Early development in the peritoneal cavity of CD49d high Th1 memory phenotype CD4 + T cells with enhanced b cell helper activity","volume":"195","author":"Moon","year":"2015","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/ftv073","article-title":"Contribution of pertussis toxin to the pathogenesis of pertussis disease","volume":"73","author":"Carbonetti","year":"2015","journal-title":"Pathog Dis"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.11.6358-6366.2003","article-title":"Pertussis toxin plays an early role in respiratory tract colonization by bordetella pertussis","volume":"71","author":"Carbonetti","year":"2003","journal-title":"Infect Immun"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007079","article-title":"Pertussis toxin stimulates IL-17 production in response to bordetella pertussis infection in mice","volume":"4","author":"Andreasen","year":"2009","journal-title":"PloS One"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00895-08","article-title":"Pertussis toxin inhibits early chemokine production to delay neutrophil recruitment in response to bordetella pertussis respiratory tract infection in mice","volume":"76","author":"Andreasen","year":"2008","journal-title":"Infect Immun"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01578-06","article-title":"Pertussis toxin targets airway macrophages to promote bordetella pertussis infection of the respiratory tract","volume":"75","author":"Carbonetti","year":"2007","journal-title":"Infect Immun"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7134168","article-title":"Neonatal immunity to bordetella pertussis infection and current prevention strategies","volume":"2019","author":"Argondizo-Correia","year":"2019","journal-title":"J Immunol Res"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.aay9258","article-title":"Neutralization of pertussis toxin by a single antibody prevents clinical pertussis in neonatal baboons","volume":"6","author":"Nguyen","year":"2020","journal-title":"Sci Adv"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1125794\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,12]],"date-time":"2023-02-12T09:39:40Z","timestamp":1676194780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1125794\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2023.1125794"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1125794","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]},"article-number":"1125794"}}