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Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner

  1. Author:
    Walker-Sperling, Victoria
    Digitale, Jean C
    Viard,Mathias [ORCID]
    Martin,Pat [ORCID]
    Bashirova,Arman
    Yuki,Yuko [ORCID]
    Ramsuran, Veron
    Kulkarni, Smita
    Naranbhai, Vivek [ORCID]
    Li,Hongchuan [ORCID]
    Anderson,Steve [ORCID]
    Yum, Lauren
    Clifford, Robert
    Kibuuka, Hannah
    Ake, Julie
    Thomas, Rasmi
    Rowland-Jones, Sarah [ORCID]
    Rek, John
    Arinaitwe, Emmanuel
    Kamya, Moses [ORCID]
    Rodriguez-Barraquer, Isabel [ORCID]
    Feeney, Margaret E
    Carrington,Mary [ORCID]

  2. Author Address

    Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892., Department of Medicine, University of California San Francisco, San Francisco, California, 94158., Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, 94143., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702., School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa., Texas Biomedical Research Institute, Host Pathogen Interaction Program, San Antonio, Texas, 78227., Dana Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts, 02215., MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, 02114., Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114., Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, 4041, South Africa., Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702., U.S. Military HIV Research Program,, Walter Reed Army Institute of Research, Silver Spring, Maryland, 20910., Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, 20817., Makerere University Walter Reed Project, Kampala, Uganda., Viral Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK., Infectious Diseases Research Collaboration, Kampala, Uganda., Department of Medicine, Makerere University, Kampala, Uganda., Department of Pediatrics, University of California San Francisco, San Francisco, California, 94158., Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, 02139.,
    1. Year: 2022
    2. Date: Jul 19
    3. Epub Date: 2022 07 13
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 119
    2. 29
    3. Pages: e2205498119
  4. Type of Article: Article
  5. Article Number: e2205498119
  1. Abstract:

    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-2a 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.

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External Sources

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  2. DOI: 10.1073/pnas.2205498119
  3. PMID: 35858344
  4. PMCID: PMC9303992

Library Notes

  1. Fiscal Year: FY2021-2022
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