Adaptive immunity against viruses and viral evasion strategies Flashcards
What is adaptive immunity to viruses?
The humoral response - Abs prod by B lymphocytes
The cellular response mediated by T-lymphocytes
Describe the humoral response to viruses
Effective at clearing cell-free viruses
Both neutralising and non-neutralising Abs can be important
Describe the cellular response to viruses
Effective at clearing cell-associated viruses
What do antibodies do?
Neutralisation - prevents receptor binding
Opsonisation - promotes phagocytosis
Complement activation - activate complement which enhances opsonisation
What viral proteins can be present on infected cells?
Haemagglutinin
Neuraminidase
M2
How do antibodies clear and neutralise non-enveloped viruses?
At fewer than 2 IgG molecules per virus BUT virus particles have hundreds of identical subunits so 1 or 2 IgG molecules per virion would not prevent receptor recognition or opsonise the virion so Abs mediate intracellular immunity through TRIM21
What is TRIM21?
A cytosolic ubiquitin ligase and high affinity IgG receptor
Detects antibody-coated viruses or bacteria that have entered the cytosol
Describe what TRIM21 does
Responsible for antibody-dependent intracellular neutralisation (ADIN)
Detects Ab-bound substrates inside the cell and mediates rapid proteasomal degradation of those substrates
When targeting a virion, this blocks infection
Describe the mechanism by which TRIM21 works to block infection
Viruses that enter the cytosol and traffic surface-bound Abs into the cell recruit TRIM21 via high affinity interaction between Fc and TRIM21 PRYSPRY domain
This triggers a coordinated effector and signalling response that prevents viral replication
Auto-ubiquitination of TRIM21 targets the viral components to the proteasome, neutralising the infection
Describe the structure of TRIM21
Fc-binding PRYSPRY domain
Coiled coil dimerisation domain
B-box domain
N-terminal RING domain with E3 ubiquitin ligase activity
How does TRIM21 have clinical relevance?
In systemic lupus erythematosus
Autoantibodies against RING and B-box domain of TRIM21 generated
How do CD8+ T cells cause lysis of target cells?
They either release cytotoxic granules at the site of contact with the target cell (must be directed to prevent damage to innocent bystander cells)
Or engage Fas/FasL interaction
What causes lysis by cytolytic CD4+ cells during infection?
Upregulation of MHC-II
e.g. WNDV-infected MHC-II positive epithelial cells, EBV-infected B cells, HIV-infected CD4+ cells
How do CD4+ T cells kill viruses that replication in macrophages?
Interacting Th1 cells secrete IFN-g
Triggers intracellular membrane fusion and ROI/NO killing of pathogens
What is required for control of acute viral infections?
Th1 and Tfh subsets of CD4+ cells
Describe the development of CD4+ subsets
Pathogen interacts with APC and detected by PAMPs
Ags presented on surface
Naive CD4+ cell activated and IL-2 released
Causes expansion of CD4+ clone
Th1 subset differentiated by release of IL-12 from APC
What do Th1 cells do?
Promote CD8+ expansion and activation and B cell maturation
What cytokines are produced by viral infection of DCs and macrophages?
Type 1 interferon - IFN-a, IFN-b
IL-12
IL-15
Type 2 interferon - IFN-g
What cells produce type 1 ifn?
DCs
Macrophages
Epithelial fibroblasts
What cells release IL-12?
DCs
Macrophages
Also prod by CD4+ engagement of DCs
What cells produce IL-15?
Macrophages
What cells produce type 2 ifn?
Macrophages
What are the 2 components of antibody memory?
Long-lived plasma cells secrete Ig of high specificity in absence of continued antigen
Memory B cells divide very slowly to maintain specific population also in absence of Ag but can be rapidly expanded in presence of Ag
What happens to mature T cells if not stimulated?
Undergo apoptosis
How long do memory T cells live?
Months (not as long as memory B cells)
What do memory T cells express?
Survival factors such as Bcl2, Bcl-XL
What stimulates memory T cell division?
IL-7 and IL-15
What drives expansion of memory T cells?
Either DCs or macrophages
What has central memory?
Lymph nodes
Poor effectors but generate effector cells when challenged
What does virus latency reduce?
Antigen expression
e.g. EBV, CMV and chickenpox all establish latent infections and only express 5-10 antigens during these infections
What is the difference in antigenic variation in acute vs chronic infections?
Acute infectious viruses e.g. flu generate antigenic variants but these are not necessary for the course of infection and is not a survival strategy for an ongoing infection
However in chronic viral infections e.g. HCV and HIV, antigenic variation is a necessary part of the infection
What are active mechanisms of evading adaptive immunity?
Viral IgG Fc receptors
- Binding of IgG and inhibition of Fc-dependent immune activation
e.g. Varicella Zoster, CMV
What are active mechanisms of evading adaptive immunity?
Viral IgG Fc receptors
- Glycoproteins of viruses act as distractor receptors for IgG, preventing ADCC and phagocytosis of infected cells
e.g. Varicella Zoster, CMV
How do viruses block cytokine secretion?
Homologues of cellular cytokine receptors produced by virus (secreted versions of cellular cytokine receptors lacking transmembrane and cytoplasmic domains)
Act as decoy receptors and bind chemokines/cytokines with high affinity and block their activity
