Impairment of Wnt/β-catenin signaling in blood cells of patients with severe cavitary pulmonary tuberculosis.
Tuberculosis (TB) remains as a leading infectious disease worldwide. Our previous study showed interferon (IFN)-γ and CD3 T cell impairment in patients with severe cavitary pulmonary TB (PTB). However, the cause of the change in immune responses during the progression of TB is still poorly understood. In this study, eight newly diagnosed patients with severe cavitary and mild lesion non-cavity PTB were recruited, and three healthy volunteers were recruited as the control. RNA extracted from blood was tested by whole genome oligo microarrays. A PCR array was used to further test the same samples. Two additional groups of patients were recruited according to the same criteria with healthy control(HC) recruited as well and subjected to peripheral blood mononuclear cell isolation (PBMC)and analysis of TCF-7, β-catenin, cyclin D2, IFN-γ, and tumor necrosis factor (TNF)-α expression in CD14- cells (lymphocytes) and CD14+ cells by quantitative PCR. The changes of expression of β-catenin, CD69+ and IFN-γ by CD3+, CD14- and CD14+ cells in vitro with stimulation of LiCl were tested by flow cytometry. Whole genome oligo microarrays showed a significant decrease in expression of the Wnt signaling pathway in severe PTB patients. Further analysis of the Wnt pathway by PCR array indicated that TCF-7, β-catenin, and cyclin D2 expression was significantly reduced in severe PTB patients compared with mild PTB patients. In the additionally recruited patients, TCF-7, β-catenin, and cyclin D2 were expressed in both CD14+ and CD14- cells, while β-catenin was decreased significantly in CD14- cells compared with CD14+ cells in severe PTB patients, and IFN-γ and TNF-α expression in CD14- cells was also reduced significantly in severe PTB patients. β-catenin can directly trigger T cell activation and IFN-γsecretion in PBMCs stimulated for 24 hours. These findings indicate that Wnt pathway and its key genes, such as β-catenin, were impaired in blood cells of patients with severe PTB. Therefore, Wnt/β-catenin pathway is closely associated with T cell proliferation and TB lesion deterioration.
Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Lin
http://orcid.org/0000-0002-9411-496X
L
Fan
Unit of Anti-tuberculosis Immunity, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Hongbo
H
Shen
Unit of Anti-tuberculosis Immunity, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Huichang
H
Huang
Unit of Anti-tuberculosis Immunity, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Rui
R
Yang
Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Lan
L
Yao
D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D056742:Cyclin D2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051822:T Cell Transcription Factor 1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
D017252:CD3 Complex; D056742:Cyclin D2; D018950:Lipopolysaccharide Receptors; D051822:T Cell Transcription Factor 1; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D007371:Interferon-gamma