TY - JOUR
T1 - Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner
AU - Walker-Sperlin, Victoria
AU - Digitale, Jean C.
AU - Viard, Mathias
AU - Martin, Maureen P.
AU - Bashirova, Arman
AU - Yuki, Yuko
AU - Ramsuran, Veron
AU - Kulkarni, Smita
AU - Naranbhai, Vivek
AU - Li, Hongchuan
AU - Anderson, Stephen K.
AU - Yum, Lauren
AU - Clifford, Robert
AU - Kibuuka, Hannah
AU - Ake, Julie
AU - Thomas, Rasmi
AU - Rowland-Jone, Sarah
AU - Rek, John
AU - Arinaitwe, Emmanuel
AU - Kamya, Moses
AU - Rodriguez-Barraque, Isabel
AU - Feeney, Margaret E.
AU - Carrington, Mary
N1 - Funding Information:
necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.
Funding Information:
ACKNOWLEDGMENTS. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under Contract No. HHSN261200800001E. The content of this publication does not
Funding Information:
This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/7/19
Y1 - 2022/7/19
N2 - HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2a transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.
AB - HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2a transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.
KW - HLA
KW - Malaria
KW - tapasin
UR - http://www.scopus.com/inward/record.url?scp=85134465278&partnerID=8YFLogxK
U2 - 10.1073/pnas.2205498119
DO - 10.1073/pnas.2205498119
M3 - Article
C2 - 35858344
AN - SCOPUS:85134465278
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
M1 - e2205498119
ER -