Viruses in the multicellular host Flashcards
a) Additional challenges of infecting a multicellular host (3)
b) How to achieve this infection
c) General concepts of viral entry
a) i) barriers to infection ii) innate immunity iii) adaptive immunity
b) i) enter by breaching these defences ii) replicate despite the immune system iii) be released to enable transmission to new hosts
c) i) viruses enter and leave by specific routes called portals of entry and exit ii) closely related to transmission mechanisms iii) some infections remain superficial (local), where the entry and exit sitrs are the same iv) some infections spread and become systemic, where the entry and exit may differ, but not always
Viruses entering by infection of
a) Oropharynx (3)
b) Respiratory tract (9)
c) Alimentary canal (4)
a) i) herpes simplex virus type 1 ii) human cytomegalovirus iii) Epstein-Barr virus
b) i) rhinovirus ii) influenza virus iii) adenovirus (respiratory types) iv) SARS-CoV-2 v) measles virus vi) mumps virus vii) rubella virus viii) varicella-zoster virus ix) variola virus
c) i) rotavirus ii) adenovirus (enteric types) iii) poliovirus iv) hepatitis A virus
Viruses entering by infection of
a) Conjunctiva (2)
b) Skin (4)
c) Genital tract (5)
d) Blood - iatrogenic (3)
e) Blood - bites (4)
a) i) herpes simplex virus ii) vaccinia virus
b) i) human papilloma virus (6 & 11) ii) herpes simplex virus iii) monkeypox virus iv) rabies virus
c) i) herpes simplex virus type 2 ii) human immunodeficiency virus iii) human papilloma virus (16 & 18) iv) monkeypox virus
d) i) hepatitis B virus ii) hepatitis C virus iii) human immunodeficiency virus
e) i) bluetongue virus ii) yellow fever virus iii) dengue virus iv) Zika virus
a) Overview of host defences
b) Innate immunity defence - against phagocytes and complement
a) i) physical, non-specific defences (skin, mucous membranes, cilia, acid pH, proteases) ii) innate immunity (phagocytes, complement, interferon, apoptosis, cytokines, chemokines, NK cells, fever) iii) adaptive immunity (antibody, CD8+ T cells)
b) Phagocytes (macrophages/neutrophils) - phagocytose virus-infected cells, cell debris or large virons, larger viruses are phagocytosed better than small ones. Some viruses can replicate in macrophages (HIV)
Complement - destruction of virus particles by membrane disruption (membrane attack complex) or aiding phagocytosis. Some viruses evade complement by expression of complement binding proteins (herpes viruses, poxviruses) or by putting host complement control proteins CD46, CD55, CD59 into the viral envelope (HIV, poxviruses)
a) How the host senses viral infection
b) Interferon types and their actions
a) PRRs detect PAMPs: i) TLRs in the endosome - TLR3 detects dsRNA; TLR9 detects CpG DNA ii) Intracellular RIG-I and MDA5 detect dsRNA or RNA with 5’-triphosphate iii) Intracellular cGAS, DNA-PK and IFI16 detect dsDNA in the cytoplasm . The PRRs activate IRF3 and NF-κB, causing expression of IFNβ, cytokines and chemokines
b) IFN - soluble factor produced by infected cells that stimulate uninfected cells to be resistant to subsequent virus infection
Type I IFNs: IFNα and IFNβ - released by infected cells and bind to type I IFN receptors on cells and induce an antiviral state. Also up-regulates MHC class I and many pro-inflammatory proteins
Type II IFNs: IFNγ- released by activated T cells and macrophages. Binds to type II IFN receptor. Promotes inflammation and Th1 (cellular) immunity
Type III IFNs: IFNλ - bind to type III IFN receptor. Important in epithelial cells
a) Induction and action of type I IFN
b) What are the two ISGs
a) (see image) Viral PAMPs bind to PRRs (TLR or others), and causes release of IRF3 and NF-κB. Causes transcription of IFNβ gene, and production of IFNβ. IFNβ then travels to uninfected cells, and binds to IFNR. Causes a JAK-1/STAT-1/2 signalling pathway, leading to ISGF-3 binding to ISRE in genome. Causes the transcription of ISG gene, which leads to production of antiviral proteins (PKR, OAS)
b) PKR - protein kinase R. OAS - 2’5’ - oligoadenylate synthetase. Both are upreculated by IFN (ISGs). Both are inactive until bound by dsRNA (dsRNA is produced by both RNA and DNA viral infections) - hence are antiviral. They cause the inhibition of viral protein synthesis
a) IFNs as antiviral agents
b) How vaccinia virus interferes with IFN
c) What this indicates
a) i) IFNs inhibit replication of virus in cell culture ii) IFNs prevent disease caused by viruses in vivo iii) Viruses expressing IFNs are avirulent iv) Loss of IFN signalling components (in transgenics) increases sensitivity to virus infection v) Viruses have evolved many mechanisms to interfere with IFNs (most viruses contain at least one IFN inhibitor, at almost every stage of the IFN action pathway)
b) Vaccinia virus produces the protein B18. This binds to type I IFNs in solution and on the cell surface, therefore, the IFN cannot signal surrounding uninfected cells to induce an antiviral state
c) This indicates the co-evolution of virus and host. Our genome and the evolution of interferons has been shaped by the threat of viruses. Equally, virus genomes have been shaped by the threat of interferons, although viruses evolve much faster than we do
a) Apoptosis and how viruses prevent this
b) Chemokines and how viruses interfere with these
a) Sensing viral infection can lead to apoptosis, a form of local suicide that can restrict virus-induced disease because the virus replication cycle is incomplete.
Viruses have many strategies to prevent apoptosis: i) block activation pathways ii) inhibit activation or activity of caspases iii) encode Bcl-2 like proteins (herpes and poxviruses) that bind and inhibit pro-apoptotic proteins
b) Chemokines (CKs) are chemoattractant cytokines that recruit leukocytes to the site of infection/inflammation. i) create a concentration gradient on the vascular endothelium ii) bind to chemokine receptors on the leukocyte surface iii) induce leukocyte activation and adherence to vasculae endothelium
Viruses (herpes and poxviruses) interfere with CKs: i) express CK receptors to ‘soak up’ CKs ii) express virus CKs to recruit cells beneficial to the virus iii) express secreted CK-binding proteins that block CK binding to receptors, or binding to endothelial cell wall (see image)
a) Cytokines and how viruses interfere
b) NK cells
a) Can promote a Th1 response (cellular immunity): Pro-inflammatory (IL-1, IL-2, IL-12, IL-18, TNFα, IFNγ) stimulate CD8+ T cells to lyse virus-infected cells. Viruses often target these cytokines (eg by secreting cytokine-binding proteins to diminish the Th1 response - poxviruses secrete binding proteins against all mentioned above)
Can promote a Th2 response (humoral): IL-4, IL-10, TGFβ. Some viruses promote a Th2 response (eg EBV expresses a virus encoded IL-10, vIL-1) which promotes the growth of B cells that are infected by EBV
b) NK cells kill virus-infected or tumour cells, mostly antigen independent. The missing-self model: loss of MHC class I causes NK cells to recognise the cell as unusual, and kills it. If viruses down-regulate MHC class I the cell may become sensitive to NK cell lysis. NK cells are important early after infection, but can also provide immunological memory.
a) How adaptive immunity defends against viruses
b) How viruses escape adaptive immunity
a) Dependent on innate immunity. Develops later, CD8+ cytotoxic T cells shortly before antibodies. Antibodies neutralise free viral particles, either alone or with complement. CD8+ T cells lyse virus-infected cells (and are particularly important for systemic virus infections)
b) i) block presentation of peptides on MHC class I - inhibit peptide transport into the ER (HCMV, HSV); capture MHCI and return it to the cytosol for destruction (HCMV); tether MHCI in the ER (HCMV, adenovirus) ii) Hide from the immune system with latency (herpes and retroviruses) iii) Mask the Fc region of antibodies by expressing an Fc receptor on infected cells and virions (HSV-1) iv) Undergo antigenic variation (HIV, influenza virus, hepatitis C virus)
Outcomes of infection: cell death - examples of viruses (what cell types they infect, and what disease they cause)
a) Poliovirus
b) Rotavirus
c) HIV
d) HBV
e) Rabies virus
a) Motor neurons (anterior horn cells, CNS) - paralysis
b) Gut epithelial cells - diarrhoea
c) CD4+ helper T cells - immunodeficiency
d) Hepatocytes - acute hepatitis
e) Purkinje cells in the cerebellum - hydrophobia
Outcomes of viral infection: diseases caused by latent or persistent viral infections (cell type infected, disease caused)
a) HBV
b) Measles virus
c) HSV-1, HSV-2
d) Varicella zoster virus
a) Hepatocytes - chronic hepatitis
b) Neurons - subacute schlerosing panencephalitis (SSPE)
c) Epithelial cells, neurons - cold sores, genital herpes
d) Epithelial cells, neurons - chickenpox, shingles
Examples of virus-induced cancers (cell type infected, disease caused)
a) Hepatitis B virus
b) Human papilloma virus types 6 & 11
c) Human papilloma virus types 16 & 18
d) Epstein-Barr virus
e) Rous sarcoma virus
a) Hepatocytes - hepatocellular carcinoma
b) Epithelial cells - common warts
c) Epithelial cells - Cervical and penile carcinoma
d) B cells - Burkitt’s lymphoma, nasopharyngeal carcinoma
e) Connective tissue - chicken sarcomas
Factors influencing the outcome of infection (5)
1) Viral dose
2) Route of infection (variolation - giving a virus by an unusual route)
3) Sex of host
4) Age of host: i) chickenpox - more severe as an adult than a child ii) Epstein-Barr virus - asymptomatic as child, glandular fever as young aduly iii) COVID-19 - more severe with increasing age iv) HBV - infection in neonates more likely to cause chronic infection
5) Physiological state. Immunodeficiency - failure to control latent or persistent infections (transplant recipients, HIV infection). Stress - associated with more sever infections or re-activation of latent infection (herpes virus)
