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Here we report that the spleen is the backup immune organ to clear the liver-resistant serotypes of\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (pneumococcus), a leading human pathogen. Asplenic mice failed to control the growth of the liver-resistant pneumococci in the blood circulation. Immunologic and genetic analyses identified splenic red pulp (RP) macrophages as the major phagocytes for bacterial clearance. Furthermore, the plasma natural antibodies against the cell wall phosphocholine and the complement system were necessary for RP macrophage\u2013mediated immunity. These findings have provided a conceptual framework for the innate defense against blood bacterial infections, a mechanistic explanation for the hyper-susceptibility of asplenic individuals to\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    , and a proof of concept for developing vaccines and therapeutic antibodies against encapsulated pathogens.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adq6399","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T13:58:57Z","timestamp":1741787937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":20,"title":["Splenic red pulp macrophages eliminate the liver-resistant\n                    <i>Streptococcus pneumoniae<\/i>\n                    from the blood circulation of mice"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5921-7402","authenticated-orcid":true,"given":"Haoran","family":"An","sequence":"first","affiliation":[{"name":"Institute of Medical Technology, Peking University Health Science Center, Beijing 100191, China."},{"name":"Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, Beijing 100191, China."},{"name":"Center for Infectious Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijia","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Parasitology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7744-7027","authenticated-orcid":true,"given":"Zhifeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Automation, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3793-8038","authenticated-orcid":true,"given":"Kunpeng","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Infectious Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Meng","sequence":"additional","affiliation":[{"name":"Institute of Medical Technology, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueting","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Infectious Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7329-639X","authenticated-orcid":true,"given":"Xianbin","family":"Tian","sequence":"additional","affiliation":[{"name":"Center for Infectious Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Automation, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3479-1026","authenticated-orcid":true,"given":"Jiamin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Automation, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7043-3061","authenticated-orcid":true,"given":"Qionghai","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Automation, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4973-4243","authenticated-orcid":true,"given":"Jing-Ren","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Infectious Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","unstructured":"H. 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