S-Space College of Veterinary Medicine (수의과대학) Dept. of Veterinary Medicine (수의학과) Theses (Ph.D. / Sc.D._수의학과)
The role of IL-1 and MyD88 signal for protective immunity against pathogenic bacteria infection
- 수의과대학 수의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 수의학과, 2013. 2. 성제경.
- Every organism has armed itself with the immune system for the protection against the infection of various pathogens. The host tried to recognize and to distinguish non-self organism for the initiation of protective immunity. The representative innate sensor is Interleukin 1 receptor (IL-1R)/ Toll-like receptor (TLR) superfamily whish is primitive signal for the induction of immune responses when the host is infected with various pathogens. In this study, I aimed to clarify the role of innate signal in the protective immunity against bacterial infection.
In the first part of this study, interleukin (IL)-1 is a well-known cytokine for the initiation of innate immunity together with TNF-a in bacterial infection. However, the underlying mechanism of IL-1 on the respiratory infection is not fully elucidated. It was studied how IL-1 signal contributes to the host defense pathway against Streptococcus (S.) pneumoniae in a mouse model. IL-1R-/- mice showed high mortality, local cytokine storm, and substantial infiltrates in the lower respiratory tract after intratracheal challenge with S. pneumoniae. The IL-1-deficient condition did not suppress the propagation of bacteria in the lung, although the recruitment and the bacteria-killing ability of neutrophils (CD11b+Ly6C+Ly6G+) were not defective compared with wild-type mice. Unexpectedly, it was found that the transcription of fibrinogen alpha and gamma genes were highly activated in the lungs of wild-type mice after S. pneumoniae infection while no significant changes were found in IL-1R-/- mice. Of note, synthesis of fibrinogen, which is crucial for clotting, in the lung in S. pneumoniae infection, was dependent on the IL-1-IL-6-Stat3 cascade. Treatment with recombinant fibrinogen improved survival and bacterial propagation in the IL-1R-/- mice and blockade of the coagulation pathway increased the susceptibility of wild-type mice to pneumococcal pneumonia. These findings suggest that IL-1 signaling leads to the synthesis of fibrinogen in the lung after S. pneumoniae infection and is followed by coagulation, which contributes to the control of bacterial infection in the pulmonary tract.
For the second part, the role of TLR signaling to link innate and adaptive immune systems has been one of controversial issues remained to be resolved. Here, it was determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella Typhimurium vaccine (RASV) strain in MyD88-/- mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4+ T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically-infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4+ T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88-/- mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1- and ICOS-dependent manner.