LCMV Flashcards
What is LCMV?
Lymphocytic choriomeningitis virus. An arenavirus with a bisegmented single strand negative sense RNA genome, contains host cell ribosomes.
Natural host is mice (can infect humans, occasionally causes fatal meningitis, most infections are asymptomatic)
How is the outcome of infection of LCMV determined?
2 way interaction with virus and immune system determines acute or persistent infection.
What is the importance of the T cell response in LCMV infection?
Assay to test CD8 T cell number (using MHC tetramer and FACS) - find high level of virus specific CTLs. Knocking out CD8 results in an inability to clear infection (whilst knocking out CD4 is ok) - shows that CTLs are important and sufficient.
Knockouts of Fas/FasL and IFNgamma can still clear infection - these aren’t important. However, knocking out perforin prevents clearing..
What conditions lead to a persistent infection of LCMV?
Weak T cell response - often occurs if virus is passed on in utero/within 48hrs of birth (T cells are tolerated to virus). Can occur in adult if rapid virus replication to high virus titres - get T cell exhaustion
Describe tolerance to LCMV
If infection occurs before birth or 48hrs after, T cells are tolerated to the virus. If a transgenic mouse with an LCMV specific TCR is used, the T cells are eradicated. Allows establishment of a persistent infection.
Describe T cell exhaustion in the context of an LCMV infection
If mouse is infected with a high viral titre/virus replicates very quickly, the T cell response expands rapidly but the virus isn’t eradicated. T cells then become exhausted - they become dysfunctional (can’t lyse virus infected cells, don’t make IL-2 to encourage proliferation, don’t proliferate, then lose TNFa then IFNy) and die.
A good model for T cell exhaustions in humans
What are the mechanisms involved in T cell exhaustion?
Active suppression including IL-10 production of APCs, T cell up regulation of inhibitory receptors e.g. PD-1
Defects in signalling and metabolism including changes in the TCR and cytokine signalling pathways and metabolites e.g. Blimp1 and T-Bet
Why does T cell exhaustion occur?
Important to prevent immunopathological damage. In LCMV infection with a medium virus titre, T cells aren’t exhausted and the liver and lung damage caused can be fatal.
What is the importance of type 1 interferons in control of LCMV?
Very important - in KO mice, get a persistent infection even with a low dose challenge. Viruses replicate rapidly and T cells are then exhausted. Type 1 interferons are important for activation of dendritic cells and T cells in the induction of the adaptive response. They also inhibit regulatory T cells for good T cell expansion
What is the importance of CD4 T cells and B cells in the control of LCMV?
CD4 KO mice can clear a low dose of virus, but T cells become exhausted with and intermediate virus dose that would normally be ok. They are important for promoting and maintaining CD8 T cell response (e.g. production of IL-2 and IL-21)
B cells are needed for formation of memory CD4 T cell responses
What is the importance of NK cells in the control of LCMV?
NK cells modulate the response by killing CD4 T cells to reduce the CD8 T cell response (so less IL-2 made for T cell proliferation)
NK cells are modulated by Qa-1b (induced by type 1 interferon) to inhibit NK mediated down regulation.
What is the difference between LCMV Armstrong and clone 13?
Clone 13 is isolated from lymphoid tissues of adult mice infected at birth. Clone 13 replicates rapidly and causes T cell exhaustion in immunocompetent adults. The sequences differs by 3 amino acids, suggested to allow tighter binding as there are changes in the viral glycoprotein (virus replicates readily in dendritic cells) and change the polymerase to reduce control of virus replication by interferons
How can LCMV evade the T cell response?
In transgenic mice expressing a TCR for a specific epitope for LCMV with high levels of virus specific T cells, the virus still persists. Selection for viral variants with mutations in the epitope, allowing viral escape.
What are the consequences of LCMV persistent infection in mice?
Immunopathological disease mediated by the LCMV specific immune response - immune complex disease (antibodies trapped in kidney, complement activated)
Immunopathological disease mediated by autoimmune response to self antigens
Virus induced disease - specific functions of infected cells are impaired e.g. some strains cause growth hormone deficiency syndrome in which virus nucleoprotein complexes with growth hormone transactivation factor GHF1 in the cytoplasm - not enough in the nucleus
How can persistent LCMV infection be controlled?
Requires CD8 and CD4 T cells and IFNgamma - unlike immune infection (found through KO experiments) as the v virus is systemic in the body - need CD4 T cells and B cells to sustain the T cell response. Need antiviral cytokines to ‘cure’ cells (as can’t just lyse them all)
