PMID- 34000990 OWN - NLM STAT- MEDLINE DCOM- 20220214 LR - 20240504 IS - 1471-2172 (Electronic) IS - 1471-2172 (Linking) VI - 22 IP - 1 DP - 2021 May 17 TI - Macrophage mediated recognition and clearance of Borrelia burgdorferi elicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation. PG - 32 LID - 10.1186/s12865-021-00418-8 [doi] LID - 32 AB - BACKGROUND: Macrophages play prominent roles in bacteria recognition and clearance, including Borrelia burgdorferi (Bb), the Lyme disease spirochete. To elucidate mechanisms by which MyD88/TLR signaling enhances clearance of Bb by macrophages, we studied wildtype (WT) and MyD88(-/-) Bb-stimulated bone marrow-derived macrophages (BMDMs). RESULTS: MyD88(-/-) BMDMs exhibit impaired uptake of spirochetes but comparable maturation of phagosomes following internalization of spirochetes. RNA-sequencing of infected WT and MyD88(-/-) BMDMs identified a large cohort of differentially expressed MyD88-dependent genes associated with re-organization of actin and cytoskeleton during phagocytosis along with several MyD88-independent chemokines involved in inflammatory cell recruitment. We computationally generated networks which identified several MyD88-dependent intermediate proteins (Rhoq and Cyfip1) that are known to mediate inflammation and phagocytosis respectively. CONCLUSION: Our findings show that MyD88 signaling enhances, but is not required, for bacterial uptake or phagosomal maturation and provide mechanistic insights into how MyD88-mediated phagosomal signaling enhances Bb uptake and clearance. FAU - Benjamin, Sarah J AU - Benjamin SJ AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. AD - Department of Immunology, UConn Health, Farmington, CT, 06030, USA. FAU - Hawley, Kelly L AU - Hawley KL AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. AD - Division of Infectious Diseases, Connecticut Children's, Hartford, CT, 06106, USA. FAU - Vera-Licona, Paola AU - Vera-Licona P AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. AD - Center for Quantitative Medicine, UConn Health, Farmington, CT, 06030, USA. AD - Department of Cell Biology, UConn Health, Farmington, CT, 06030, USA. AD - Institute of Systems Genomics, UConn Health, Farmington, CT, 06030, USA. FAU - La Vake, Carson J AU - La Vake CJ AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. FAU - Cervantes, Jorge L AU - Cervantes JL AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. AD - Division of Infectious Diseases, Connecticut Children's, Hartford, CT, 06106, USA. AD - Present Address: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. FAU - Ruan, Yijun AU - Ruan Y AD - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA. FAU - Radolf, Justin D AU - Radolf JD AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. AD - Department of Immunology, UConn Health, Farmington, CT, 06030, USA. AD - Department of Medicine, UConn Health, Farmington, CT, 06030, USA. AD - Department of Molecular Biology and Biophysics, UConn Health, Farmington, CT, 06030, USA. AD - Department of Genetics and Genomic Sciences, UConn Health, Farmington, CT, 06030, USA. FAU - Salazar, Juan C AU - Salazar JC AUID- ORCID: 0000-0003-3881-546X AD - Department of Pediatrics, UConn Health, Farmington, CT, 06030, USA. jsalaza@connecticutchildrens.org. AD - Department of Immunology, UConn Health, Farmington, CT, 06030, USA. jsalaza@connecticutchildrens.org. AD - Division of Infectious Diseases, Connecticut Children's, Hartford, CT, 06106, USA. jsalaza@connecticutchildrens.org. AD - Department of Medicine, UConn Health, Farmington, CT, 06030, USA. jsalaza@connecticutchildrens.org. AD - Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's, 282 Washington Street, Hartford, CT, 06106, USA. jsalaza@connecticutchildrens.org. LA - eng GR - R01 AI029735/AI/NIAID NIH HHS/United States GR - R01 AI090166/AI/NIAID NIH HHS/United States GR - R56 AI090166/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 - 20210517 PL - England TA - BMC Immunol JT - BMC immunology JID - 100966980 RN - 0 (Actins) RN - 0 (Chemokines) RN - 0 (Interferon Regulatory Factor-1) SB - IM MH - Actins/genetics MH - Animals MH - Borrelia burgdorferi/*physiology MH - Cells, Cultured MH - Chemokines/genetics MH - Cytoskeleton/genetics MH - Female MH - Inflammation/*immunology MH - Interferon Regulatory Factor-1/genetics/metabolism MH - Lyme Disease/*immunology MH - Macrophages/*immunology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Phagocytosis MH - Phagosomes/*metabolism MH - Sequence Analysis, RNA MH - Signal Transduction PMC - PMC8127205 OTO - NOTNLM OT - Borrelia OT - Inflammation OT - Macrophage OT - MyD88 OT - Phagocytosis COIS- The authors declared that they have no conflict of interest. EDAT- 2021/05/19 06:00 MHDA- 2022/02/15 06:00 PMCR- 2021/05/17 CRDT- 2021/05/18 06:02 PHST- 2020/10/29 00:00 [received] PHST- 2021/04/22 00:00 [accepted] PHST- 2021/05/18 06:02 [entrez] PHST- 2021/05/19 06:00 [pubmed] PHST- 2022/02/15 06:00 [medline] PHST- 2021/05/17 00:00 [pmc-release] AID - 10.1186/s12865-021-00418-8 [pii] AID - 418 [pii] AID - 10.1186/s12865-021-00418-8 [doi] PST - epublish SO - BMC Immunol. 2021 May 17;22(1):32. doi: 10.1186/s12865-021-00418-8.