Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88
Cecile M. Fremond, Vladimir Yeremeev, Delphine M. Nicolle, Muazzam Jacobs, Valerie F. Quesniaux, Bernhard Ryffel
Cecile M. Fremond, Vladimir Yeremeev, Delphine M. Nicolle, Muazzam Jacobs, Valerie F. Quesniaux, Bernhard Ryffel
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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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Cell recruitment in the lungs of vaccinated and MTB-challenged MyD88–/– ...
Cell recruitment in the lungs of vaccinated and MTB-challenged MyD88–/– mice. MyD88–/– and control mice were immunized by s.c. injection of M. bovis BCG (105 CFU) and 5 weeks later challenged by MTB aerogenic infection (200 CFU) as in Figure 6. Leukocytes from infected lung were isolated 4 weeks after infection and analyzed by flow cytometry for CD44 expression in CD4- and CD8-positive T cells (A and B); for CD11b-, CD11c-, and Ly-6G–positive cells (B); and for MHC class II IA–IE expression (C) as in Figure 4. Results are expressed as absolute numbers of positive cells. Mean ± SD from 2 MyD88–/– mice are shown and are representative of 2 independent experiments.