infection Flashcards
Mendelian susceptibility to mycobacterial disease (MSMD)
defects in IFNgamma and IL12 pathway -> impaired production of / impaired response to IFNgamma
leads to increased susceptibility to mycobacteria
immunodeficiencies predisposing to mycobacterial infection (6)
congenital: MSMD, NEMO, ectodysplasia w hyper IgM (impaired NFkB signalling)
acquired: HIV, anti-TNF antibodies
maturational i.e. immune system immature as child
mechanism of genetic predisposition to invasive pneumococcal disease (IPD)
IRAK4-MyD88 mutation-> loss of TLR function (except TLR3) -> loss of TNF and IL-1beta signalling
TLRs crucial in protection against invasive infections by pyogenic bacteria
mechanism of genetic predisposition to herpes simplex encephalitis
Unc93b1 / TRIF mutation -> loss of normal TLR3 signalling -> loss of IFN
dsRNA (e.g. HSV1) -> TLR3 (important in protection against viral infection)
innate immunity: physical and chemical barriers
Physical barrier: skin, cilia of respiratory tract
Chemical barrier: lysozymes/defensins in mucosal secretions, pH of stomach/vagina (↑oestrogen in pregnancy → ↑lactobacillus → further ↓pH)
which cytokines are anti-inflammatory and which are pro (8)
pro-inflammatory: IL-12, IL-8, TNF-α, IFN-γ, IL-1
anti-inflammatory: IL-10, IL-4
IL-5 is mixed
cytotoxic T cells vs helper T cells
both CD3+
Cytotoxic T cells (CD8+)
1. destroy cells containing intracellular pathogens (virus)
2. recognise targets by binding to antigen-MHC class 1
T helper cells (CD4 +)
1. assist other leukocytes w immune response
2. activated when presented w antigen by MHC class 2
a. Th1 → activation of cytotoxic cells (regulated by IFN-γ)
b. Th2 → maturation of B cells into plasma cells
MHC class I vs II
MHC class I (HLA A, B and C)
- present on all nucleated cells (i.e. not RBCs)
- presents epitopes (of non-self) to cytotoxic T cells (CD8+) → apoptosis (if recognised) ∴ kills cell which contains intracellular pathogen
MHC class II (HLA DP, DM, DOA, DOB, DQ, DR)
- expressed on APCs (B cells, macrophages, dendritic cells)
- take up antigen, process and present part of antigen as epitope on APC’s surface within MHC class II molecule
- bind to naïve T helper cells Th0 (CD4 cells) → activation depending on local environment and cytokines produced by APC ∴ can aid cell death (Th1, Th17), antibody production (Th2), or immune tolerance (T-reg)
active vs passive immunity
Passive immunity: immunoglobulins directly given
Active immunity: small part of antigen given → activates immune response
central vs peripheral tolerance
Central tolerance: destruction of self-reactive T or B cells before they enter circulation
Peripheral tolerance: destruction/control of any self-reactive T or B cells which do enter circulation
signals required for adaptive immune response activation (3)
- Antigen recognition
- Co-stimulation
- Cytokine release
risk factors for non-tuberculous mycobacterial infection (4)
rarely causes disease in immunocompetent hosts
- Immunodeficiency; primary/acquired e.g. immunodeficiency (HIV)
- Central venous catheters
- Solid and hematopoietic stem cell transplant → disseminated disease (due to strong immunosuppression)
- Cystic fibrosis and Mendelian susceptibility to mycobacterial disease (MSMD)
timeline of TB infection
- Innate response: macrophages, neutrophils engulf bacteria
- Acquired response: bacteria become contained within granulomas
- Latent infection: bacteria reside within granulomas in non-replicating state
Can survive in this way for entire lifetime; may be completely asymptomatic
1/3 population are latently infected - Reactivation of disease can occur
Immunocompromised pts: acquired response insufficient → primary active TB disease (fever, night sweats, weight loss)
immune response to TB
- Macrophages:
a. Activated by Mtb binding to PRRs
b. Phagocytosis of bacteria and fusion with lysomes
c. Growth inhibition and killing by NO - Formation of granulomas; multi-nucleated giant cells
T cells surround and hold structure together, enclosing mycobacterium
TB evasion of host immune defences (4)
- Genotypic/phenotypic diversity between strains
- Resistance to microbiocidal mechanisms in phagocytic cells e.g. NO
- Subversion of intracellular pathway: inhibition of phagosome maturation, phagosome-lysosome fusion and/or acidification
- Subvert induction of pro-inflammatory cytokines
diagnostic tests for TB (6)
- tuberculin skin test (Mantoux)
- culture for acid-fast bacilli
- IGRAs (interferon-gamma release assays)
- Microscopic observation drug susceptibility testing (MODS)
- GeneXpert
- Lipoarabinomannan (LAM)
tuberculin skin test
how it works
advs + disadvs (2)
Intradermal injection of tuberculin (containing >200 Mtb Ags) into forearm
If prev exposure to Mtb, inflammation (redness, swelling) will occur due to primed T cells in immune system
1. Poor specificity; does not distinguish between active TB disease, latent TB infection, BCG and environmental mycobacteria
2. Poor sensitivity; can be falsely negative in early infection, immunocompromised
culture for acid-fast bacilli
how it works
advs + disadvs (2)
Using sputum, gastric washings or bronchioalveolar lavage (difficult to obtain in children)
Mycobacteria have mycolic acid in cell wall ∴ take up carbol-fuschin stain (pink) and resist decolourisation w acidified alcohol
1. Culture takes 4-6 weeks
2. Children are often paucibacillary (numbers of bacteria too low)
interferon-gamma release assays
how it works
advs + disadvs (4)
Measures host immune response to mycobacterial antigens
- More specific than tuberculin, but does not distinguish between infection and disease
- Technically challenging
- Expensive
- Venepuncture required; difficult for children
Microscopic observation drug susceptibility testing (MODS)
how it works
advs + disadvs (4)
Sputum: decontaminated → culture in broth (8-15 days) → inverted light microscope
- Sensitive
- High specificity
- Low cost
- Can determine antibiotic susceptibility at the same time
lipoarabinomannan testing for TB
how it works
advs + disadvs (2)
Based on identification of LAM in cell wall of mycobacterium tuberculosis
Secreted in urine; test uses lateral flow dipstick
1. 30 minutes
2. Poor sensitivity in children
differences to consider when treating children for TB (vs adults) (5)
- Most drug studies done in adults ∴ little evidence for what is effective for children
- Dose adjustment needed frequently due to growth
- Compliance issues
- Often treat w/o culture confirmed diagnosis
- Metabolism and excretion differs from adults due to large liver to body ratio
life cycle of HIV (7)
- Virion attaches to CD4 receptor and CCR5/CXCR4 co-receptor
- Virion fuses w human cell membrane releasing viral content
- Reverse transcription of viral RNA into dsRNA
- Viral DNA integrated into human genome
- Human machinery hijacked for replication
- Assembly and repackaging: capsid of virion cleaved by protease
- Viral release
HIV timeline of infection
which cells does it infect + consequences of this
- HIV targets and causes depletion of CD4 T cells →
a. ↓CD4 priming of B cells for Ab production
b. ↓recruitment of CD8+ CTL which destroy infected cells
c. Eventual decline in CD4 T cells → ↑viral → AIDS - HIV also infects macrophages (which are also targeted by TB)