2. Host genetics and infectious diseases Flashcards
Does everyone who is infected with an ID have a classical disease picture?
Only a few have the classical disease picture
A larger minority have less severe disease
While the majority have asymptomatic infection (individual infects others, seroconverts and resists reinfection)
What are the evolutionary considerations of infectious diseases?
Infectious diseases are a major selective force in human evolution
Host defence genes are more diverse than any other genes
Human immune response is more polymorphic than any other species’
Clinical considerations of IDs and host genetics
Many are exposed to infection but few develop disease
ID clustering is often familial, with inter-population differences in prevalence
5.8x increased risk for adoptees with a biological parent who died from ID
Concordant pair ID also more common in twins, especially monozygotic
IDs as traits
Complex traits with genetic and environmental factors
Also the disease depends on the exposure and the pathogen’s genome too
Why identify genes which predispose to/protect from disease?
to understand pathogenesis
To identify pathways important in immunity e.g. new treatments and new vaccines
How are human ID susceptibility genes identified?
Animal models
Mendelian disease in humans
Analysis of IDs as complex traits - family based linkage studies vs population based association studies using high throughput genotyping and human genome project
Quantitative trait analysis
Distribution of endemic falcipurum malaria
Central Africa, India, East Asia, parts of Oceania, parts of the mediteranean
Distribution of B-globin sickle cell polymorphism
Central Africa, India, parts of the mediteranean
Coincides with falcipurum malaria
What receptor needs to be present for plasmodium vivax (malaria agent) to invade?
DARC receptor.
P vivax can only invade erythrocytes which express DARC
Duffy positive blood groups express DARC which allows P vivax to invade. Duffy negative do not get infected by malaria
How is DARC activated?
In Duffy-positive individuals, the transcription factor GATA-1 activates the DARC gene, which allows p. vivax to invade the cell. In Duffy negative individuals the GATA-1 binding site is mutated so DARC does not get expressed.
In which cells is GATA-1 necessary for DARC gene activation?
GATA-1 binding is essential for DARC gene activation in erythrocytes, but not in leukocytes. This means that leukocytes don’t need GATA1 for the DARC receptor so it is expressed in both the duffy positive and negative groups. Erythrocytes only express DARC in Duffy positive individuals
What is duffy positve and negative?
Duffy positive individuals have a normal GATA1 binding site, so GATA1 binds and expresses DARC on erythrocytes whic allows p. vivax to invade the cell.
Duffy negative individuals have a mutated GATA1 binding site so do not express DARC on their erythrocyte cell surfaces, so cannot be invaded by p vivax.
Both express DARC on their leukocytes.
Genes associated with malaria
HLA-B - a-globin HLA-DRB1 - B-globin TNF - G6PDH iNOS - spectrin ABO blood group - erythrocyte band 3 ICAM-1 - glycophorin A complement receptor - glycophorin B CD40L - Duffy chemokine receptor IFNgR1 - CD36
Where do people not express DARC on RBCs (Duffy negative)
West Africa. Due to evolution.
HIV infection
Some people stay uninfected by HIV despite repeated exposure
Others become HIV+ but don’t develop the disease
Human CD4 transgenic mice couldn’t be infected with HIV despite carrying CD$, a known receptor for HIV
What genetic mutations do HIV resistant individuals have?
they have homozygous 32bp deletions in the CCR5 gene
which result in a frameshift mutation and premature stop codon
resulting in the CCR5 protein is not expressed at cell surface
CCR5 is a coreceptor for HIV
Receptors for HIV
CD4 and CCR5
gp120 and gp41 are HIV proteins which bind these receptors
What antiretroviral is used to block the CCR5 receptor
maraviroc
TB a global problem
more common in subsaharan Africa and Russia
Correlation between endemic TB and HIV because HIV wipes out CD4 which deals with intracellular pathogens like TB
TB is a complex trait
Pathogen
Plus host immune response
Plus
environment
Outcome of mycobacterial infection
Exposure to infection leads to primary infection
90% of primary infection develop good immune response, become tuberculin positive, and are well
10% develop poor immune response, become tuberculin negative, and have disease
The importance of an intact immune response
Extremes of age coinfection with HIV post-measles Diabetes Renal disease Steroid therapy Anti-TNF treatment (TNF needed to fight TB)
Why identify TB susceptibility genes?
Prolonged treatment with several drugs and poor compliance leads to MDRTB
The BCG does not protect in endemic regions
Which gene mutations cause Mendelian TB disease in humans?
Mutations in five genes within the IL-12/IFNG axis
