APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis

Junnan Wu; Ziyuan Ma; Archana Raman; Pazit Beckerman; Poonam Dhillon; Dhanunjay Mukhi; Matthew Palmer; Hua Chang Chen; Cassiane Robinson Cohen; Thomas Dunn; John Reilly; Nuala Meyer; Michael Shashaty; Zoltan Arany; György Haskó; Krzysztof Laudanski; Adriana Hung; Katalin Susztak

doi:10.1016/j.immuni.2021.10.004

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis

Immunity. 2021 Nov 9;54(11):2632-2649.e6. doi: 10.1016/j.immuni.2021.10.004. Epub 2021 Oct 12.

Authors

Junnan Wu¹, Ziyuan Ma², Archana Raman², Pazit Beckerman², Poonam Dhillon², Dhanunjay Mukhi², Matthew Palmer³, Hua Chang Chen⁴, Cassiane Robinson Cohen⁵, Thomas Dunn⁶, John Reilly⁶, Nuala Meyer⁶, Michael Shashaty⁷, Zoltan Arany⁸, György Haskó⁹, Krzysztof Laudanski¹⁰, Adriana Hung⁵, Katalin Susztak¹¹

Affiliations

¹ Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
² Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Department of Pathology and Laboratory Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Division of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Division of Nephrology & Hypertension, Tennessee Valley Healthcare System, Nashville Campus and Vanderbilt University Medical Centre, Nashville, TN, USA; Division of Nephrology & Hypertension, Vanderbilt Precision Nephrology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Anesthesiology, Columbia University, New York, NY 10032, USA.
¹⁰ Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: ksusztak@pennmedicine.upenn.edu.

Abstract

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.

Keywords: APOL1; COVID-19; endothelial cell; mitophagy; sepsis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoprotein L1 / blood
Apolipoprotein L1 / genetics*
Black People / genetics*
Black People / statistics & numerical data
COVID-19 / genetics*
COVID-19 / pathology
DNA, Mitochondrial / metabolism
Endothelial Cells / metabolism
Genetic Predisposition to Disease / genetics*
Humans
Inflammation / genetics
Inflammation / pathology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Knockout
Mitophagy / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Risk Factors
Sepsis / genetics*
Sepsis / pathology
Severity of Illness Index
White People / genetics
White People / statistics & numerical data

Substances

APOL1 protein, human
Apolipoprotein L1
DNA, Mitochondrial
Membrane Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Sting1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding