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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

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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 5

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Reduced DTH response, but normal IFN-γ secretion, to mycobacterial antig...
Reduced DTH response, but normal IFN-γ secretion, to mycobacterial antigens stimulation in MyD88–/– mice. (A) Cutaneous DTH response was performed 3 weeks after vaccination with M. bovis BCG (105 CFU s.c.; v) by assessing the footpad swelling in response to PPD injection as described. Paw swelling is defined as the difference in thickness between the left paw injected with PPD and the right paw injected with saline. DTH responses of nonvaccinated MyD88–/– and MyD88+/+ mice are shown as control (nv). Data are expressed as mean ± SD (n = 7–8) and are from 1 representative experiment out of 2. **P – 0.01. (B) For the T cell response, spleen cells from M. bovis BCG–vaccinated MyD88-deficient and control mice were harvested 4 weeks after inoculation (105 CFU s.c.) and were restimulated in vitro in the presence of soluble BCG antigens (SupBCG, 10 μg/ml) or unrelated antigen (HKLM, 100 bacteria per cell). Naive MyD88–/– mice and wild-type mice were used as negative control. IFN-γ production was quantified in the supernatants after 48 hours of incubation. Results are mean ± SD from n = 2 mice per genotype and are representative of 3 independent experiments. (C) Intracellular IFN-γ staining of CD4+ or CD8+ splenocytes from BCG-infected MyD88-deficient and control mice 4 weeks after infection, restimulated for 18 hours in the presence of soluble BCG antigens (SupBCG, 10 μg/ml) or unrelated antigen (HKLM, 100 bacteria per cell). Typical dot blots are shown for CD4+ T cells (numbers indicate percentage of IFN-γ–positive CD4+ cells).

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