Transgenic mice expressing human apolipoprotein A-I have sera with modest trypanolytic activity in vitro but remain susceptible to infection by Trypanosoma brucei brucei.
Although Trypanosoma brucei brucei fatally infects livestock in much of sub-Saharan Africa, humans are innately resistant to infection, apparently because high-density lipoproteins (HDL) in human serum lyse this unicellular protozoan parasite. Recently, we demonstrated that purified human apolipoprotein (apo) A-I, the major protein (M(r) 28,016) constituent of HDL, had full trypanolytic activity in vitro whereas the apoA-I of cattle and sheep was non-lytic. In the present study, we have sought to confirm the trypanocidal capability of human apoA-I by studying four lines of transgenic mice expressing (supra)physiological serum levels of this polypeptide. Although trypanolysis in vitro by sera from transgenic mice (15.1 +/- 1.3% [mean +/- SEM], n = 30) was considerably less than by human sera (typically 60-80%), it was nevertheless significantly greater than by control sera (8.5 +/- 1.1%, n = 10; P < 0.001) and correlated with the concentration of human apoA-I (r = 0.56, P < 0.001). When trypanosomes were incubated at 37 degrees C with human serum or with human apoA-I for 30 min (i.e., within the pre-lytic period) they lost their ability to subsequently infect mice; trypanosomes incubated with transgenic mice serum remained infective. Furthermore, transgenic mice were fully susceptible to infection when inoculated with 10(3) trypanosomes; both the initial detection of trypanosomes in the blood (3-4 days) and the time to death (5-6 days) were no longer than control mice. This apparent paradox between the action of human apoA-I in human serum and in mouse serum was investigated further.(ABSTRACT TRUNCATED AT 250 WORDS)
Owen
J S
JS
University Department of Medicine, Royal Free Hospital School of Medicine (University of London), England.
Gillett
M P
MP
Hughes
T E
TE
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014344:Trypanocidal Agents / Q000097:blood; D014346:Trypanosoma brucei brucei; D014353:Trypanosomiasis, African / Q000097:blood / Q000209:etiology* / Q000235:genetics
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D014344:Trypanocidal Agents