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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? - PowerPoint PPT Presentation
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Molecular Mimicry
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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?
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Key Terms
• Homology
• Epitome
• Endogenous
• Domain
• Conformation
• Autoimmune response
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Molecular Mimicry
• 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(Oldstone, 1998)
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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)
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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.
Human Immunodeficiency Virus (HIV)
(USDHHS, NIAID, 2006)
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HIV
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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
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EspFU
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.
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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)
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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?
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Questions?