PMID- 33376222 OWN - NLM STAT- MEDLINE DCOM- 20210210 LR - 20221005 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 117 IP - 52 DP - 2020 Dec 29 TI - Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging. PG - 33561-33569 LID - 10.1073/pnas.2015368117 [doi] AB - Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen. CI - Copyright (c) 2020 the Author(s). Published by PNAS. FAU - Inomata, Megumi AU - Inomata M AUID- ORCID: 0000-0003-2409-2694 AD - Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111. AD - Department of Oral Microbiology, Asahi University School of Dentistry, Mizuho, 501-0296 Gifu, Japan. FAU - Xu, Shuying AU - Xu S AUID- ORCID: 0000-0003-4572-8663 AD - Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111. AD - Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111. FAU - Chandra, Pallavi AU - Chandra P AUID- ORCID: 0000-0001-6301-7617 AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110. AD - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Meydani, Simin N AU - Meydani SN AD - Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111. FAU - Takemura, Genzou AU - Takemura G AD - Department of Internal Medicine, Asahi University School of Dentistry, Mizuho, 501-0296 Gifu, Japan. FAU - Philips, Jennifer A AU - Philips JA AUID- ORCID: 0000-0002-9476-0240 AD - Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110. AD - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Leong, John M AU - Leong JM AD - Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; john.leong@tufts.edu. LA - eng GR - R01 AI087682/AI/NIAID NIH HHS/United States GR - R01 AI130454/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201221 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Bacterial Proteins) RN - 0 (Lipids) RN - 0 (Map1lc3b protein, mouse) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Reactive Oxygen Species) RN - 0 (Streptolysins) RN - 0 (plY protein, Streptococcus pneumoniae) SB - IM MH - Aging/*immunology MH - Animals MH - Autophagy MH - Bacterial Proteins/metabolism MH - Host-Pathogen Interactions/*immunology MH - Lipids/chemistry MH - Macrophages/*metabolism/*microbiology/ultrastructure MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microbial Viability MH - Microtubule-Associated Proteins/*metabolism MH - *Phagocytosis MH - RAW 264.7 Cells MH - Reactive Oxygen Species/metabolism MH - Streptococcus pneumoniae/*immunology/ultrastructure MH - Streptolysins/metabolism PMC - PMC7776987 OTO - NOTNLM OT - LC3-associated phagocytosis OT - Streptococcus pneumoniae OT - aging OT - autophagy OT - bone-marrow-derived macrophages COIS- The authors declare no competing interest. EDAT- 2020/12/31 06:00 MHDA- 2021/02/11 06:00 PMCR- 2020/12/21 CRDT- 2020/12/30 05:18 PHST- 2020/12/30 05:18 [entrez] PHST- 2020/12/31 06:00 [pubmed] PHST- 2021/02/11 06:00 [medline] PHST- 2020/12/21 00:00 [pmc-release] AID - 2015368117 [pii] AID - 202015368 [pii] AID - 10.1073/pnas.2015368117 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33561-33569. doi: 10.1073/pnas.2015368117. Epub 2020 Dec 21.