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.
View: Text | PDF
Categories: 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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Impaired proinflammatory cytokine and NO production in MyD88–/– macropha...
Impaired proinflammatory cytokine and NO production in MyD88–/– macrophages and DCs. BM-derived macrophages (A, C, and E) and DCs (B, D, and F) (5 × 105 cells/ml) prepared from MyD88–/– (white bars) and wild-type (black bars) mice were incubated with LPS (100 ng/ml), M. bovis BCG, MTB H37Ra, or MTB H37Rv (all at 2 bacteria per cell). After 24 hours, the production of TNF (A and B), IL-12 p40 (C and D), or nitrite (E and F) was determined in the supernatant by ELISA or Griess reaction. TNF and IL-6 production by pulmonary macrophages stimulated in the same conditions was also measured (G and H). Upregulation of CD40 (I) and CD86 (J) expression by DCs stimulated with LPS or M. bovis BCG were analyzed by FACS. Data are from 1 experiment, representative of 3 independent experiments with n = 2 mice per genotype; mean values ± SD are shown. MFI, mean fluorescence intensity.