SALMONELLA INFECTION AND CYTOKINES-ANALYSIS USING KNOCK-OUT MICE

1996 Fiscal Year Final Research Report Summary

• Project/Area Number: 07670321
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: KITASATO UNIVERSITY
• Principal Investigator: KUMAZAWA Yoshio SCHOOL OF SCIENCE,DEPARTMENT OF BIOSCIENCES,KITASATO UNIVERSITY,PROFESSOR, 理学部, 教授 (30072375)
• Project Period (FY): 1995 – 1996
• Keywords: Th1 & Th2 / LPS / S.typhimurium / macrophage / IL-4 / IFNgamma / TNFalpha / NK1+T cells

Research Abstract

Cytokines produced by type-1 helper T cells (Th1) play important roles in defense mechanisms to infection with S.typhimurium which belongs to the intracellular parasites. The aim of this study clarifies the role of involved cytokines and host responses to bacterial lipopolysaccharide (LPS) in the activation of peritoneal macrophages during infection using different mouse strains such as BALB/c, BALB/c IL-4^<-1->, BALB/c IFNgamma^<-1-> and LPS-nonresponder BALB/1psd. Until 20 days after an intraperitoneal infection with a vaccine strain S.typhimurium aro A (1.5x10^6 cfu), all of IFNgamma^<-1-> mice and more than half of BALB/1ps^d mice did not survive, whereas all of BALB/c and IL-4^<-1-> mice survived. This shows that the most important cytokine for protection is IFNgamma and the inflammatory responses induced by LPS also influence on the host defense mechanisms. Resident macrophages from IFNgamma^<-1-> showed weaker killing activity than those of BALB/c and IL-4^<-1->. Increase in Mac 1^+ cells in the peritoneal cavity of IFNgamma^<-1-> mice after infection was less than that in BALB/c and IL-4^<-1-> mice. Similarly, TNFalpha mRNA expression and its production by peritoneal macrophages were weaker than those of BALB/c. These results indicates that induction of inflammatory responses and activation peritoneal macrophages by infection with Salmonella are weakerin IFNgamma^<-1-> mice.
Unique TCRalpha/beta^<int>CD4^+NK1^+T cells (termed as NK1^+T cells) are present at high frequency in liver which is the central site at the early stage of infection to Salmonella. As seen in infections with BCG and Listeria, IL-4-producing NK1+T cells disappeared in B10Sn mice from the early stage of infection. Delayd disappearance of liver NK1+T cells by infection was observed in LPS-nonresponder B10Cr mice. Administration of recombinant mouse IFNbeta to normal B10Sn and infected B10Cr mice did not induce accelerated disappearance of NK1^+T cells. This delayd disappearance seems to be dependent on amounts of IL-12 produced during infection. Similarily, decrease in TCRalpha/beta^<int>CD4^+CD11a^+ T cells and TCRalpha/beta^<int>CD44^+T cells was observed in BALB/c mice infected with S.typhimurium.