Abstract:To investigate the role of TLR in the development of murine tuberculosis in vivo, TLR2 and TLR6 knockout (KO) mice were infected with Mycobacterium tuberculosis by placing them in the exposure chamber of an airborne infection apparatus. Both TLR2 and TLR6 KO mice survived until sacrifice at 12 weeks after infection. Infected TLR2 KO mice developed granulomatous pulmonary lesions with neutrophil infiltration, which were slightly larger in size than those in wild-type mice. Pulmonary levels of the mRNAs for inducible nitric oxide synthase (iNOS), TNF-␣, TGF-␤, IL-1␤, and IL-2 were significantly lower, but levels of the mRNAs for IL-4 and IL-6 were higher, than in wild-type (WT) mice. No significant difference was recognized in cytokine mRNA expression between TLR2 KO and WT mice at 12 weeks after infection. DNA binding by NF-B was low in TLR2 KO mice. On the other hand, TLR6 KO mice were not different from WT mice in terms of pulmonary histopathology, mRNA expression and CFU assay. Therefore, TLR2 does not play an essential role in the pathogenesis of murine tuberculosis, although it is important for defense against mycobacterial infection.

Abstract:It is important to gain a better understanding of IL-I-mediated signaling events in mycobacterial infection. In order to clarify the role oflL-1 receptor type I (IL-I RI) in IL-I RI, knockout (KO) mice were infected with either Mycobacterium tuberculosis H37Rv or Kurono strain by the respiratory route, and their ability to control mycobacterial growth, pulmonary granuloma formation, and cytokine mRNA expression was investigated. IL-I RI KO mice developed significantly larger (P

To understand the role of NF-B in the development of murine tuberculosis in vivo, NF-B p50 knockout mice were infected with Mycobacterium tuberculosis by placing them in the exposure chamber of an airborneinfection apparatus. These mice developed multifocal necrotic pulmonary lesions or lobar pneumonia. Compared with the levels in wild-type mice, pulmonary inducible nitric oxide synthase, interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha mRNA levels were significantly low but expression of IL-10 and transforming growth factor ␤ mRNAs were within the normal ranges. The pulmonary IL-6 mRNA expression level was higher. Therefore, NF-B and its interaction with host cells play an important role in the pathogenesis of tuberculosis.

on July 4, 2020 by guest http://iai.asm.org/ Downloaded fromEditor: E. I. Tuomanen FIG. 5. Nitric oxide production by the peritoneal macrophages from IL-18-KO and WT mice stimulated with the Kurono strain overnight in the presence or absence of recombinant IL-18 or with IFN-␥. Thereafter, the NO-producing ability of the macrophages was determined by the Griess reagent.

MyD88 is an adaptor protein that plays a major role in TLR/IL‐1 receptor family signaling. To understand the role of MyD88 in the development of murine tuberculosis in vivo, MyD88 knockout (KO) mice aerially were infected with Mycobacterium tuberculosis. Infected MyD88 mice were not highly susceptible to M. tuberculosis infection, but they developed granulomatous pulmonary lesions with neutrophil infiltration which were larger than those in wild‐type (WT) mice (P<0.01). The pulmonary tissue levels of mRNA for iNOS and IL‐18 were slightly lower, but levels of mRNA for IL‐1β, IL‐2, IL‐4, IL‐6, IL‐10, IFN‐γ, and TGF‐β were higher in MyD88 KO mice. IFN‐γ, TNF‐α, IL‐1β, and IL‐12 also were high in the sera of MyD88 KO mice. There were no statistically significant differences in the expression of TNF‐α, IL‐12, and ICAM‐1 mRNA between MyD88 KO and WT mice. Thus, MyD88 deficiency did not influence the development of murine tuberculosis. NF‐κB activity was similar in the alveolar macrophages from the lung tissues of MyD88 KO and WT mice. Also, there may be a TLR2‐specific, MyD88‐independent IL‐1 receptor/TLR‐mediated pathway to activate NF‐κB in the host defense against mycobacterial infection.