Jennings Fw

Major acute phase response of haptoglobin and serum amyloid-P following experimental infection of mice with Trypanosoma brucei brucei

Investigation of the pathophysiological role of the systemic cytokines, including interleukin-1, interleukin-6 and tumour necrosis factor α, in the host response to infection with African trypanosomes is hampered by the low and transient concentrations of these cytokines in plasma. One of the actions of these cytokines is the stimulation of hepatocyte production of acute phase proteins such as serum amyloid-P and haptoglobin. These acute phase proteins are more stable in the circulation than the cytokines and can be measured as a means of assessing the systemic cytokine response in the trypanosome-infected host. The plasma concentrations of serum amyloid-P and haptoglobin were measured in an experimental mouse model of Trypanosoma brucei brucei infection. Both serum amyloid-P and haptoglobin, increased markedly following infection. Peak concentrations of serum amyloid-P at 125 μg/ml and haptoglobin at 2 g/l were attained 10 to 12 days after infection. Thereafter, serum amyloid-P concentration decreased to approximately 40 μg/ml while the haptoglobin concentration remained elevated at approximately 1.5 g/l. The reactions of the serum amyloid-P and haptoglobin following experimental Trypanosoma brucei brucei infection in mice demonstrate that a major acute phase response has occurred indicating that the systemic cytokine network has been activated. Further studies are required to identify whether the response is stimulated by the parasite or indirectly by tissue damage.

Immune mechanisms in C57B1 mice genetically resistant to Trypanosoma congolense infection. I. Effects of immune modulation

Summary The effect of immune modulation on the pattern and course of infection with T. congolense was investigated in a strain of mice (C57B1) which is known to possess a significant degree of trypanotolerance, and a susceptible strain (CFLP) which rapidly succumbs to infection. Immunosuppression of C57B1 mice by splenectomy, cyclophosphamide treatment or gamma irradiation reduced their survival to near that of susceptible strains of mice. In contrast, attempts to enhance the immune response of susceptible CFLP mice using either a variety of immunostimulants, simultaneous vaccination with irradiated parasites at the time of infection, passive immunization or reducing the number of parasites used for infection, failed to confer a level of protection comparable to that of C57B1 mice. It was concluded that the basis of trypanotolerance, although immunological in nature, is associated with, as yet, undetermined factors.

Secondary bacterial infection in plasma endotoxin levels and the acute-phase response of mice infected with Trypanosoma brucei brucei.

Murine Trypanosoma brucei brucei infection leads to elevated plasma endotoxin‐like activity levels not related to parasitaemia levels accompanied by the development of acute‐phase response and increased plasma levels of serum amyloid P (SAP) and haptoglobin (Hp). To determine the source of the endotoxin‐like activity and role of secondary bacterial infection in the pathogenesis of trypanosomosis, infected mice were treated with the antibiotic ciprofloxacin. Plasma endotoxin‐like activity levels, irrespective of treatment, were elevated three‐ to fourfold, beginning 7 days after infection. Plasma protein concentrations increased markedly following infection from 7 days after infection (DAI). Peak Hp and SAP concentrations in ciprofloxacin‐treated and ‐untreated infected mice were attained 7 and 14 DAI, respectively. Thereafter, both protein levels gradually declined until the end of the experiment, but Hp levels for non‐treated mice declined up to 21 DAI and thereafter significantly increased on 28 and 35 DAI. Whole‐trypanosome lysate and the membrane‐enriched fraction demonstrated endotoxin‐like activity, with the former having higher levels. The results suggest that the endotoxin‐like activity in trypanosome fractions and plasma of infected mice is due to the trypanosome. Further elevation of haptoglobin during the late stages of infection in non‐treated mice suggests the involvement of secondary bacterial infection.

Immune mechanisms in C57B1 mice genetically resistant to Trypanosoma congolense infection. II. Aspects of the humoral response.

Summary Some aspects of the humoral response in trypanotolerant C57B1 mice and susceptible A/J mice were investigated to determine the possible basis of trypanotolerance. When the hepatic uptake of 75Se‐labelled T. congolense by infected mice was measured as an index of antibody production, it was found that only C57B1 mice could remove circulating labelled parasites, this ability persisting for several weeks after infection. Estimation of the immunoglobulin concentrations in both strains of mice showed that C57B1 mice developed a pronounced IgM response during the first parasitaemic wave, while A/J mice did not. Over the same period the IgM concentrations in C57B1 mice initially fell, but recovered at the time of peak parasitaemia. In contrast, A/J mice showed a continual fall in total IgG concentrations in the circulation until death 10 days after infection. Finally, it was shown that during the initial rising parasitaemia, the plaque forming cell responses of both strains of mice to sheep red blood cells were normal indicating that neither strain of mice was immunosuppressed. Also, A/J mice vaccinated with irradiated T. brucei on day 4 and C57B1 mice vaccinated either on day 4 or day 60 of a T. congolense infection were able to mount an effective immune response to the vaccine, as judged by the hepatic uptake of radiolabeled parasites. All of the results indicate that the trypanotolerance of C57B1 mice depends, at least in part, on their more efficient antibody response.

Lipopolysaccharide binding protein in the acute phase response of experimental murine Trypanosoma brucei brucei infection

Cellular responses to lipopolysaccharide (LPS) are enhanced by LPS-binding protein (LBP). The present study investigated the acute phase response of LBP during Trypanosoma brucei brucei infection in mice. Mean plasma concentrations of LBP increased two-fold by the seventh day following infection, but decreased to intermediate levels by the 14th day. There were no significant differences in LBP concentrations of infected/antibiotic-treated and infected/untreated mice. At 35 days post-infection, the infected mice were treated with the anti-trypanosomal diminazine aceturate (Berenil). LBP levels of the mice then decreased to pre-infection levels within one-week. This demonstrated that LBP is an acute phase protein during murine trypanosomosis. Furthermore, opportunistic secondary bacterial infection during trypanosomosis did not seem to play an important role in the changes in plasma LBP levels. We speculate that the marked concomitant increases in plasma LBP and endotoxin-like activity following murine trypanosome infection might play an important role in the pathogenesis of trypanosomosis.