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FIGURE 19.13 Structure and Location of VSG Protein

FIGURE 19.13 Structure and Location of VSG Protein

The VSG protein is expressed on the cell surface of the trypanosome. The protein has two domains, the conserved region anchors the protein in the membrane and does not change. The second domain or variable region extends to the outside of the cell and changes shape to evade the immune system.

Trypanosomas cycle between insects and mammals and change their surface proteins when they shift hosts.

The trypanosome nucleus contains a mixture of normal sized and miniature chromosomes.

than average bacteria) and swim around in the blood by means of a flagellum. Insects harbor these parasitic eukaryotes in their saliva, and when the insect bites a person or animal, the eukaryotic parasite invades the bloodstream of the new host. For example, tsetse flies carry the trypanosomes that cause sleeping sickness, whereas malarial parasites are carried by mosquitoes.

While growing and dividing in the insect gut, the trypanosomes are covered with a layer of a protein called procyclin that protects them from digestion by the insect. The trypanosomes then move to the salivary glands where they stop dividing and wait for the insect to bite someone. While waiting, they convert their surface layer to the variant surface glycoprotein (VSG), designed to protect against animal immune systems. The VSG protein has a variable region that is displayed on the trypanosome surface and a conserved portion that anchors it to the membrane. It is found as a dimer, as shown in Figure 19.13.

After transfer to a human, the trypanosomes grow and divide in the blood until the immune system kills most of them. However, a few of the trypanosomes switch their VSG shape and escape recognition by the immune system. Eventually, the immune system learns about the new surface protein and kills off most of the second wave of trypanosomes. Meanwhile, some of the invaders have switched their VSG type again. This continues and the infection therefore goes in waves, each spreading the invaders further inside each human victim. The immune system never catches up with the constantly changing outer layer of the trypanosome, and the normal result is death of the victim. When tsetse flies suck blood from humans or animals with the disease, they become re-infected. And so the cycle continues (Fig. 19.14).

To understand how the VSG protein is constantly altered, we must first discuss the genomic structure of the trypanosomes. Both the nuclear and mitochondrial genomes of trypanosomes are divided up in a peculiar manner. In addition, trypanosomes indulge in the trans-splicing of many genes at the RNA level as well as RNA-editing as already discussed in Chapter 12.

Each trypanosome cell contains one giant mitochondrion, the so-called "kineto-plast". This contains about 50 copies of a large circular DNA molecule that ranges from 20 to 80 kbp depending on the species. These "maxi-circles" encode the normal mitochondrial genes. In addition there are approximately 10,000 mini-circles that encode only the guide RNAs used in splicing (see Ch12). The mini-circles range from 1.5 to 10 kbp and are often catenated (i.e. interlocked).

The nuclear genome is divided into 11 pairs of large "normal" or "megabase" chromosomes plus about 100 mini-chromosomes of 50-150 kbp. The only protein-coding genes found on the mini-chromosomes are silent copies of the VSG gene, located close to one or both ends (Fig. 19.15). The rest mostly comprises a kinetoplast Single giant mitochondrion found inside the cells of protozoans such as trypanosomes minichromosomes Miniature chromosomes of 50-150 kbp found in trypanosomes that carry silent copies of the VSG gene variant surface glycoprotein (VSG) Glycoprotein found on surface of trypanosomes that is encoded by multiple gene copies and varied to avoid recognition by the animal immune system

FIGURE 19.14 Trypanosome Life Cycle

Trypanosomes alternate between two hosts, humans or other mammals and the tsetse fly. While residing in the fly, trypanosomes acquire a procyclin coat to protect against the fly's digestive enzymes. After moving to the salivary glands of the fly, trypanosomes start to express VSG proteins on the cell surface. When the tsetse fly bites a human, the trypanosome enters the mammalian bloodstream and starts to divide. Changes in VSG surface expression allow a few of the trypanosomes to evade the immune system. If a tsetse fly bites an infected human, the cycle starts all over again.

FIGURE 19.15 Genome Components of the Trypanosome

Trypanosome genomes consist of four different genetic elements. The mitochondria or kinetoplast has maxi-circles and mini-circles. The nucleus has eleven pairs of megabase chromosomes, and about 100 mini-chromosomes. The VSG genes are located at the ends of both the megabase and minichromosomes.

Normal "megabase" chromosomes

Minichromosomes

Mitochondrial maxicircles

Telomere VSG gene Repeat

Normal "megabase" chromosomes

Minichromosomes

FIGURE 19.15 Genome Components of the Trypanosome

Trypanosome genomes consist of four different genetic elements. The mitochondria or kinetoplast has maxi-circles and mini-circles. The nucleus has eleven pairs of megabase chromosomes, and about 100 mini-chromosomes. The VSG genes are located at the ends of both the megabase and minichromosomes.

Mitochondrial maxicircles

Mitochondrial minicircles (encode gRNA)

Telomere VSG gene Repeat

Repeat VSG gene Telomere i Minichromosome

Megabase chromosome

Mitochondrial minicircles (encode gRNA)

Repeat VSG gene Telomere i Minichromosome

Repeat VSG gene omere

Megabase chromosome

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