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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MyD88–/– mice exhibit acute necrotic pneumonia with large nodules but de...
MyD88–/– mice exhibit acute necrotic pneumonia with large nodules but defective granuloma formation in response to MTB infection. Lung tissue from MyD88–/– (A, C, E, and G) and wild-type (B, D, F, and H) mice was analyzed 27 days after MTB H37Rv infection (200 CFU i.n.). Lungs of MyD88–/– mice showed large and confluent nodules (A) in comparison with those of wild-type mice (B). Microscopic examination showed extensive inflammation and necrosis in infected MyD88–/– lungs (C–F; H&E) with abundant mycobacteria in the extracellular space (G and H; Ziehl-Neelsen). Low-power micrographs of representative lung sections are shown in C and D (magnification, ×50), and higher magnification shows details in E–H (magnification, ×400).