Nutrient Acquisition in Pathogens

Question 1

What are 4 different nutrient uptake methods used by pathogens?

Answer 1

• Transporters
• Ion channels
• ATP-powered pumps
• Receptor-mediated endocytosis

Question 2

What is a good example of receptor-mediated endocytosis?

Answer 2

Trypanasomes using transferrin for iron intake

Question 3

Why do trypanasomes need iron?

Answer 3

They need it as a cofactor for important enzymes:
- Important in energy production (iron needed for alternative oxidase enzyme)
- Combats oxidative stress (iron needed for superoxide dismutase)

Question 4

Why must Trypanasomes have a specialised mechanism to get iron?

Answer 4

Their thick VSG coat makes it difficult for larger molecules to reach the cell surface

Question 5

How do Trypanasomes overcome the VSG blocking issue?

Answer 5

They have a transferrin receptor, which pokes above the VSG. The receptors sweep transferrin (which is a rich source of iron) to an area on the trypanasome surface at which it can be endocytosed

Question 6

What combine to form the transferrin receptor?

Answer 6

ESAG 6 and ESAG7

Question 7

Why is there transferrin receptor variation?

Answer 7

Matches tranferrin from different mammals; enables cross-species infection

Question 8

What is the importance of ion channels?

Answer 8

Maintaining cellular homeostasis of ions.
Ions are crucial for signalling and homeostasis

Question 9

Example of pathogen targeting host ion channel

Answer 9

Staph toxin A is a pore-forming toxin, that allows indiscriminate flux of ions across membranes, causing cells to lyse

Question 10

Example of antimicrobial targetting pathogen ion channel

Answer 10

Nematode helminths have a glutamate gated chloride channel.
Ivermectin targets this channel; binds to it, leaving them open (huge Cl- influx).
Causes parasites to enter a state of “flaccid paralysis”

Question 11

What are the two glucose transporters found in T. brucei?

Answer 11

THT1 and THT2

Question 12

What is the glucose transporter used in the bloodstream form of T. brucei and why?

Answer 12

THT1
Bloodstream is rich in glucose.
Glucose transporter is high capacity, low affinity

Question 13

What is the glucose transporter used in the procyclic form of T. brucei and why?

Answer 13

THT2
Tseste fly midgut is very glucose-sparse.
Glucose transporter is low capacity, high affinity

Question 14

What does affinity and capacity refer to?

Answer 14

Affinity refers to the kM; how readily and tightly a transporter binds to its substrate (glucose)

Capacity refers to the Vmax; the maximum rate of transport at which the transporter is saturated

Question 15

What does a higher kM indicate?

Answer 15

A low affinity.
THT1 has a high kM; low affinity for glucose

Question 16

What does a higher Vmax indicate?

Answer 16

A high capacity.
THT1 has a high Vmax; high capacity for glucose

Question 17

Why is having different transporters important for T. brucei?

Answer 17

Different hosts = different environmental conditions (high vs low glucose)

Question 18

How many glucose transporters does T. cruzi have?

Answer 18

Only one- TcHT1

Question 19

Why is TcHT1 the only glucose transporter for T. cruzi?

Answer 19

Mammalian form of T. cruzi lives intracellularly, where free glucose is scarce (i.e. both hosts have limited glucose)

Question 20

What are the properties of TcHT1?

Answer 20

High affinity
Low capacity
(same as THT2 in brucei)

Question 21

How many glucose transporters does T. congolese have?

Answer 21

2: TcoHT1 and TcoHT2

Question 22

Explain the 2 transporters for T. congolese

Answer 22

Same logic as brucei.
Bloodstream form = high capacity, low affinity
Tseste fly = low capacity, high affinity

Question 23

What disease does T. congolese cause?

Answer 23

Nagana (in livestock)

Question 24

How many glucose transporters do T. vivax have?

Answer 24

Only 1

Question 25

What is the properties of the T. vivax glucose transporter?

Answer 25

Low capacity high affinity

Question 26

Why does T. vivax only have one glucose transporter isoform?

Answer 26

Mainly resides in mammalian hosts. When in the fly, it does not leave the proboscis, and only resides there a few days. Perhaps no need for a second specialised transporter

Question 27

What are the two hosts of Leishmania?

Answer 27

Mammals and sand flies

Question 28

How many glucose transporters does Leishmania have?

Answer 28

3

Question 29

Where does Leishmania live in their mammalian host?

Answer 29

Mammalian form amastigotes live intracellularly (inside phagolysosome of macrophages), where glucose is scarce

Question 30

Why does Leishmania have multiple transporters if they are constantly in scarce glucose environments?

Answer 30

Because of pH. The pH in the phagolysosome is more acidic (around pH 5), compared to the sand fly midgut (around ph 7). Therefore there needs to be different isoforms adapted to different environments

Question 31

What is the role of the 3rd Leishmania transporter?

Answer 31

Unknown

Question 32

How does glucose enter RBCs for Plasmodium?

Answer 32

Via host erythrocytes transporters GLUT1 and GLUT5

Question 33

Where does Plasmodium reside within the RBC?

Answer 33

In the parasitophorous vacuole

Question 34

How do Plasmodium uptake glucose into the parasitophorous vacuole?

Answer 34

It has its own dedicated glucose transporter: PfHT1

Question 35

What is the properties of PfHT1?

Answer 35

Low affinity high capacity- likely due to the strady influx of glucose by GLUT1 and GLUT5

Question 36

Why is PfHT1 important clinically?

Answer 36

A PfHT1 KO is lethal; it is structurally distinct from human glucose transporters, therefore shows potential as an anti-malarial drug target

Question 37

What are new permeability pathways?

Answer 37

The malaria parasite can induce the expression of pores in the red blood cell membrane, called the new permeability pathway (NPP). These are not believed to be used for glucose, but are used for many other substances (like amino acids)

Question 38

How can the transporters discussed in these flashcards be used therapeutically?

Answer 38

Antimicrobial drugs can mimic nutrients and exploit transporters/pathways unique to pathogens. Allows for selective toxicity

Question 39

What is an example of a transporter being hijacked by antimicrobial drugs?

Answer 39

Diamidine drugs for T. brucei hijack adenosine P2 transporter. However, loss of P2 transporter by parasite allows for resistance, as P1 can still import adenosine