Trypanosomiasis: Parasite, lysis by serum

T. b. brucei cannot infect humans since it undergoes lysis in human serum. There are two distinct circulating trypanosome lytic factors (TLFs) in human blood. TLF1 is a lipid-rich subtype of high density lipiprotein (HDL), whereas TLF2 is a lipid-poor particle complexed with IgM. TLF2 is a lipoprotein composed of apolipoprotein A-I, haptoglobin-related protein (Hpr) and IgM and is composed of less than 1% lipid. Persons suffering from Tangier disease (analphalipoproteinaemia; HDL deficiency) do not produce TLF1.

The hpr-gene is present in the genomes of humans, Old World monkeys and chimpanzees. Of these primates, only chimpanzee serum is not trypanolytic. A functional Hpr is not synthetised by the chimpanzee because the chimp hpr-gene has a single-base deletion that results in a frameshift. Hpr is 94% identical to haptaglobin. Its physiological function, aside from a role in trypanolysis, is not known. TLF1 is completely inhibited by haptaglobin, whereas TLF2 is not. Therefore, it is possible that TLF2 may be the only active factor in vivo, considering that normal serum levels of haptaglobin are likely to completely inhibit endogenous TLF1 activity. Haptoglobin is a heterotetrameric protein consisting of two alpha-subunits and two glycosylated beta-subunits. There are 3 common types of haptaglobin in human populations, namely Hp 1:1, Hp 2:1 and Hp 2:2. All are inhibitory for TLF1. Haptoglobin binds free haemoglobin in human plasma. In individuals with severe haemolysis, haptaglobin decreases in plasma with the formation of haptaglobin-haemoglobin complexes that are cleared via the liver. In contrast, Hpr does not bind haemoglobin and Hpr serum levels remain constant at 25-50 µg/ml in normal and haemolytic sera. Individuals who have a haemolytic disease have high levels of TLF1 activity, which has been revealed as a consequence of depleted haptaglobin.

Parasite lysis by TLF1 and probably also TLF2 requires their uptake by receptor-mediated endocytosis in the flagellar pocket. After uptake, both lytic factors apparently need to enter an intracellular acidic vesicle to be activated. Lysis is inhibited by reagents that prevent acidification of lysosomes, even though TLFs are still delivered to the vesicles. The mechanism by which trypanosomes resist lysis by normal human serum is not known in detail, but it is thought to be associated with a defect in uptake and processing of TLF1 and TLF2. This may be the result of altered TLF receptors or other mechanisms.

Category: Medicine Notes