Tumor necrosis factor alpha is a key mediator in the regulation of experimental Trypanosoma brucei infections

Abstract

In order to evaluate during experimental Trypanosoma brucei infections the potential role of tumor necrosis factor alpha (TNF-alpha) in the host-parasite interrelationship, C57BL/6 TNF-alpha knockout mice (TNF-alpha-/-) as well as C57BL/6 wild-type mice were infected with pleomorphic T. brucei AnTat 1.1 E parasites. In the TNF-alpha-/- mice, the peak levels of parasitemia were strongly increased compared to the peak levels recorded in wild-type mice. The increased parasite burden did not reflect differences in clearance efficacy or in production of T. brucei-specific immunoglobulin M (IgM) and IgG antibodies. Trypanosome-mediated immunopathological features, such as lymph node-associated immunosuppression and lipopolysaccharide hypersensitivity, were found to be greatly reduced in infected TNF-alpha-/- mice. These results demonstrate that, during trypanosome infections, TNF-alpha is a key mediator involved in both parasitemia control and infection-associated pathology.

FIG. 1

Parasitemia development of pleomorphic T. brucei AnTat 1.1 parasites in C57BL/6 wild-type (■) and TNF-α^−/− (□) mice. Ten mice per group were infected at day 0 by intraperitoneal injection of 5,000 parasites. Results are expressed as means ± standard deviations.

FIG. 2

Development of an antiflagellar pocket immune response during the experimental infection with T. brucei AnTat 1.1. Antibody titers were determined with the serum of both infected wild-type and TNF-α^−/− C57BL/6 mice. Preimmune serum was used to determine aspecific binding. Serum samples were analyzed in triplicate (mean ± standard deviation) at day 6 (A), day 7 (B), day 14 (C), and day 35 (D), and serum antibody titers were checked for the wild-type IgM (●) and IgG (■) responses and the TNF-α^−/− IgM (○) and IgG (□) responses.

FIG. 3

Survival of T. brucei AnTat 1.1-infected C57BL/6 wild-type (■) and TNF-α^−/− (□) mice. Ten mice per group were infected at day 0 by intraperitoneal injection of 5,000 parasites.

FIG. 4

Locomotor activity was measured as the total time per hour spent by mice on running in their cage, eating, drinking, and cleaning their fur and nest. Locomotor activity was recorded during a 24-h period 8 days postinfection for noninfected wild-type mice (A), T. brucei AnTat 1.1-infected wild-type mice (B), and infected TNF-α^−/− mice (C). Mice were kept in an animal facility with a 12-h-light–12-h-dark regimen. Three mice per experimental group were used, and the results are expressed as means ± standard deviation.

FIG. 5

The coat condition of T. brucei AnTat 1.1-infected wild-type mice (A) was compared to the coat condition of infected TNF-α^−/− mice (B). Both mice were photographed on day 30 of infection.

FIG. 6

Survival after LPS challenge of noninfected (■) and T. brucei AnTat 1.1-infected (□) C57BL/6 wild-type mice (A) was compared to the survival after LPS challenge of noninfected (●) and infected (○) TNF-α^−/− mice (B). Mice were infected at day 0 by intraperitoneal injection of 5,000 parasites, and at day 14 postinfection, LPS was administered via intraperitoneal injection. LPS sensitivity was analyzed in an LPS dose range from 0.01 μg/mouse up to 10 mg/mouse in both infected and noninfected mice, with five mice used per LPS data point.