Lecture 15 - Pathogen Immune Evasion

• How viruses subvert multiple stages of MHC class I antigen presentation

  1. Block degradation of viral proteins by proteasome

  2. Inhibit proteasome, which is essential for protein homeostasis and cell cycle

  3. Epstein Barr Virus (EBV) produces the EBNA1 protein, which inhibits proteasome and causes glandular fever

  4. Viral proteins promote proteasome degradation of anti-viral proteins, such as STAT1 and STAT2, which inhibits type 1 interferon-driven responses

  5. Rh178 protein from Rhesus cytomegalovirus (RhCMV) binds nascent MHC I signal peptide and stops MHC I translation

  6. Viral proteins prevent peptide translocation by binding to TAP transporter

  7. HCMV US3 binds and inhibits tapasin, preventing stable peptide binding in ER and reducing cell surface MHC class I

  8. Adenovirus E3/19K protein binds HLA-A & HLA-B and ensures ER retention, reducing cell surface MHC I

  9. Viral proteins recruit ubiquitin ligases to promote MHC class I ubiquitination and proteasome degradation

  10. Viral proteins promote endocytosis and degradation of surface MHC class I
• How viruses prevent NK-mediated killing

  1. Viruses interfere with MHC-I antigen presentation at multiple points, including blocking degradation of viral proteins by proteasome and inhibiting TAP and PLC

  2. Viral proteins prevent NK-mediated killing by inhibiting the proteasome, which is essential for protein homeostasis and cell cycle, leading to apoptosis in infected cells

  3. Viral MHC, such as HCMV UL18, acts as a viral homolog of MHC class I that binds to NK inhibitory receptors to prevent NK killing

  4. Viral UL40 contains a peptide that binds to HLA-E, ensuring HLA-E surface expression even when classical MHC-I is reduced by other viral proteins, thus ensuring a negative NK signal even if host MHC-I is reduced

  5. DNA viruses can encode cytokine/cytokine receptor mimics and cytokine receptor mimics, which inhibit pro-inflammatory cytokines and type 1 immunity, contributing to the prevention of NK-mediated killing
• Viral homologs of other immune genes

  • Cytokine mimics
  • Cytokine receptor mimics
• Cytokine mimics


  Some viruses, such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), produce viral cytokines that mimic host cytokines, such as vIL-10 and vIL-6, respectively. These mimicry molecules can promote the production of pro-inflammatory cytokines and inhibit type 1 immunity, ultimately benefiting the virus by creating an environment conducive to its survival and replication.
• Cytokine receptor mimics


  DNA viruses also secrete soluble homologs of host cytokine receptors, which can bind to host cytokines and prevent their binding to host receptors, effectively neutralizing cytokine signaling pathways. Examples of viral cytokine receptors include vTNF-R, vIL-1-R, and vInterferon gamma-R. By inhibiting pro-inflammatory cytokines and type 1 immunity, these viral mimics contribute to the evasion of host immune responses and the establishment of viral infection.
• Why parasitic worms are "masters of regulation"

  • Chronic infections: Helminth infections can last for years or even decades, allowing the parasites to establish prolonged interactions with the host immune system
  • Limited evidence of antigenic variation: Unlike other pathogens such as T. brucei VSG or Plasmodium var genes, helminths show limited antigenic variation, which may contribute to their ability to evade host immune responses
  • Direct contact with the immune system: Helminths live in direct contact with the immune system, residing in the blood, lymphatics, and tissues, allowing them to modulate immune responses and ensure their prolonged survival
  • Immune modulation: Helminths are capable of turning off protective type 2 immune responses, which are essential for killing parasitic worms. They achieve this through the secretion of immune modulatory molecules that affect the function of dendritic cells, macrophages, T cells, and B cells
  • Secreted molecules: Helminths secrete a variety of immune modulatory molecules, including TGF beta, schistosome lipids (lysophosphatidylserine), schistosome glycans (Lewis-X), and schistosome proteins (IPSE), which contribute to immune suppression and impaired anti-parasite immunity
  • Impaired responses to other immune challenges: In addition to affecting anti-parasite immunity, helminth immune modulation can also impair responses to other immune challenges, such as co-infections, vaccines, autoantigens, and allergens, supporting the hygiene hypothesis