Trading Kidney Disease for Protection from Trypanosomiasis
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is on the speaker's bureau for GSK and Cubist Pharmaceuticals, and is a consultant for Siemens Diagnostics.
Synopsis: Two apolipoprotein L1 (ApoL1) variants were found to be associated with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) in African-American patients. These two ApoL1 variants (G1 and G2) were common in controls from Africa but were not present in European chromosomes. In-vitro assays showed that only kidney disease-associated ApoL1 lysed Trypanosoma brucei rhodesiense.
Source: Genovese G, et al. Association of trypanolytic ApoL1 variants with kidney disease in African-Americans. Science. 2010;329:841-845.
Initial association analysis was performed on 205 african-americans with biopsy-proven FSGS and 180 African-American controls. A two-locus allele, G1, in the last exon of ApoL1, was found to have a frequency of 52% in FSGS cases and 18% in the controls. By using logistic-regression analysis to control for G1, a six base-pair deletion near G1 (termed G2) was also found to be strongly associated with FSGS. Next, a larger cohort of 1,030 African-American cases with H-ESKD and 1,025 African-American controls from the Southeastern United States were examined. Again, G1 and G2 were found to be strongly associated with kidney disease. Using other available sequence data, G1 was found in 40% of Yoruba tribesmen (Nigeria in West Africa) and in a smaller number G2 was found. These alleles were not seen in individuals of European, Japanese, or Chinese background. In-vitro trypanolytic activity of plasma from 75 individuals with different combinations of G1 and G2 genotypes was determined. All samples efficiently lysed T. brucei brucei, but none lysed T. brucei gambiense. Serum-resistant T. brucei rhodesiense was more efficiently lysed by G2 than G1 plasma, although both homozygous, heterozygous variants and G1/G2 double-heterozygous plasma resulted in lysis of trypanosomes. These results were confirmed in trypanolytic experiments using recombinant ApoL1 proteins.
Commentary
Innate immunity to T. brucei brucei is due to the trypanolytic activity of a human-specific apolipoprotein bound to high-density lipoproteins, termed ApoL1. This protein contains an ionic pore-forming domain consisting of nine alpha helixes and a pH-sensitive membrane-addressing domain consisting of two alpha helixes. ApoL1 is taken up by the trypanosome, and the resultant pore formation and loss of osmotic stability results in lysis. T. brucei rhodesiense and T. brucei gambiense have acquired resistance to ApoL1. Resistance to lysis in normal human serum in T. brucei rhodesiense is conferred by a single protein, serum-resistance-associated protein (SRA), which binds specifically to ApoL1. The mechanism of serum resistance of T. brucei gambiense is not known. Another hemoflagellate that infects domestic animals, T. evansi, is generally not pathogenic for humans, although a case of human infection due to T. evansi was recently reported in India, and subsequent investigation revealed the patient lacked ApoL1.1 Another recent paper shows that ApoL1 may also be implicated in innate anti-Leishmania activity.2
I thought this was a fascinating paper. The data show that sequence variation in ApoL1 contributes to the increased prevalence of renal disease in African-Americans (most came to the United States originally as slaves captured or sold from West Africa). While the mechanism of the association between the G1 and G2 variants and renal disease has yet to be defined, the data suggest that ApoL1 performs a critical role in the kidney and that it is impaired in the setting of ApoL1 variants (or that these variants may directly cause kidney toxicity). The data also show that both the G1 and G2 variants effectively lyse a T. brucei rhodesiense subspecies that is normally resistant to serum ApoL1 lytic activity. These kidney disease-associated variants are located on haplotypes that the authors state show statistical evidence of natural selection and these ApoL1 risk alleles occur in more than 30% of African-Americans. Elucidating the molecular mechanisms by which these alleles contribute to renal injury will make for some very interesting science of great potential relevance to treating or preventing kidney disease in patients of African origin.
References
- Vanhollebeke B, et al. Human Trypanosoma evansi infection linked to a lack of Apolipoprotein L-I. N Engl J Med. 2006; 355: 2752-6.
- Semanovic M, et al. Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection. PLoS Pathog. 2009; 5: e1000685.
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