The Heparin-Binding Hemagglutinin of Nocardia cyriacigeorgica GUH-2 Stimulates Inflammatory Cytokine Secretion Through Activation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Pathways via TLR4

• Published in: Frontiers in cellular and infection microbiology 2020-02, Vol.10, p.3-3
• Main Authors: Ji, Xingzhao, Zhang, Xiujuan, Sun, Lina, Hou, Xuexin, Song, Han, Han, Lichao, Xu, Shuai, Li, Heqiao, Qiu, Xiaotong, Li, Minghui, Wang, Xuebing, Zheng, Ningwei, Li, Zhenjun
• Format: Article
• Language: English
• Subjects: adhesion; Animals; Bacterial Adhesion; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - isolation & purification; Bacterial Proteins - metabolism; Cell Line; Cellular and Infection Microbiology; cytokines; Cytokines - metabolism; HBHA; Humans; Immunity, Innate; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Lectins - chemistry; Lectins - genetics; Lectins - isolation & purification; Lectins - metabolism; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; MAP Kinase Signaling System; MAPK; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF-κB; Nocardia - genetics; Nocardia - growth & development; Nocardia - physiology; Nocardia cyriacigeorgica; Nocardia Infections - immunology; Nocardia Infections - microbiology; Signal Transduction; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2235-2988
• DOI: 10.3389/fcimb.2020.00003

Heparin-binding hemagglutinin (HBHA) from mycobacteria is involved in the dissemination of infection and the activation of the host immune response. However, the interaction of HBHA with the host cells remains unknown. In the present study, we describe HBHA interactions with epithelial cells and organ colonization. We then investigate the mechanisms by which HBHA induces the production of inflammatory cytokines in macrophages. Immunofluorescent microscopy showed that HBHA adhered to A549 cells and HeLa cells and that the C-terminal fragment, which contains a Pro-Ala-Lys-rich domain, was responsible for adhesion. The deletion of the gene in mutant strains impaired adhesion to A549 cells and HeLa cells. In addition, the HBHA protein activated the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways and promoted the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10 in macrophages. HBHA-mediated TNF-α production was dependent on the activation of the c-Jun N-terminal kinase (JNK) signal pathways, and the IL-6 and IL-10 production was dependent on the activation of extracellular regulated kinase (ERK) 1/2, MAPK p38 (p38), JNK, and nuclear NF-κB signaling pathways. Additionally, the HBHA-mediated activation of innate immunity was dependent on Toll-like receptor 4 (TLR4). Taken together, these results indicate that HBHA not only adheres to epithelial cells and may be involved in organ colonization, but also plays a critical role in the modulation of innate immunity through the MAPK and NF-κB signaling pathways via TLR4.