5. Genetic resistance and susceptibility to infectious disease Flashcards
Structure of the lecture
- Genetic variants that prevent disease
- Genetic variants that limit disease severity
- Genetic diversity that contributes to host immunity
What are the 4 primary examples of genetic variants that prevent pathogen entry?
- The Duffy Negative Blood Group and P. vivax via DARC protein
- The Dantu Bood group and P. falciparum via cell membrane tension
- CCD5-∆32 mutation and HIV-1 resistance via white-blood cells
- FUT2 non-secretor phenotype and norovirus/rotavirus
Describe the Duffy negative phenotype example
Genetic variants that PROTECT
Duffy is one classification of blood group. Individuals with Duffy negativity have a lack of DARC protein in the cell membrane due to a mutation in the FY promoter of the gene (FY*O)
P. vivax will usually bind to DARC. A lack of DARC via homozygosity prevents malarial entry to RBCs
Howes et al., shown to be most prevalent in sub-Saharan Africa via using multi-locus Bayesian geostatistical models. Corresponds to low P. vivax
McManus et al., showed a soft positive selective sweep for the FYO phenotype due to coevolution
Twohig et al., showed that protection associated from Duffy negativity depends on whether the population is symptomatic or not
Aunin et al., showed that rapid gene evolution between gene and malaria is essential by modelling a descendant group of malaria, Hepatocystis
Tung et al., showed that the FY locus in baboons impacts Hepatocystis in the same way that Duffy negativity impacts humans
Describe the Dantu Blood group
Genetic variants that PROTECT
Dantu is another type of antigen blood group. It is an unusual form of glycophorin that may have arisen from recombination of GYPA and GYPB genes
Boyle et al., illustrated mechanism of protection. A parasite must deform the membrane when it invades the cell. This is regulated by merozoite proteins in the parasite. Higher tension = harder to invade.
Kariuki et al., showed that Dantu has higher tension than non-Dantu, and that this results in resistance to merozoite invasion. Measured the contact region between merozoite and low/high-tension cells.
Describe the CCR5-∆32 mutation
Genetic variants that PROTECT
This is a good counter example
Human CC-type chemokine receptors are expressed on the surface of WBCs. HIV-1 uses CCR5 as a co-receptor for invasion during early stages of infection.
CCR5- ∆32 mutation is a truncated and non-functional form of CCR5, and therefore HIV-1 cannot enter cells
CCR5- ∆32 highly, but not completely, resistant to HIV-1 infection
Previously thought to be linked to the rise of Vikings/early Scandinavian ancestors colonising the global North.
However, mutation arose ~7000 years ago and reached status quo around ~2000 years ago. This doesn’t align with the spread of HIV-1, suggesting mutation was not driven by HIV-1 and no coevolution
Describe the FUT-2 non-secretor phenotype
Genetic variants that PROTECT
Individuals can be secretors or non-secretors of their ABO self-antigens into their blood (either way is obvs fine it’s just a fact)
Non-secretors are homozygotes for mutations that prevent expression of FUT-2 enzymes
Currier et al., 2015 modelled the innate susceptibility of norovirus infections influenced by FUT2 in paediatric populations of the USA. Found that FUT2 is highly correlated to protection to norovirus and rotavirus
What are the 3 primary examples of genetic variants that help host survival?
- Heterozygosity in sickle-cell mutations is highly protective against severe and non-serve P. falciparum
- Haemoglobinopathies in other primates
- Heterozygosity for Ovalocytosis protecting against P. vivax and P. falciparum
Describe sickle-cell heterozygosity and malaria
Genetic variants that aid SURVIVAL
Sickle-cell haemoglobin undegoes polymerisation under low-oxygen conditions, changing structure.
Homozygosity for sicke-cell is very bad - can be lethal.
Heterozygosity appears to afford protection against severe and non-severe cases of P. vivax and P. falciparum
Therefore, this acts as a form of balancing selection, since normal phenotype is not advantageous either (can get malaria).
An example of heterozygote advantage
Heterozygosity leads to a direct reduction of growth in RBCs due to changed ‘knobs’ on membrane, and therefore reduced pathogen adherence. Enhanced pathogen clearance in the spleen.
Describe other haemoglobinopathies that aid malarial survival
Genetic variants that aid SURVIVAL
Different regions of the world are associated with different genetic variants
Long-tailed macaques have adapted to malarial selection via alpha-globin mutation in a process that mirrors human co-evolution to malaria
Describe how heterozygosity for ovalocytosis affords improve malarial survival rates
Genetic variants that aid SURVIVAL
Heterozygosity for Southeast Asian ovalocystosis will have oval-shaped RBCs
This is due to a deletion in a gene in Band 3 of RBCs leading to the removal of 9 amino acids.
Leads to high malarial protection.
Homozygote form is lethal.
An example of heterozygote advantage and balancing selection
Why do we have so much data on malaria?
- Massive public health issue at the moment, and therefore loads of data
- Particularly effects kids, meaning more data tends to be collected
- Still co-evolving! Therefore is good study example
What are the 2 major mechanisms of genetic diversity that improve host immunity?
MHC
KIRS
How can HLA-B53 protect against severe malaria?
Genetic DIVERSITY - MHC
HLA-B53 can present a specific, conserved peptide from liver-stage malaria called LSA1 that could afford a degree of protection
Pathogen-driven selection has shaped the global distribution of HLA-B53 and the malarial landscape
There are parallels between human HLA-B53 and malaria, and Bonobo B07 resistance to malaria
How are HLA alleles linked to HIV protection?
Genetic DIVERSITY - MHC
HLA Class I alleles host immense promise for universal T-cell based HIV-1 vaccines
International HIV Controllers Study in 2011 identified >300 genome-wide HLA SNPs that may be linked to HIV/AIDS progression e.g., HLA-B57
Wroblewksi et al., showed that chimpanzee PatrB06:03 is associated with lower viral loads of SIV, in the same way human HLA-B57 is linked to lower viral loads of HIV
What does KIRS stand for?
Genetic DIVERSITY - KIRS
Killer-cell Immunoglobulin Like Receptors (KIRS)
What are the two classes of KIRS
Genetic DIVERSITY - KIRS
- Inhibitory
- Activating
Link between KIR2DL3 and HLAC1?
Genetic DIVERSITY - KIRS
Homozygosity for KIRS2DL3 and HLAC1 offers better resolutions for HepC infections, and is a lower risk factor for cerebral malaria
Link between KIRS and HLA-Bw4?
Genetic DIVERSITY - KIRS
KIR3DS1 with putative ligand HLA-Bw4 is associated with delayed AIDS progression
High expressing KIR3DL1 with putative HLA-Bw4 ligands also associated with delayed AIDS progression!
