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Molecular Mimicry

Molecular Mimicry. Objectives. Describe molecular mimicry How does mimicry induce autoimmune responses? Describe how HIV binds to a T-Cell Does HIV-1 mimic an agent to gain access? How does HCMV affect the cell’s growth machinery? How does EspFU activate WASP proteins?

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Molecular Mimicry

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  1. Molecular Mimicry

  2. Objectives • Describe molecular mimicry • How does mimicry induce autoimmune responses? • Describe how HIV binds to a T-Cell • Does HIV-1 mimic an agent to gain access? • How does HCMV affect the cell’s growth machinery? • How does EspFU activate WASP proteins? • How does PKR battle Poxviruses?

  3. Key Terms • Homology • Epitome • Endogenous • Domain • Conformation • Autoimmune response

  4. Microbe and Host Cell: Share of a linear amino acid sequence Share of conformation fit Host immune response against the microbe reacts if the host sequence comprises a biologically important domain Autoimmunity may occur Molecular Mimicry (Oldstone, 1998)

  5. How does it work? • Host develops an immune response to an agent that cross-reacts with a host antigen • Results in autoimmune disease • Structural mimicry, rather than sequence mimicry, is more common • Molecular mimicry plays significant role in: • Guillain-Barr Syndrome (GBS) • Myasthenia gravis (MG) • Epilepsy • Celiac disease • Antiphospholipid syndrome (APS)

  6. Auto-Immune Disease • When molecular mimicry induces autoimmune diseases • An adjuvant is required. • Prime challenge model • Virus mimicking a host CNS protein can prime animals for disease induced by a different virus infection later in life • Virus primes T cells, but not to the point where they can initiate autoimmune inflammatory CNS disease • Later events may trigger these cells to cause disease. • Viruses that have molecular mimicry with host proteins may be used as vaccines to prevent autoimmune disease later in life.

  7. Human Immunodeficiency Virus (HIV) (USDHHS, NIAID, 2006)

  8. HIV 8

  9. Human cytomegalovirus (HCMV) • Dupes hosts cell to grow and spread • Mimics a regulatory protein to hijack a healthy cell’s growth machinery • Disrupts primary anti-cancer mechanism • Virus protein UL97 • Mimics regulatory enzyme that controls tumor-suppressing protein • Lacks on/off trigger to control growth

  10. a: EspFU is secreted from E. Coli into a host cell where it stimulates actin polymerization through N-WASP and ARP2/3, leading to pedestal formation. b: N-WASP is inhibited, but can be activated by inputs such as CDC42. c: Multiple activators are necessary to potently activate N-WASP. d: EspFU potently activates N-WASP via in vitro pyrene-actin-polymerization assay. EspFU

  11. Battling mimics like the Poxviruses • Many pathogens use mimicry to subvert cellular processes: • Cell cycle • Apoptosis and • Cytoskeletal dynamics1 • Immunity • Although pathogens gain advantages by mimicking cellular components • PKR competes in a molecular ‘arms races’ with mimics • Evolutionary flexibility • Figure: single substitutions in either the aE or aG helices produces resistance (Elde et al., 2009) 11

  12. Summary Describe molecular mimicry How does mimicry induce autoimmune responses? Describe how HIV binds to a T-Cell Does HIV-1 mimic an agent to gain access? How does HCMV affect the cell’s growth machinery? How does EspFU activate WASP proteins? How does PKR battle Poxviruses? 12

  13. Questions?

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