Abstract

We isolated a peripheral membrane protein interactive with lymphocytic choriomeningitis virus (LCMV) from cells permissive to LCMV infection. Examination of tryptic peptides revealed its identity as alpha-dystroglycan (alpha-DG). Four strains of LCMV, ARM 53b, Traub, E-350, WE54 and ARM C1 13 and other arenaviruses, Lassa fever virus (LFV), Oliveros, Mobala and Mopeia bound to purified alpha-DG protein. Several lines of evidence indicated that alpha-DG is required for virus infection: 1) soluble alpha- DG blocked either LCMV or LFV infection; 2) cells bearing a null mutation of the DG gene were resistant to LCMV infection; 3) reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Some viruses bound at high affinity to alpha-DG (C1 13, Traub, WE54, LFV) while others (ARM 53b, E-350) bound at lower affinity (100- to 1000-fold less). The high affinity alpha-DG binders, when injected into mice, preferentially infected cells in the splenic white pulp (preliminary identified as interdigitating dendritic cells (IDDC), the major antigen presenting cell), caused immunosuppression and a persistent infection. In contrast, low alpha-DG binders preferentially bound to cells in the red pulp (primarily F4/80+ cells), there was no suppression of immune response, CD8+ T cells were generated and infection terminated. We propose three specific aims. First, to determine whether alpha-DG is a common cellular receptor for all arenaviruses. Study of BSL-4 and BSL-3 arenaviruses will be done in the BSL-4 facilities at CDC and BSL-2 arenaviruses at TSRI. Second, we will make a series of alpha-DG deletion mutants and reconstitute these into DG null cells to map out the portion on alpha-DG that arenaviruses bind to to determine different or similar sites on alpha-DG that these viruses recognize. Third, we will test the hypothesis that binding to IDDC is dependent on specific aa(s) in the viral GPI (aa 260 aliphatic: high affinity binder; aromatic: low affinity). We will also analyze alpha-DG content on IDDC and F4/80+ cells and look for coreceptor(s).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045927-02
Application #
6362424
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Meegan, James M
Project Start
2000-03-15
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$310,275
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Lee, Andrew M; Paulsson, Johan F; Cruite, Justin et al. (2011) Extraneural manifestations of prion infection in GPI-anchorless transgenic mice. Virology 411:1-8
Ward, Simone V; George, Cyril X; Welch, Megan J et al. (2011) RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci U S A 108:331-6
Hara, Yuji; Balci-Hayta, Burcu; Yoshida-Moriguchi, Takako et al. (2011) A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med 364:939-46
Saphire, Erica Ollmann; Oldstone, Michael B A (2011) Measles virus fusion shifts into gear. Nat Struct Mol Biol 18:115-6
Sullivan, Brian M; Emonet, Sébastien F; Welch, Megan J et al. (2011) Point mutation in the glycoprotein of lymphocytic choriomeningitis virus is necessary for receptor binding, dendritic cell infection, and long-term persistence. Proc Natl Acad Sci U S A 108:2969-74
Ng, Cherie T; Sullivan, Brian M; Oldstone, Michael B A (2011) The role of dendritic cells in viral persistence. Curr Opin Virol 1:160-6
Oldstone, Michael B A; Campbell, Kevin P (2011) Decoding arenavirus pathogenesis: essential roles for alpha-dystroglycan-virus interactions and the immune response. Virology 411:170-9
Yoshida-Moriguchi, Takako; Yu, Liping; Stalnaker, Stephanie H et al. (2010) O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding. Science 327:88-92
Brooks, David G; Walsh, Kevin B; Elsaesser, Heidi et al. (2010) IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection. Proc Natl Acad Sci U S A 107:3018-23
Liou, Li-Ying; Walsh, Kevin B; Vartanian, Arineh R et al. (2010) Functional glycosylation of dystroglycan is crucial for thymocyte development in the mouse. PLoS One 5:e9915

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