1. Academic Validation
  2. Mycobacterium tuberculosis Utilizes Host Histamine Receptor H1 to Modulate Reactive Oxygen Species Production and Phagosome Maturation via the p38MAPK-NOX2 Axis

Mycobacterium tuberculosis Utilizes Host Histamine Receptor H1 to Modulate Reactive Oxygen Species Production and Phagosome Maturation via the p38MAPK-NOX2 Axis

  • mBio. 2022 Aug 24;e0200422. doi: 10.1128/mbio.02004-22.
Siwei Mo  # 1 2 3 Jiubiao Guo  # 4 Taosheng Ye 5 Ximeng Zhang 1 Jiang Zeng 6 Yuzhong Xu 7 Bin Peng 1 Youchao Dai 1 Wei Xiao 1 Peize Zhang 5 Guofang Deng 5 Dechang Xu 6 Xiaoru Long 2 3 Yi Cai 1 Xinchun Chen 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen Universitygrid.263488.3, Shenzhen, China.
  • 2 Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
  • 3 National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 4 College of Pharmacy, Shenzhen Technology University, Shenzhen, China.
  • 5 Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
  • 6 The Fifth People's Hospital of Ganzhou, Ganzhou, Jiangxi Province, China.
  • 7 Department of Clinical Laboratory, Shenzhen Baoan Hospital, Shenzhen Universitygrid.263488.3, Shenzhen, China.
  • # Contributed equally.
Abstract

Tuberculosis (TB), which is caused by the single pathogenic bacterium, Mycobacterium tuberculosis, is among the top 10 lethal diseases worldwide. This situation has been exacerbated by the increasing number of cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Histamine is an organic nitrogenous compound that mediates a plethora of cell processes via different receptors. The expression of Histamine Receptor H1 (HRH1), one of the four histamine receptors identified to date was previously reported to be augmented by M. tuberculosis Infection, although the underlying mechanism is unclear. In the present study, we applied confocal microscopy, flow cytometry, and Western blotting to show that HRH1 expression was enhanced in macrophages following mycobacterial Infection. Furthermore, by combining techniques of gene knockdown, immunoprecipitation, intracellular Bacterial burden analysis, fluorescence labeling, and imaging, we found that M. tuberculosis targeted the host HRH1 to suppress NOX2-mediated cROS production and inhibit phagosome maturation and acidification via the GRK2-p38MAPK signaling pathway. Our findings clarified the underlying mechanism of the M. tuberculosis and host HRH1 interaction and may provide useful information for the development of novel antituberculosis treatments. IMPORTANCE Once engulfed in macrophage phagosomes, M. tuberculosis adopts various strategies to take advantage of the host environment for its intracellular survival. Histamine is an organic nitrogen-containing compound that mediates a plethora of cellular processes via different receptors, but the crosstalk mechanism between M. tuberculosis and HRH1 in macrophages is not clear. Our results revealed that M. tuberculosis Infection enhanced HRH1 expression, which in turn restrained macrophage bactericidal activity by modulating the GRK2-p38MAPK signaling pathway, inhibiting NOX2-mediated cROS production and phagosome maturation. Clarification of the underlying mechanism by which M. tuberculosis utilizes host HRH1 to favor its intracellular survival may provide useful information for the development of novel antituberculosis treatments.

Keywords

HRH1; Mycobacterium tuberculosis; NOX2; ROS; p38MAPK.

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