Kinetics of Myeloid Dendritic Cell Trafficking and Activation: Impact on Progressive, Nonprogressive and Controlled SIV Infections

PLoS Pathogens

George Haret-Richter¹  Benjamin B. Policicchio¹  Rebecca Nusbaum¹  Anita Trichel¹  Cristian Apetrei¹  Viskam Wijewardana¹  Cuiling Xu¹  Dongzhu Ma¹  Ivona Pandrea²  Hadega Aamer³  Ruy M. Ribeiro³  Jan Kristoff⁴  Jennifer L. Stock⁴  Adam D. Mobley⁵ 

[1] Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America;Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America

关键词: Dendritic cells;    Gastrointestinal tract;    SIV;    Gastrointestinal infections;    Pathogens;    Infectious disease control;    Apoptosis;    Cytokines;   

DOI  :  10.1371/journal.ppat.1003600

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

We assessed the role of myeloid dendritic cells (mDCs) in the outcome of SIV infection by comparing and contrasting their frequency, mobilization, phenotype, cytokine production and apoptosis in pathogenic (pigtailed macaques, PTMs), nonpathogenic (African green monkeys, AGMs) and controlled (rhesus macaques, RMs) SIVagmSab infection. Through the identification of recently replicating cells, we demonstrated that mDC mobilization from the bone marrow occurred in all species postinfection, being most prominent in RMs. Circulating mDCs were depleted with disease progression in PTMs, recovered to baseline values after the viral peak in AGMs, and significantly increased at the time of virus control in RMs. Rapid disease progression in PTMs was associated with low baseline levels and incomplete recovery of circulating mDCs during chronic infection. mDC recruitment to the intestine occurred in all pathogenic scenarios, but loss of mucosal mDCs was associated only with progressive infection. Sustained mDC immune activation occurred throughout infection in PTMs and was associated with increased bystander apoptosis in blood and intestine. Conversely, mDC activation occurred only during acute infection in nonprogressive and controlled infections. Postinfection, circulating mDCs rapidly became unresponsive to TLR7/8 stimulation in all species. Yet, stimulation with LPS, a bacterial product translocated in circulation only in SIV-infected PTMs, induced mDC hyperactivation, apoptosis and excessive production of proinflammatory cytokines. After infection, spontaneous production of proinflammatory cytokines by mucosal mDCs increased only in progressor PTMs. We thus propose that mDCs promote tolerance to SIV in the biological systems that lack intestinal dysfunction. In progressive infections, mDC loss and excessive activation of residual mDCs by SIV and additional stimuli, such as translocated microbial products, enhance generalized immune activation and inflammation. Our results thus provide a mechanistic basis for the role of mDCs in the pathogenesis of AIDS and elucidate the causes of mDC loss during progressive HIV/SIV infections.

【 授权许可】

CC BY