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

Author:

Walker-Sperling Victoria1,Digitale Jean C.23,Viard Mathias14ORCID,Martin Maureen P.14ORCID,Bashirova Arman14,Yuki Yuko14ORCID,Ramsuran Veron5,Kulkarni Smita6,Naranbhai Vivek578910ORCID,Li Hongchuan411ORCID,Anderson Stephen K.411ORCID,Yum Lauren1213,Clifford Robert1213,Kibuuka Hannah14,Ake Julie12,Thomas Rasmi12,Rowland-Jones Sarah15ORCID,Rek John16,Arinaitwe Emmanuel16,Kamya Moses1617ORCID,Rodriguez-Barraquer Isabel2ORCID,Feeney Margaret E.218,Carrington Mary1419ORCID

Affiliation:

1. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892

2. Department of Medicine, University of California San Francisco, San Francisco, California, 94158

3. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, 94143

4. Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702

5. School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa

6. Texas Biomedical Research Institute, Host Pathogen Interaction Program, San Antonio, Texas, 78227

7. Dana Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts, 02215

8. MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, 02114

9. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114

10. Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, 4041, South Africa

11. Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702

12. U.S. Military HIV Research Program,, Walter Reed Army Institute of Research, Silver Spring, Maryland, 20910

13. Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, 20817

14. Makerere University Walter Reed Project, Kampala, Uganda

15. Viral Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK

16. Infectious Diseases Research Collaboration, Kampala, Uganda

17. Department of Medicine, Makerere University, Kampala, Uganda

18. Department of Pediatrics, University of California San Francisco, San Francisco, California, 94158

19. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, 02139

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 regulateTAPBPmessenger RNA (mRNA) expression in Africans,rs111686073(G/C) andrs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively.rs111686073Gandrs59097151Ainduced significantly higherTAPBPmRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lowerPlasmodium falciparumparasite 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 imputedTAPBPmRNA 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.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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