Toll-like receptor 4 signaling-mediated responses are critically engaged in optimal host protection against highly virulent Mycobacterium tuberculosis K infection

Jaehun Park, Hongmin Kim, Kee Woong Kwon, Hong Hee Choi, Soon Myung Kang, Jung Joo Hong, Sung Jae Shin

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8 Citations (Scopus)


Toll-like receptors (TLRs) play critical roles in the innate recognition of Mycobacterium tuberculosis (Mtb) by host immune cells. However, controversy has arisen regarding the role of TLR4 in determining the outcomes of Mtb infection. To address this controversy, the function of TLR4 in the induction of an optimal protective immune response against the highly virulent Mtb K-infection was comparatively investigated in C3 H/HeJ (TLR4-deficient mutant) and C3 H/HeN (TLR4-competent wild-type) mice. Interestingly, following Mtb infection, C3 H/HeJ mice showed a more severe disease phenotype than C3 H/HeN mice, exhibiting reduced weight and a marked increase in bacterial burden along with necrotic lung inflammation. Analysis of the immune cell composition revealed significantly increased neutrophils in the lung and significant production of IL-10 accompanied by the impairment of the protective Th1 response in C3 H/HeJ mice. Reducing the neutrophil numbers by treating C3 H/HeJ mice with an anti-Ly6 G monoclonal antibody (mAb) and blocking IL-10 signaling with an anti-IL-10 receptor mAb reduced the excessive lung inflammation and bacterial burden in C3 H/HeJ mice. Therefore, abundant IL-10 signaling and neutrophils have detrimental effects in TLR4-deficient mice during Mtb infection. However, the blockade of IL-10 signaling produced an increase in the CD11bhiLy6 Ghi neutrophil population, but the phenotypes of these neutrophils were different from those of the CD11bintLy6 Gint neutrophils from mice with controlled infections. Collectively, these results show that TLR4 positively contributes to the generation of an optimal protective immunity against Mtb infection. Furthermore, investigating the TLR4-mediated response will provide insight for the development of effective control measures against tuberculosis.

Original languageEnglish
Pages (from-to)430-445
Number of pages16
Issue number1
Publication statusPublished - 2020 Jan 1

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2019R1A2C2003204) and the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program (KGM4572013), Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SJS, JHP and HMK designed the experiments. JHP, HMK, KWK, H-HC, JJH and SMK performed the experiments and contributed to interpretation of the outcomes. JHP, HMK and SJS wrote the manuscript. SJS conceived the study, supervised the team and critically revised the manuscript. All the authors participated in the preparation and editing of the manuscript.

Publisher Copyright:
© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases


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