Bryostatin 1, a potent activator of
protein kinase C, has antitumor activity against murine
lymphoma,
leukemia, and
melanoma. In vitro, this compound stimulates the release of
gamma-interferon,
interleukins, and hematopoietic
growth factors from accessory cells and activates both T- and B-cells.
Bryostatin 1 is also able to stimulate neutrophils to undergo oxidative burst and degranulation. Because of the ability of this compound to stimulate the immune system, cause release of immune mediators, and activate neutrophils, we have examined its effect on
bacterial infection by using the gram-negative bacterium Salmonella typhimurium in mice. We find that animals given
injections i.v. of S. typhimurium have a shortened life span if they are also given
injections i.p. of nonlethal doses of
bryostatin 1. There is a dose-response relationship with 100 micrograms/kg
bryostatin 1 having a greater effect on survival than 40 micrograms/kg. Below 40 micrograms/kg there are no effects on survival. Analysis of the first 4 h of
Salmonella infection demonstrates that
bryostatin 1 does not affect the blood clearance of the bacterium. However, by day 2 of
infection greater numbers of bacteria are found in the livers and spleens of mice given
injections of
bryostatin 1. By day 5, 10-fold more S. typhimurium bacteria are found in the livers and spleens of mice receiving 40 micrograms/kg of
bryostatin 1. To determine whether
bryostatin 1 was affecting growth or causing the death of bacteria, we used a Salmonella carrying a plasmid which has a temperature-sensitive origin of replication and is unable to replicate when the bacteria are in mice. This experiment demonstrates that
bryostatin 1 represses bacterial killing but does not affect bacterial growth.
Bryostatin 1 given i.p. stimulates a transient syndrome of
weight loss and
diarrhea from which the mice recover and regain weight, suggesting that
bryostatin 1 may release a number of important humoral mediators in vivo. The
weight loss is exacerbated by
Salmonella infection with mice receiving
bryostatin 1 and S. typhimurium, in that they lose approximately 33% of
body weight prior to death. Thus, at doses used to treat murine
tumors,
bryostatin 1 treatment does not affect the clearance of S. typhimurium from the blood but does decrease the killing of bacteria in the liver and spleen, leading to early animal death. Such potential effects of
bryostatin 1 on the outcome of
bacterial infections should be evaluated in ongoing human trials of this agent.