Molecular Mimicry

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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?