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Role of Apolipoproteins L in immunity and disease

Objective

Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification
of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities
with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under
inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA
protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect
humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and
therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.
Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished
results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral
stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the
control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.
This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of
activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and
(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the
physiological function of APOLs by studying the phenotype of transgenic mice either expressing human
APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we
propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce
SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in
podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new
perspectives to treat kidney disease.

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/clinical medicine/nephrology/kidney diseases
  • /medical and health sciences/clinical medicine/psychiatry/sleep disorders
  • /medical and health sciences/basic medicine/immunology

Call for proposal

ERC-2014-ADG
See other projects for this call

Funding Scheme

ERC-ADG - Advanced Grant

Host institution

UNIVERSITE LIBRE DE BRUXELLES
Address
Avenue Franklin Roosevelt 50
1050 Bruxelles
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 250 000

Beneficiaries (1)

UNIVERSITE LIBRE DE BRUXELLES
Belgium
EU contribution
€ 2 250 000
Address
Avenue Franklin Roosevelt 50
1050 Bruxelles
Activity type
Higher or Secondary Education Establishments