immunology 6: dual case study Flashcards
Mycobacterium overview
- Bacterium
- Slow replication
- Aerosol transmission
- Intracellular
- It can be latent or active
- Over 10 million new cases each year
HIV overview
- Virus
- Rapid replication
- Sexual transmission
- Obligate pathogen of humans
- Intracellular
- Can develope into aids (opportunist infections -> developement of TB is leading cause of HIV death)
- Over 500,000 deaths a year
TB immune response
1) breathed into the lungs
2) Macrophages engulf pathogens and release cytokines + complement cascade initiated -> innate immune response
3) Denritic cells present antigen to naive T cells -> adaptive immune response
Importance of CD4+ cells
- Mice with depleted CD4 cells died sooner than those with depleted CD8 cells
Importance of IFN-y
- Knocking out IFN-Y in mice leads to much higher levels of bacteria and more severe disease.
TB immune evasion
- Infection of APCs (macrophages)
- TB creates a blockade of phagosome-lysosome fusion-> Avoids exposure to lysosomal hydrolases, low pH, other components of lysosomes with bactericidal properties
- Evasion of innate signalling eg. by TLRs (eg. producing agonists for antagonists of TLR-9)
- Secretion of immunological ‘decoys’ -> smoke screen
- Manipulation of MHC class II antigen presentation
HIV immune evasion
1) HIV infects CD4 cells leading to cytolysis, programmed cell death, killing by CD8 cells and attack NK cells depleting supply
2) Viral protein production killing neighboring cells
3) HIV leads to excessive NET production from neutrophils, trapping immune cells
4) HIV can induce accumulation of Tregs which lead to immuno supression
5) Modifies pamps -> hides nucleic acid in viral capsid
6) minimises IFNy production
7) dysregulates NK cells
8) Downregulates MHCI
9) generates escape mutations
HIV immune response
Importance of CD8 cells
- CD4+ levels are depleted leading to a strong CD8+ T cell response -> recognise and kill infected CD4+ cells (early viral control)
Importance of antibodies
- elite controllers can control HIV with broadly neutralizing antibodies
HIV effect on Tb
Effect:
HIV depletes M.tb specific CD4+ genes
But also other important factors as study showed that HIV patients with artificially increased CD4 still had greater risk of M.tb
- impairs early innate macrophage responses to M.tb -> HIV can enter macrophages
- HIV immune evasion depletes IFNy production which a key factor for supressing tb.
- Impairs macrophage apoptosis
results:
*Increased susceptibility to initial infection with M.tb
- Rapid progression to active disease following de novo infection
-> HIV depletes M.tb specific CD4+ genes
-> But also other important factors as study showed that HIV patients with artificially increased CD4 still had greater risk of M.tb - Increased risk of reactivation of Latent tb to active TB disease
- Increased risk of TB recurrence/reinfection after successful treatment
- Increased risk of death from TB
Evidence:
- Higher Tb incidences in countries with higher HIV prevalence
- TB cases decreased gradually from 1980 in NYC, but then HIV epidemic began in 1984 and there was an uplift in Tb vases.
Effects of Tb on HIV
Tb increases HIV replication
- enhance viral entry into cells
- activate HIV transcription (stimualte reverse transcriptase activity)
Uncertain whether this is due to general inflmmation or specific to tb
results
- increased viral load
- faster progression
- Increases risk of opportunist infection
Evidence:
- Monocytes from TB patients are more susceptible to HIV
- Study found those infected with TB has higher viral load (observed patients over multiple years)
Overview
- TB and HIV are very different pathogens but epidemics overlap (both common in Africa-> Many socioeconomic determinants of TB are also drivers of risk behaviours for HIV transmission)
- Key immune response in TB is IFN-γ production by CD4+ T cells
- Key immune response in HIV is CD8+ T cells and antibodies
- Act synergistically to worsen outcomes of one another