Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88
Cecile M. Fremond, … , Valerie F. Quesniaux, Bernhard Ryffel
Cecile M. Fremond, … , Valerie F. Quesniaux, Bernhard Ryffel
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1790-1799. https://doi.org/10.1172/JCI21027.
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Article Immunology

Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

Abstract

Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88–/– macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88–/– mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88–/– mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88–/– mice to control MTB infection.

Authors

Cecile M. Fremond, Vladimir Yeremeev, Delphine M. Nicolle, Muazzam Jacobs, Valerie F. Quesniaux, Bernhard Ryffel

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Figure 9

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The high pulmonary levels of cytokines and chemokines in MTB-infected My...
The high pulmonary levels of cytokines and chemokines in MTB-infected MyD88–/– mice is reduced upon vaccination. Cytokine and chemokine concentrations were determined in lung homogenates from MyD88–/– and control mice immunized by s.c. injection of M. bovis BCG (105 CFU) and challenged 5 weeks later by MTB aerogenic infection (200 CFU) as in Figure 6. IL-1β (A), IFN-γ (B), TNF (C), MIP-1α (D), MCP-1 (E), and RANTES (F) were quantified by SearchLight protein array. Results are expressed as mean ± SD from 4 mice per group (*P – 0.05; **P – 0.01).