Lipopolysaccharide binding protein in the acute phase response of experimental murine Trypanosoma brucei brucei infection
Introduction
Exposure to lipopolysaccharide (LPS) induces a wide variety of host defence mechanisms, including macrophage/monocyte activation. The plasma LPS-binding protein (LBP) and monocyte CD14 are central molecules of the innate immune system, involved in the response to LPS (Le Roy et al., 2001). LBP is known to augment the host response to low doses of LPS, triggering synthesis of high levels of pro-inflammatory cytokines (Gallay et al., 1994, Le Roy et al., 1999). Indeed the LPS-LBP complex has been shown to be 1000-fold more potent than LPS alone, in the induction of pro-inflammatory cytokines (Schumann et al., 1990, Heumann et al., 1992).
Acute phase response (Eckersall et al., 2001) and tissue damage during pathogenesis of trypanosomosis is mediated through production of pro-inflammatory cytokines (MacLean et al., 2001, Maina et al., 2004). Mice infected with Trypanosoma brucei brucei (T. b. brucei) have been observed to develop a major acute phase response demonstrated by an increase in plasma levels of acute phase proteins haptoglobin and serum amyloid P (Ngure et al., 1997, Eckersall et al., 2001).
Trypanosome-infected mice and rats have also been observed to have high plasma levels of endotoxin-like activity believed to be derived from the infecting trypanosomes (Alafiatayo et al., 1993), secondary bacterial infection or leakage from damaged gastro-intestinal tract (Nyakundi et al., 2002). Moreover, trypanosome-infected mice appear to be highly susceptible to low levels of artificially administered LPS that would normally have no effect in healthy, uninfected mice (Singer et al., 1964, Ferrante et al., 1984). This enhanced susceptibility to LPS is usually accompanied by a decrease in the lethal dose (LD50) of LPS by up to 1000-fold.
Although changes in plasma LBP levels have been extensively investigated in bacterial infections (Bannerman et al., 2003), no such studies have been done for trypanosome infections. In order to develop more effective treatment strategies for trypanosomosis, it is important to unravel the parasite-host interactions, including the role of various factors in the pathogenesis of the disease. The present study was carried out to determine whether LBP is an acute phase protein during murine trypanosomosis, in an attempt to elucidate its role in the increased susceptibility to LPS observed in trypanosome-infected mice. The findings of the study implicate LBP as a possible factor in the pathogenesis of murine trypanosomosis and call for further investigations to define the role of LBP and other factors that may be involved in the development of the disease.
Section snippets
Experimental animals
Experiments were conducted using 320 adult female inbred NIH mice with a body weight of 25–30 g. The mice were randomly divided into two major groups; one group to be infected with trypanosomes (IF), and the other to remain as uninfected controls (UIF). The infected and uninfected groups of mice were each further subdivided into two sets. One set was put under ciprofloxacin antibiotic (TX) (Norfloxacin®, Sigma Chemicals Company, Poole Dorset, UK) treatment while the other was not treated (UTX).
Parasitaemia
Trypanosomes were demonstrated in the blood circulation of all infected animals 4–5 days post- infection, and were detected at all sampling points before treatment with diminazine aceturate. Following treatment with diminazine aceturate, parasites were cleared from circulation within 2–3 days and were not detected until termination of the experiment on Day 49 post-infection.
Plasma LBP Levels
The mean plasma LBP concentrations (±SEM) in infected and control mice are presented in Fig. 1. The plasma LBP
Discussion and conclusion
This present investigation was designed to determine if LBP is an acute phase protein during trypanosomosis, and the role of gut and secondary bacterial endotoxin in such acute phase response. Acute phase responses, demonstrated by an increase in the serum concentration of serum amyloid P and haptoglobin, have been observed in the blood of mice infected with trypanosomes (Ngure et al., 1997, Eckersall et al., 2001). However, LBP responses have not been studied during trypanosome infections.
Acknowledgements
Special thanks go to Dr. Frank Jennings of the Department of veterinary medicine, University of Glasgow, for his technical advice in setting up the experiment and to the British council and Welcome trust for funding the work.
References (28)
- et al.
Increased levels of LPS-binding protein in bovine blood and milk following bacterial lipopolysaccharide challenge
Journal of Dairy Science
(2003) - et al.
Cytokine and the acute phase response in post-treatment reactive encephalopathy of Trypanosoma brucei brucei infected mice
Parasitology International
(2001) - et al.
Radioimmunoasay versus flow cytometric assay to quantify LPS-binding protein (LBP) concentration in human plasma
Journal of Immunological Methods
(1994) - et al.
Major Acute phase response of haptoglobin and serum amyloid P following experimental infection of mice with Trypanosoma brucei brucei
Parasitology International
(1997) - et al.
Endotoxins and the pathogenesis of Trypanosoma brucei brucei infection in mice
Parasitology
(1993) - et al.
Some characteristics of the reactivity to bacterial lipopolysaccharide induced in mice by Trypanosoma cruzi infection
Memoria do Institute Oswald Cruz
(1984) - et al.
Mechanism of bacterial lipopolysaccharide-induced endothelial apoptosis
American Journal of Physiology Lung Cellular and Molecular Physiology
(2003) - et al.
Effects of zymosan on endotoxin toxicity in mice
Proceedings of the Society of Experimental Biology and Medicine
(1959) - et al.
Increased hepatotoxicity of bacterial lipopolysaccharide in mice infected with Schistosoma mansoni
Parasite Immunology
(1979) - et al.
Lipopolysaccharide hypersensitivity of animals infected with Trypanosoma lewisi or Trypanosoma musculi
Infection and Immunity
(1984)
Lipopolysaccharide-binding protein as a major plasma protein responsible for endotoxin shock
Proceedings of the National Academy of Science
Mode of action of anti-lipopolysacharide binding protein (LBP) antibodies for prevention of endotoxic shock
Proceedings of the National Academy of Science
Fatal effect of some bacterial toxins on mice pre-infected with mouse hepaptitis virus (MHV1)
Journal of General Microbiology
Control of LPS binding and LPS-induced TNF secretion in human peripheral blood monocytes
Journal of Immunology
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