{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:19:26Z","timestamp":1791145166415,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AI128527"],"award-info":[{"award-number":["R21 AI128527"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL118408"],"award-info":[{"award-number":["R01 HL118408"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Secondary Streptococcus pneumoniae infection is a significant cause of morbidity and mortality during influenza epidemics and pandemics. Multiple pathogenic mechanisms, such as lung epithelial damage and dysregulation of neutrophils and alveolar macrophages (AMs), have been suggested to contribute to the severity of disease. However, the fundamental reasons for influenza-induced susceptibility to secondary bacterial pneumonia remain unclear. In this study, we revisited these controversies over key pathogenic mechanisms in a lethal model of secondary bacterial pneumonia with an S. pneumoniae strain that is innocuous to mice in the absence of influenza infection. Using a series of in vivo models, we demonstrate that rather than a systemic suppression of immune responses or neutrophil function, influenza infection activates IFN-\u03b3R signaling and abrogates AM-dependent bacteria clearance and thereby causes extreme susceptibility to pneumococcal infection. Importantly, using mice carrying conditional knockout of Ifngr1 gene in different myeloid cell subsets, we demonstrate that influenza-induced IFN-\u03b3R signaling in AMs impairs their antibacterial function, thereby enabling otherwise noninvasive S. pneumoniae to cause deadly pneumonia.<\/jats:p>","DOI":"10.4049\/jimmunol.2000094","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T21:25:20Z","timestamp":1599600320000},"page":"1601-1607","source":"Crossref","is-referenced-by-count":69,"title":["Influenza Infection Induces Alveolar Macrophage Dysfunction and Thereby Enables Noninvasive\n                    <i>Streptococcus pneumoniae<\/i>\n                    to Cause Deadly Pneumonia"],"prefix":"10.1093","volume":"205","author":[{"given":"Atul K","family":"Verma","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruti","family":"Bansal","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-9582","authenticated-orcid":false,"given":"Christopher","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abenaya","family":"Muralidharan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-9584","authenticated-orcid":false,"given":"Keer","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,15]]},"reference":[{"key":"2025030417505046200_r1","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.4049\/jimmunol.1301152","article-title":"Immune dysfunction and bacterial coinfections following influenza","volume":"191","author":"Metzger","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417505046200_r2","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1086\/591708","article-title":"Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness","volume":"198","author":"Morens","year":"2008","journal-title":"J. Infect. Dis."},{"key":"2025030417505046200_r3","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.3201\/eid1408.070751","article-title":"Bacterial pneumonia and pandemic influenza planning","volume":"14","author":"Gupta","year":"2008","journal-title":"Emerg. Infect. Dis."},{"key":"2025030417505046200_r4","first-page":"941","article-title":"Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection - United States, April-August 2009","volume":"58","author":"Centers for Disease Control and Prevention (CDC)","year":"2009","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"2025030417505046200_r5","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1128\/CMR.00058-05","article-title":"Insights into the interaction between influenza virus and pneumococcus","volume":"19","author":"McCullers","year":"2006","journal-title":"Clin. Microbiol. Rev."},{"key":"2025030417505046200_r6","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1073\/pnas.1414422112","article-title":"Influenza viral neuraminidase primes bacterial coinfection through TGF-\u03b2-mediated expression of host cell receptors","volume":"112","author":"Li","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417505046200_r7","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1042\/BST0370811","article-title":"The innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia","volume":"37","author":"Hussell","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"2025030417505046200_r8","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.4049\/jimmunol.173.7.4576","article-title":"An important role for polymeric Ig receptor-mediated transport of IgA in protection against Streptococcus pneumoniae nasopharyngeal carriage","volume":"173","author":"Sun","year":"2004","journal-title":"J. Immunol."},{"key":"2025030417505046200_r9","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1093\/infdis\/jit375","article-title":"Serotype-specific effect of influenza on adult invasive pneumococcal pneumonia","volume":"208","author":"Weinberger","year":"2013","journal-title":"J. Infect. Dis."},{"key":"2025030417505046200_r10","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1172\/JCI35412","article-title":"Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice","volume":"119","author":"Shahangian","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2025030417505046200_r11","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/emmm.201302890","article-title":"Activation of IL-27 signalling promotes development of postinfluenza pneumococcal pneumonia","volume":"6","author":"Cao","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"2025030417505046200_r12","doi-asserted-by":"crossref","first-page":"12304","DOI":"10.1128\/JVI.01269-12","article-title":"Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of \u03b3\u03b4 T cells","volume":"86","author":"Li","year":"2012","journal-title":"J. Virol."},{"key":"2025030417505046200_r13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.4049\/jimmunol.1701406","article-title":"Effects of influenza on alveolar macrophage viability are dependent on mouse genetic strain","volume":"201","author":"Califano","year":"2018","journal-title":"J. Immunol."},{"key":"2025030417505046200_r14","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nm1765","article-title":"Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection","volume":"14","author":"Sun","year":"2008","journal-title":"Nat. Med."},{"key":"2025030417505046200_r15","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003238","article-title":"Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae","volume":"9","author":"Smith","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025030417505046200_r16","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.4049\/jimmunol.1300014","article-title":"Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections","volume":"191","author":"Ghoneim","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417505046200_r17","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1172\/JCI57762","article-title":"Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice","volume":"121","author":"Nakamura","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2025030417505046200_r18","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201899176","article-title":"Loss of T-bet confers survival advantage to influenza-bacterial superinfection","volume":"38","author":"Er","year":"2019","journal-title":"EMBO J."},{"key":"2025030417505046200_r19","doi-asserted-by":"crossref","first-page":"9565","DOI":"10.1073\/pnas.92.21.9565","article-title":"Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5","volume":"92","author":"Robb","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417505046200_r20","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.4049\/jimmunol.1300910","article-title":"Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-\u03b3 receptor subunit 1 (IFNGR1)","volume":"191","author":"Lee","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417505046200_r21","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1008942828960","article-title":"Conditional gene targeting in macrophages and granulocytes using LysMcre mice","volume":"8","author":"Clausen","year":"1999","journal-title":"Transgenic Res."},{"key":"2025030417505046200_r22","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1084\/jem.20062648","article-title":"Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen","volume":"204","author":"Caton","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030417505046200_r23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.immuni.2012.12.001","article-title":"Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. [Published erratum appears in 2013 Immunity 38: 1073\u20131079.]","volume":"38","author":"Yona","year":"2013","journal-title":"Immunity"},{"key":"2025030417505046200_r24","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.cell.2004.10.010","article-title":"JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells","volume":"119","author":"Passegu\u00e9","year":"2004","journal-title":"Cell"},{"key":"2025030417505046200_r25","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"2025030417505046200_r26","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.4049\/jimmunol.1700210","article-title":"IL-1 signaling prevents alveolar macrophage depletion during influenza and Streptococcus pneumoniae coinfection","volume":"200","author":"Bansal","year":"2018","journal-title":"J. Immunol."},{"key":"2025030417505046200_r27","doi-asserted-by":"crossref","first-page":"6058","DOI":"10.4049\/jimmunol.175.9.6058","article-title":"MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages","volume":"175","author":"Arredouani","year":"2005","journal-title":"J. Immunol."},{"key":"2025030417505046200_r28","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1004053","article-title":"Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection","volume":"10","author":"Schneider","year":"2014","journal-title":"PLoS Pathog."},{"key":"2025030417505046200_r29","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00441-017-2737-2","article-title":"Neutrophil evasion strategies by Streptococcus pneumoniae and Staphylococcus aureus","volume":"371","author":"Lewis","year":"2018","journal-title":"Cell Tissue Res."},{"key":"2025030417505046200_r30","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00329-19","article-title":"Interleukin 17 receptor E (IL-17RE) and IL-17C mediate the recruitment of neutrophils during acute Streptococcus pneumoniae pneumonia","volume":"87","author":"Steck","year":"2019","journal-title":"Infect. Immun."},{"key":"2025030417505046200_r31","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.4049\/jimmunol.1402401","article-title":"The \u03b1-tocopherol form of vitamin E reverses age-associated susceptibility to streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment","volume":"194","author":"Bou Ghanem","year":"2015","journal-title":"J. Immunol."},{"key":"2025030417505046200_r32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.chom.2010.09.003","article-title":"A mouse model for the human pathogen Salmonella typhi","volume":"8","author":"Song","year":"2010","journal-title":"Cell Host Microbe"},{"key":"2025030417505046200_r33","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1073\/pnas.1019682108","article-title":"Human IL-3\/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung","volume":"108","author":"Willinger","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417505046200_r34","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/90795","article-title":"Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice","volume":"19","author":"Saito","year":"2001","journal-title":"Nat. Biotechnol."},{"key":"2025030417505046200_r35","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1172\/JCI31990","article-title":"Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens","volume":"117","author":"Miyake","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025030417505046200_r36","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1002\/eji.201344359","article-title":"Transient ablation of alveolar macrophages leads to massive pathology of influenza infection without affecting cellular adaptive immunity","volume":"44","author":"Purnama","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"2025030417505046200_r37","doi-asserted-by":"crossref","first-page":"6911","DOI":"10.1128\/JVI.02943-12","article-title":"Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection","volume":"87","author":"Ivanov","year":"2013","journal-title":"J. Virol."},{"key":"2025030417505046200_r38","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/mi.2016.49","article-title":"Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection","volume":"10","author":"Barthelemy","year":"2016","journal-title":"Mucosal Immunol."},{"key":"2025030417505046200_r39","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1038\/s41564-019-0447-0","article-title":"Direct interactions with influenza promote bacterial adherence during respiratory infections","volume":"4","author":"Rowe","year":"2019","journal-title":"Nat. Microbiol."},{"key":"2025030417505046200_r40","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1126\/science.1233632","article-title":"Role of tissue protection in lethal respiratory viral-bacterial coinfection","volume":"340","author":"Jamieson","year":"2013","journal-title":"Science"},{"key":"2025030417505046200_r41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.chom.2010.01.010","article-title":"Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection","volume":"7","author":"Jamieson","year":"2010","journal-title":"Cell Host Microbe"},{"key":"2025030417505046200_r42","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.15252\/embr.201540473","article-title":"TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection","volume":"16","author":"Ellis","year":"2015","journal-title":"EMBO Rep."},{"key":"2025030417505046200_r43","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1093\/infdis\/jir467","article-title":"Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection","volume":"204","author":"Goulding","year":"2011","journal-title":"J. Infect. Dis."},{"key":"2025030417505046200_r44","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1189\/jlb.0313168","article-title":"Opposite regulatory effects of IFN-\u03b2 and IL-3 on C-type lectin receptors, antigen uptake, and phagocytosis in human macrophages","volume":"95","author":"Cardone","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"2025030417505046200_r45","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0163889","article-title":"Viral inhibition of bacterial phagocytosis by human macrophages: redundant role of CD36","volume":"11","author":"Cooper","year":"2016","journal-title":"PLoS One"},{"key":"2025030417505046200_r46","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1128\/JVI.02408-09","article-title":"A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection","volume":"84","author":"Sun","year":"2010","journal-title":"J. Virol."},{"key":"2025030417505046200_r47","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1128\/iai.36.3.1154-1159.1982","article-title":"Role of macrophage activation and interferon in the resistance of alveolar macrophages from infected mice to influenza virus","volume":"36","author":"Rodgers","year":"1982","journal-title":"Infect. Immun."},{"key":"2025030417505046200_r48","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0121527","article-title":"Viral infection of human lung macrophages increases PDL1 expression via IFN\u03b2","volume":"10","author":"Staples","year":"2015","journal-title":"PLoS One"},{"key":"2025030417505046200_r49","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1084\/jem.20040731","article-title":"The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles","volume":"200","author":"Arredouani","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030417505046200_r50","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1165\/rcmb.2006-0128OC","article-title":"The macrophage scavenger receptor SR-AI\/II and lung defense against pneumococci and particles","volume":"35","author":"Arredouani","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030417505046200_r51","doi-asserted-by":"crossref","first-page":"L138","DOI":"10.1152\/ajplung.00075.2017","article-title":"Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia","volume":"313","author":"Wu","year":"2017","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/6\/1601\/61880062\/ji2000094.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/6\/1601\/61880062\/ji2000094.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T13:22:06Z","timestamp":1741094526000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/205\/6\/1601\/7930844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9]]},"references-count":51,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2000094","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,9]]},"published":{"date-parts":[[2020,9]]}}}