Macrophages in resistance to rickettsial infections: genetic analysis of susceptibility to lethal effects of Rickettsia akari infection and development of activated, cytotoxic macrophages in A and B10.a mice.

Abstract

Susceptibility to lethal effects of Rickettsia akari varies among mouse strains. Although most strains are resistant, A/J mice are extremely sensitive (10,000-fold difference in LD50 between resistant and sensitive strains). In contrast to most strains of mice, A/J mice also fail to develop activated, tumoricidal macrophages after any of several in vivo or in vitro treatments. Are susceptibility to R. akari and inability to develop activated, cytotoxic macrophages in the A/J strain causally related traits? Genetic analysis of macrophage tumoricidal activity in responsive B10.A and nonresponsive A mice suggested this trait was controlled by a single, autosomal, dominant gene. Among (F1 X A) backcross mice, the traits for defective macrophage cytotoxicity and abnormal accumulation of macrophages during inflammation (a response controlled by a single, autosomal, dominant gene) segregated independently. Genetic analysis of resistance to R. akari in sensitive A and resistant B10.A mice suggested this trait was also controlled by a single, autosomal, dominant gene. Among (F1 X A) backcross mice, however, traits for defective macrophage cytotoxicity and R. akari resistance segregated independently. Thus, development of activated tumoricidal macrophages, accumulation of macrophages at sites of inflammation, and resistance to the lethal effects of R. akari in A and B10.A mice were each controlled by single, autosomal, dominant, non-H-2-linked genes. However, genes for control of macrophage activation for tumoricidal activity and for resistance to lethal effects of R. akari infection are distinct.