Pneumolysin-dependent and independent non-canonical autophagy processes mediate host defense against pneumococcal infection.
| Title: | Pneumolysin-dependent and independent non-canonical autophagy processes mediate host defense against pneumococcal infection. |
|---|---|
| Authors: | Michno BJ; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland.; Pooranachandran N; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland.; Smith TC; School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield, UK.; Faught E; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands.; Lipowská S; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland.; Fenton AK; School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield, UK.; Meijer AH; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands.; Prajsnar TK; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland. |
| Source: | Autophagy [Autophagy] 2025 Dec; Vol. 21 (12), pp. 3077-3096. Date of Electronic Publication: 2025 Sep 23. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101265188 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8635 (Electronic) Linking ISSN: 15548627 NLM ISO Abbreviation: Autophagy Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2015- : Philadelphia, PA : Taylor & Francis; Original Publication: Georgetown, TX : Landes Bioscience, 2005- |
| MeSH Terms: | Streptolysins*/metabolism ; Streptococcus pneumoniae*/physiology ; Pneumococcal Infections*/immunology ; Pneumococcal Infections*/microbiology ; Bacterial Proteins*/metabolism ; Autophagy*; Zebrafish/microbiology ; Macrophages/microbiology ; Macrophages/metabolism ; Microtubule-Associated Proteins/metabolism ; Phagosomes/metabolism ; Zebrafish Proteins/metabolism ; Autophagy-Related Protein 5/metabolism ; Animals ; Phagocytosis |
| Abstract: | Streptococcus pneumoniae is an opportunistic pathogen responsible for life-threatening diseases including pneumonia and meningitis. The host defense against pneumococci relies heavily on macrophages, which can effectively internalize and degrade bacteria. Recent studies have implicated both canonical and non-canonical autophagy-related processes in bacterial clearance, but the precise pathways mediating defense against S. pneumoniae remain unknown. Here, we utilize a well-established zebrafish larval infection model to investigate the role of autophagy in host defense against pneumococci in vivo. Using a transgenic macroautophagy/autophagy reporter line, we found the autophagy marker Map1lc3/Lc3 being recruited to pneumococci-containing vesicles upon bacterial internalization by zebrafish macrophages. The genetic inhibition of core autophagy gene atg5 led to loss of the Lc3 associations and their impaired acidification, significantly delaying bacterial clearance. This Lc3 recruitment is partially mediated by LC3-associated phagocytosis (LAP), as knockdown of cyba and rubcn moderately reduced Lc3 association with phagosomes and diminished pneumococcal degradation. Interestingly, we observed no involvement of xenophagy components in S. pneumoniae-infected macrophages, suggesting the activation of another non-canonical autophagy pathway, distinct from LAP, targeting pneumococci-containing phagosomes. Instead, we found that the pneumococcal pore-forming toxin pneumolysin induces ROS-independent CASM pathways, one of which is abolished by knockdown of tecpr1a indicating the involvement of sphingomyelin-Tecpr1-induced LC3 lipidation (STIL). Collectively, our observations shed new light on the host immune response against S. pneumoniae, demonstrating that several distinct non-canonical autophagy pathways mediate bacterial degradation by macrophages and providing potential targets for the development of novel therapies to combat pneumococcal infections.Abbreviations: ATG: autophagy related; BMDM: bone marrow-derived macrophage; CASM: conjugation of ATG8 to single membranes; CFU: colony-forming units; Cyba: cytochrome b-245, alpha polypeptide; DPI: diphenyleneiodonium, GFP: green fluorescent protein; hpf: hours post-fertilization; hpi: hours post-infection; LAP: LC3-associated phagocytosis; Map1lc3/Lc3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NADPH: nicotinamide adenine dinucleotide phosphate; Optn: optineurin; PINCA: pore-forming toxin-induced non-canonical autophagy; Ply: pneumolysin; ROS: reactive oxygen species; SLR: sequestosome-like receptors; Sqstm1: sequestosome 1; STIL: sphingomyelin-TECPR1-induced LC3 lipidation; Tecpr1: tectonin beta-propeller repeat containing 1. |
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| Contributed Indexing: | Keywords: LAP; STIL; Streptococcus; macrophage; pneumoniae; zebrafish |
| Substance Nomenclature: | 0 (Streptolysins); 0 (plY protein, Streptococcus pneumoniae); 0 (Bacterial Proteins); 0 (Microtubule-Associated Proteins); 0 (Zebrafish Proteins); 0 (Autophagy-Related Protein 5) |
| Entry Date(s): | Date Created: 20250923 Date Completed: 20251226 Latest Revision: 20260104 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12758243 |
| DOI: | 10.1080/15548627.2025.2559728 |
| PMID: | 40987772 |
| Database: | MEDLINE |
Journal Article