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The Resistance-Promoting Activity of Endotoxins and Other Microbial Products

I. Their Effect on Salmonella Typhosa Infections of Mice^1,2,

Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland

Abstract

Summary and Conclusions: These studies emphasize the exacting conditions required for demonstration of endotoxin-induced resistance to typhoid infection. The degree of protection is never very great and can be readily overcome by increasing the challenge dose. It is also dependent upon the routes of inoculation and the interval of time between protective and challenge injections. Enhanced resistance to peritoneal typhoid infection was most marked in mice previously injected intraperitoneally with endotoxin. The incidence of death from cerebral typhoid infection was only slightly affected by intravenous or intraperitoneal injection of endotoxin, and not at all by subcutaneous injection. However, striking protection against cerebral typhoid infection was noted in mice pretreated with endotoxin by the intracerebral route. These observations suggest that local alterations of tissue susceptibility occur at the site of injection of endotoxin. The significance of these findings is discussed in the following paper on resistance to virus neurotoxicity.

An advantage accruing to the use of the brain as the site of infection is the relative ease with which reproducible growth curves of typhoid bacilli could be obtained. In support of the findings of Landy and Pillemer on typhoid peritonitis, the bacterial titers in the brains of resistant mice were appreciably lower than those in fully susceptible controls. Despite the favorable outcome of infection in mice pretreated with endotoxin, typhoid bacilli persisted at relatively high and constant levels throughout an observation period of 10 days.

Refractoriness to cerebral typhoid infection induced by prior injection of typhoid vaccine or xerosin is almost undoubtedly related to the endotoxin present in these materials. In contrast to its antiviral action, xerosin was the least effective of the products derived from Gram-negative bacteria. Slightly increased resistance to cerebral typhoid infections could also be demonstrated by pretreatment with influenza virus. The results with staphylococcus vaccine were uncertain and the inflammatory response produced by intracerebral injection of aleuronat was not accompanied by protection aginst typhoid infection.

Intracerebral injection of endotoxin or typhoid vaccine did not alter susceptibility to cerebral infection with streptococci or pneumococci. The capacity of bacterial products to bolster host resistance appears to be demonstrated most easily in infections with Gram-negative bacteria and, as will be shown in the following report, to the toxic action of viruses.

Footnotes

¹ Presented in part at the annual meetings of the Eastern Section of the American Federation for Clinical Research (Clin. Res. Proc., 5: 22, 1957) and the American Society for Clinical Investigation (J. Clin. Invest., 37: 903, 1958).

² Supported by Grant C-2813 (C2R1) from the U. S. Public Health Service, and Contract DA-18-064-404-CML-100 with the U. S. Army Chemical Corps, Fort Detrick, Frederick, Maryland.