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The Antirickettsial Effect of Thionine Dyes. II on the Mode of Action of the Thionine Dyes in Combatting Experimental Infections of Mice with Rickettsia Orientalis and Rickettsia Mooseri

From the Laboratories of the International Health Division, The Rockefeller Foundation, New York City

Abstract

Toluidine blue (TB) and methylene blue MB exert against R. orientalis, in vitro, only a slight rickettsiacidal effect, which is independent of light or oxygen.

Treatment with TB or MB of mice infected with R. orientalis impedes the localization and multiplication of rickettsiae in the brain, causes a diminution in the infectivity of the blood, and results in an inconstant inhibition of rickettsial multiplication in the liver. However, maximal tolerated doses of dye do not prevent small infecting doses of rickettsiae from initiating an immunizing infection; greater, eventually lethal, amounts of dye do not exert a completely suppressive effect; and, finally, great prolongation of treatment (a total of 65 days) does not sterilize the tissues.

As a corollary observation, a strain of rickettsiae recovered after the prolonged treatment shows no evidence of having become fast to MB.

As shown by limited histopathologic observations, MB largely prevents the development of the anatomic lesions of scrub typhus but, presumably secondary to its destructive effect upon red cells, does exert a marked stimulus to hemopoietic activity.

As noted by other workers, treatment with MB is effective against experimental murine typhus. In mice receiving such treatment, however, no inhibition of rickettsial multiplication in the liver is demonstrable.

In addition to TB and MB, six structurally related compounds, azure C, azure A, brilliant cresyl blue, azure B, thionin blue, and selenium methylene blue, also are effective in combatting rickettsial infections. In contrast, an additional and greater number of related compounds appear to possess no such activity.

The foregoing evidence does not permit definite conclusions to be drawn regarding the mode of action of TB and MB in combatting rickettsial infections. It is suggested that the mechanism is independent of the in vitro rickettsiacidal activity of the dyes and is only partly dependent upon the irregular rickettsiostatic effect observed in vivo. An additional possibility is that the dyes also operate to spare the cells from the usual harmful effects produced by the rickettsiae by virtue of their ability to mediate intracellular oxidation. A survey of related compounds further indicates that antirickettsial activity requires some degree of structural specificity.