Ehrlichia chaffeensis Outer Membrane Protein 1-Specific Human Antibody-Mediated Immunity Is Defined by Intracellular TRIM21-Dependent Innate Immune Activation and Extracellular Neutralization
| Autor: | Thangam Sudha Velayutham, Sandeep Kumar, Nurgun Kose, Jere W. McBride, James E. Crowe, Gary M. Winslow, Xiaofeng Zhang, David H. Walker |
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| Rok vydání: | 2019 |
| Předmět: |
Chemokine
THP-1 Cells Immunology Fc receptor Microbiology Bacterial Adhesion Gene Knockout Techniques Cell Line Tumor Autophagy Extracellular Humans Ehrlichia chaffeensis neutralizing antibodies Spotlight selective autophagy Antigens Bacterial Innate immune system LAMP2 biology Adenine NF-kappa B Antibodies Monoclonal biology.organism_classification Antibodies Neutralizing Immunity Humoral Cell biology Infectious Diseases Ribonucleoproteins human monoclonal antibodies Microbial Immunity and Vaccines biology.protein bacteria Parasitology CRISPR-Cas Systems antibody function TRIM21 Intracellular Bacterial Outer Membrane Proteins |
| Zdroj: | Infection and Immunity |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.00383-19 |
| Popis: | Antibodies are essential for immunity against Ehrlichia chaffeensis, and protective mechanisms involve blocking of ehrlichial attachment or complement and Fcγ-receptor-dependent destruction. In this study, we determined that major outer membrane protein 1 (OMP-19) hypervariable region 1 (HVR1)-specific human monoclonal antibodies (huMAbs) are protective through conventional extracellular neutralization and, more significantly, through a novel intracellular TRIM21-mediated mechanism. Antibodies are essential for immunity against Ehrlichia chaffeensis, and protective mechanisms involve blocking of ehrlichial attachment or complement and Fcγ-receptor-dependent destruction. In this study, we determined that major outer membrane protein 1 (OMP-19) hypervariable region 1 (HVR1)-specific human monoclonal antibodies (huMAbs) are protective through conventional extracellular neutralization and, more significantly, through a novel intracellular TRIM21-mediated mechanism. Addition of OMP-1-specific huMAb EHRL-15 (IgG1) prevented infection by blocking attachment/entry, a mechanism previously reported; conversely, OMP-1-specific huMAb EHRL-4 (IgG3) engaged intracellular TRIM21 and initiated an immediate innate immune response and rapid intracellular degradation of ehrlichiae. EHRL-4-TRIM21-mediated inhibition was significantly impaired in TRIM21 knockout THP-1 cells. EHRL-4 interacted with cytosolic Fc receptor TRIM21, observed by confocal microscopy and confirmed by co-immunoprecipitation. E. chaffeensis-EHRL-4-TRIM21 complexes caused significant upregulation of proinflammatory cytokine/chemokine transcripts and resulted in rapid ( |
| Databáze: | OpenAIRE |
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