Genetics of susceptibility and resistance against infections

Question 1

Infectious Agents

Answer 1

• bacteria
• Virus
• Eukaryotic microbes
• Parasites
• Prions

Question 2

Prionen

Answer 2

PrP(c) gesunde Form. Wird zu PrP(sc), pathologische form, umgewandelt wenn diese in Kontakt kommen. Somit sind Prionen infektiös und akkumulieren

Question 3

Prionen Krankheiten

Answer 3

• Human: Creutzfeldt-Jakob disease (CJD)
• Cattle: Bovine spongiform encephalopathy (BSE)
• Sheep: Scrapie

Question 4

Louis Pasteur

Answer 4

• disproved miasma theory (disease due to “bad air”)
• Verified germ theory
• exposed boiled broth to air via filters that prevented particles. No microorganism growth until flasks were broken open -> Growth not spontaneous but due to biogenesis
• 1st vaccine against rabies and anthrax
• invented pasteurization
• 1/3 founders of modern microbiology

Question 5

Van Leeuwenhoek

Answer 5

improved microscopy to directly observe microorganisms

Question 6

Robert Koch

Answer 6

• isolated B. anthracis, T. bacillus, V. cholerae
• developed Kochs postulates
• Nobel prize
• 1/3 founders of modern microbiology

Question 7

Koch’s postulates

Answer 7

• MO found in abundance in all organisms suffering from the disease, but not in healthy individuals
• MO isolated from diseased organism, grown in pure culture
• Cultured MO causes disease when introduced into healthy organism
• MO reisolated from exp. host, identified as identical to orginal causative agent

Question 8

Ferdinand Cohn

Answer 8

• classified bacteria into 4 groups based on shape
• bacillus can change from vegetative to endospore state
• 1/3 founders of modern microbiology

Question 9

Charles Nicolle

Answer 9

• Lice, fleas, ticks and mice transmitter of epidemic typhus

- identified toxoplasma gondii

Question 10

Malaria transmission

Answer 10

Plasmodium falciparum, protozoan parasite, causes malaria in humans. Transmitted by female Anopheles mosquito.
P. falciparum malaria infection accounts for 91% worldwide malaria cases, 90% of the deaths

Question 11

Malaria cases

Answer 11

• 3.3 billion at risk
• poor countries most vulnerable
• 20% of childhood deaths due to malaria in Africa

Question 12

P. falciparum life cycle

Answer 12

1. Sporozoite form injected into human by mosquito
2. Travel to liver and develop into merozoites
3. Invade and multiply via trophozoite form in red blood cells (<10% infected)
4. Merozoites develop into Gametocytes
5. Another mosquito bites infected person, takes up blood with gametocytes that develop into gametes.
6. They fuse in the insect gut and form a zygote. Develops into ookinete, forms a sporozite filles oocyst.
7. when oocyst bursts, sporocytes move to mosquitos salvatory glands. Cycle repeats

Question 13

Sickle-cell disease

Answer 13

• homozygous for pathogenic allele
• HbS instead of HbA
• Single nucleotide subst. (T -> A) causes Amino- acid subst. (Beta-Glu -> Val)
• more resistant to P. falciparum infections

Question 14

Sickle- cell Trait

Answer 14

• heterozygous fo HbS and HbA
• demonstration of mendelian inheritance determining physical properties of proteins
• More resistant to P. falciparum infections

Question 15

HbS

Answer 15

• Hemoglobin when deoxygenated polymerizes and distorts red blood cells -> sickle shape
• These cells stick to vesser walls causing blockage and stop the flow of blood
• Erythrocytes lyse more often and quicker
• HbA stops polymerization

Question 16

Malaria and sickle cell anemia

Answer 16

• High Prevalence of both directly correlates
• Malaria caused strongest known selective pressure on human genome
• Heterozygous for HbS and HbA has greater fitness in malarious environments
• sickle-cell mutation occured min. 5x independantly in africa and india
• Darwinian selection in humans

Question 17

HbS-med. resistance to Malaria:

Answer 17

• reduced cytoadherence
• phagocytosis
• lower oxygen tension
• higher levels of hydrogen peroxide and superoxide anion produced

Question 18

Reduced cytoadherence (HbS)

Answer 18

• cytoadherence:
  PfEMP-1 (parasite-encoded p. falciparum erythrocyte membrane protein 1) on erythrocyte membrane of infected cells -> adhere to endothelial cells
• PfEMP-1 surface signal reduced in HbS.
• oxidized haemoglobin interferes with actin re-organization -> impaired vesicular transport to erythrocyte surface -> altered PfEMP-1 surface expression
• leads to increased splenic clearance -> improved presentation of antigens to IS
• higher IgG levels towards PfEMP-1

Question 19

Phagocytosis (HbS)

Answer 19

• enhanced in HbS
• increased presentation of opsonins (incl. membrane bound IgG, C3c,…)
• enhanced opsonization and clearence of parasite erythrocytes -> increased antigen presentation and earlier acquired immune reaction

Question 20

Thalassemia

Answer 20

• hemoglobinopathy
• production of globin protein subunits out of balance
• autosomal recessive
• alpha thalassemia: deficiency in alpha globin
• beta thalassemia: deficiency in beta globin
• chromsome 11: one beta globin gene each
• chromosome 16: two alpha globin genes each -> each gene produces 1/2 protein quantity compared to beta gene
• dependant on how many genes missing
• 1 alpha: asymp. carrier
• 2 alpha: minor, asymptomatic
• 3 alpha: HbH disease
• 4 alpha: incompatible with life
• resistance to malaria sim. to HbS-med. presumably

Question 21

DANTU bloodgroup and malaria

Answer 21

• Dantu RBCs have a higher avg. tension -> resist invasion, weaker membrane deformation during contact