2. Host genetics and infectious diseases

Question 1

Does everyone who is infected with an ID have a classical disease picture?

Answer 1

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)

Question 2

What are the evolutionary considerations of infectious diseases?

Answer 2

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’

Question 3

Clinical considerations of IDs and host genetics

Answer 3

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

Question 4

IDs as traits

Answer 4

Complex traits with genetic and environmental factors

Also the disease depends on the exposure and the pathogen’s genome too

Question 5

Why identify genes which predispose to/protect from disease?

Answer 5

to understand pathogenesis

To identify pathways important in immunity e.g. new treatments and new vaccines

Question 6

How are human ID susceptibility genes identified?

Answer 6

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

Question 7

Distribution of endemic falcipurum malaria

Answer 7

Central Africa, India, East Asia, parts of Oceania, parts of the mediteranean

Question 8

Distribution of B-globin sickle cell polymorphism

Answer 8

Central Africa, India, parts of the mediteranean

Coincides with falcipurum malaria

Question 9

What receptor needs to be present for plasmodium vivax (malaria agent) to invade?

Answer 9

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

Question 10

How is DARC activated?

Answer 10

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.

Question 11

In which cells is GATA-1 necessary for DARC gene activation?

Answer 11

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

Question 12

What is duffy positve and negative?

Answer 12

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.

Question 13

Genes associated with malaria

Answer 13

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

Question 14

Where do people not express DARC on RBCs (Duffy negative)

Answer 14

West Africa. Due to evolution.

Question 15

HIV infection

Answer 15

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

Question 16

What genetic mutations do HIV resistant individuals have?

Answer 16

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

Question 17

Receptors for HIV

Answer 17

CD4 and CCR5

gp120 and gp41 are HIV proteins which bind these receptors

Question 18

What antiretroviral is used to block the CCR5 receptor

Answer 18

maraviroc

Question 19

TB a global problem

Answer 19

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

Question 20

TB is a complex trait

Answer 20

Pathogen
Plus host immune response
Plus
environment

Question 21

Outcome of mycobacterial infection

Answer 21

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

Question 22

The importance of an intact immune response

Answer 22

Extremes of age
coinfection with HIV
post-measles
Diabetes
Renal disease
Steroid therapy
Anti-TNF treatment (TNF needed to fight TB)

Question 23

Why identify TB susceptibility genes?

Answer 23

Prolonged treatment with several drugs and poor compliance leads to MDRTB

The BCG does not protect in endemic regions

Question 24

Which gene mutations cause Mendelian TB disease in humans?

Answer 24

Mutations in five genes within the IL-12/IFNG axis