Analysis of the molecular mechanisms for early host defense against bacterial infection

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The host defense mechanisms are largely divided into three phases. Most of microorganisms are detected and destroyed within hours by innate immunity which preexists and is not antigen-specific. Innate immunity is mainly mediated by eptithelial cells and phagocytes such as macrophages and neutrophils. Innate immunity is followed by some hours later by early induced responses which can be activated by infection but do not generate lasting protective immunity. NK cells, γδT cells, NKαβT cells and memory phenotype of CD8ィイD1+ィエD1T cells are responsible for early induced responses. Late adaptive response is mediated by antigen-specific lymphocytes, which require several days for clonal expansion and differentiation of naive lymphocytes into effector cells. We examined the roles of early induced responses mediated by NK cells, γδT cells and NK αβT cells in bacterial infection using gene-knock out mice. Our findings are as follows :(1) The bacterial growth in TCRβィイD1-/-ィエD1 mice had kinetics … More similar to that seen control mice (TCRβィイD1+/+ィエD1) after infection with avirulent Salmonella chorelaesuis 31N-1. The number of NK cells in the peritoneal cavity equally increased on day 3 after infection and thereafter decreased in both TCRβィイD1-/-ィエD1 mice and TCRβィイD1+/+ィエD1 mice, whereas the number of γδT cells were remarkably increased in the peritoneal cavity of TCRβィイD1-/-ィエD1 mice on day 6 after infection in place of αβT cells. The NK cells produced IFN-γ, whereas the γδT cells produced both IFN-γand IL-13 but no IL-4 in response to immobilized anti-TCR mAb. Anti-NK1.1mAb inhibited the reduction of bacteria after Salmonella infection, whereas anti-TCRγδmAb treatment did not. On the other hand, neutralization of endogenous IL-13 with anti-IL13mAb enhanced the bacterial clearance in TCRβィイD1-/-ィエD1 mice after Salmonella infection. These results indicate that NK1.1ィイD1+ィエD1 cells can serve to protect against avirulent Salmonella infection in the absence of αβT cells, whereas γδT cells may play at least dichotomus roles in Salmonella infection through IFN-γand IL-13 production.(2) We next examined serum alanine aminotransferase (ALT), histopathology, and bacterial numbers in liver after infection with Salmonella choleraesuis strain 31N-1 in mice genetically lacking NK1.1ィイD1+ィエD1T cells. In control (ィイD1+/+ィエD1) mice, serum ALT reached a peak level by day 7 after an intraperitoneal inoculation of Salmonella choleraesuis 31N-1, whereas serum ALT levels were significantly decreased in b2mィイD1-/-ィエD1 and Ja281ィイD1-/-ィエD1 mice, which lacked in NK1.1ィイD1+ィエD1T cells that bearing TCR Val4-Jα281. αβT cells bearing NK1.1 may be main effector cells for liver injury after Salmonella infection. Less