B. abortus RNA is the component involved in the down-modulation of MHC-I expression on human monocytes via TLR8 and the EGFR pathway

PLoS Pathogens

Sergio Costa Oliveira¹  Fábio V. Marinho¹  M. Victoria Delpino²  Guillermo H. Giambartolomei²  Sonia L. Espindola³  Mónica Vermeulen⁴  Nahuel Rodriguez-Rodrigues⁴  Gabriela C. Fernández⁴  Aldana Trotta⁴  Lis N. Velásquez⁴  Paula Barrionuevo⁴  M. Ayelén Milillo⁴  Luciana Balboa⁴ 

[1] Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Instituto de Inmunología, Genética y Metabolismo (CONICET-UBA), Laboratorio de Inmunogenética, Buenos Aires, Argentina;Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), CONICET, Buenos Aires, Argentina;Instituto de Medicina Experimental (CONICET-Academia Nacional de Medicina), Buenos Aires, Argentina

关键词: T cells;    Cytotoxic T cells;    Monocytes;    Flow cytometry;    Brucella;    Double str;    ed RNA;    Virulence factors;    Golgi apparatus;   

DOI  :  10.1371/journal.ppat.1006527

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Despite eliciting a potent CD8+ T cell response, Brucella abortus is able to persist and establish a chronic infection inside its host. We have previously reported that the infection of human monocytes/macrophages with B. abortus inhibits the IFN-γ-induced MHC-I cell surface expression down-modulating cytotoxic CD8+ T cell responses. MHC-I down-modulation depends on bacterial viability and results from the capacity of B. abortus to retain the MHC-I molecules within the Golgi apparatus. Furthermore, we recently demonstrated that epidermal growth factor receptor (EGFR) pathway is involved in this phenomenon and that this is an early event during infection. However, the components and mechanisms whereby B. abortus is able to down-modulate MHC-I remained to be elucidated. In this study we demonstrated that the down-modulation of MHC-I expression is not mediated by well-known Brucella virulence factors but instead by B. abortus RNA, a PAMP associated to viability (vita-PAMP). Surprisingly, completely degraded RNA was also able to inhibit MHC-I expression to the same extent as intact RNA. Accordingly, B. abortus RNA and its degradation products were able to mimic the MHC-I intracellular retention within the Golgi apparatus observed upon infection. We further demonstrated that TLR8, a single-stranded RNA and RNA degradation products sensor, was involved in MHC-I inhibition. On the other hand, neutralization of the EGFR reversed the MHC-I inhibition, suggesting a connection between the TLR8 and EGFR pathways. Finally, B. abortus RNA-treated macrophages display diminished capacity of antigen presentation to CD8+ T cells. Overall, our results indicate that the vita-PAMP RNA as well as its degradation products constitute novel virulence factors whereby B. abortus, by a TLR8-dependent mechanism and through the EGFR pathway, inhibits the IFN-γ-induced MHC-I surface expression on human monocytes/macrophages. Thus, bacteria can hide within infected cells and avoid the immunological surveillance of cytotoxic CD8+ T cells.

【 授权许可】

CC BY