Trypanosome Life Cycle: Difference between revisions

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==Antigenic Variation==
==Antigenic Variation==
<br>Trypanosomes in general exist in a very exposed and vulnerable ecological niche within their human hosts: the bloodstream.  In this environment most pathogens would be susceptible to not only the damaging effects of the innate immune response (inflammation, leukocytes, etc) but also the adaptive immune response (antibodies, killer T cells, etc.).  Some hemolytic bacteria and protists have developed methods to avoid the innate immune response through the expression of a lipo-polysaccharide coat (gram-negative bacteria only) or even thick cellular walls, but it is difficult for either of these methods to avoid the specific targeting mechanisms of the adaptive immune system.
<br>Trypanosomes have evolved to thwart the adaptive immune response of the host by maintaining a variant surface glycoprotein (VSG) coat which expresses one of ~1500 surface glycoprotein genes.  A new set of surface glycoproteins are expressed in T. brucei outer membranes in approximately 1 out of every 100 cell divisions.  This ensures that once the host mounts an effective complementary immune response to the predominantly expressed VSG variant, the infection will persist into the next generation until the host mounts another complementary response.  This variable expressive pattern is the main reason patients with chronic trypanosomiasis show cyclical bouts of infection followed by a period of relative latency.  By the time the host’s immune system identifies and synthesizes antibodies to combat certain trypanosomes, a percentage of the total trypanosome population has evaded detection and continued the infection.
<br>For each trypanosome organism, only one VSG gene is expressed at a time.  Genomic research has identified ~20 VSG expression sites (ES) along a telomere where VSG mRNA is transcribed.  Each ES is a polycistronic unit where 13 different genes are expressed including the VSG gene.  Further analysis of the trypanosome genome has shown that there are upwards of 1500 “silent” VSG genes that are not associated with the polycistronic ES.  1250 of these silent genes are hidden on subtelomeres with several silent genes located on the same chromosome.  These subtelomeres exist in close proximity to the.  ~150 of these silent genes are found in the telomeres of tightly packed 80-100kb minichromosomes.  These minichromosomes contain only one actual coding gene on an inactive polycistronic ES unit while most of the minichromosome consists of non-coding palindrome sequences.
The particular mechanisms of VSG gene switching can vary depending on the source of the VSG gene itself.  VSG genes associated with a VSG ES, but are not expressed may simply be preferentially activated by the cell during cell replication.  For a silent VSG gene found on a minichromosome, the typical method of activation is to actually transfer an entire coding sequence from an inactive telomere to a telomere containing a promoter sequence replacing the VSG gene that was previously located there.  Silent genes found on the subtelomeres also transfer through this method, but these complexes transfer only one particular VSG gene rather than an entire ES from one telomere to another. 
<br>These advantageous VSG coats are only found within the metacyclic stages of the trypanosomes life cycle which exist only in the salivary gland of the Tsetse fly and in the mammalian host bloodstream.  Within the midgut of the tsetse fly, a separate series of cell surface molecules known as procyclins dominate the cell membrane.


==Development within Insect Vector==
==Development within Insect Vector==

Revision as of 02:30, 18 April 2009

General diagram of the Trypanosoma brucei life cycle [1]



















Introduction

Microscopic image of Trypanosoma brucei during replication. Slide taken from a thick blood smear, stained with Giemsa [2]



Trypanosoma brucei and its related subspecies are parasitic hemoflagellate protists that are implicated in a severe meningoencephalitic disease, African trypanosomiasis, more commonly known as “sleeping sickness.” Sleeping sickness itself is identified as a neurological disorder preceded by an acute lymphatic infection. The disease garners its name from the effect it has of creating severe fatigue in a patient followed by bouts of mania and eventually causing coma and death. It is known to have affected up to 36 sub-Saharan countries with an estimated 300,000 new infections each year. A more complete understanding of the life cycle of this particularly fatal disease has been incited by organizations such as the WHO in order to create novel treatments for the disease before it develops into a much more deadly issue.

Protists of the genus trypanosoma are a fairly typical eukaryotic flagellates with fully intact and functional organelles including mitochondria and nuclei (which is atypical of most obligate parasites). T. brucei mitochondria contain kinetoplasts, condensed regions of mitochondrial DNA maintained within the mitochondria. The kinetoplast is closely associated with the flagellum of the trypanosome and is believed to be an essential part of the regulation of flagellar motility as the parasite enters different stages of its life cycles. Perhaps the most fascinating and unique characteristic of T. brucei is the ability to alter the composition of a dense glycoprotein coat in order to evade the specific immune response mechanisms of the host body.

Ecologically, T. brucei is an obligate parasite and requires the presence of a host cell to function. However, it is not readily transmittable between mammalian hosts and facilitates the use of an insect vector: the flies of the genus Glossina, otherwise known as the Tsetse flies. These flies are endemic to 36 sub-Saharan countries and are found, unsurprisingly, within the range of trypanosomiasis infections. Tsetse flies themselves are not fatally infected by the parasites as their hemolymph is not capable of providing the amount of sustenance necessary for trypanosomal reproduction, but they are mildly affected by the trypanosomes presence.
Within both the human and fly hosts, T. brucei undergoes a series of wildly pleomorphic events that are necessary for the successful transmission of the parasite. For example, within the fly the parasite expresses a coat that is made of several different procyclin molecules. Before transmission to the human host, the trypanosome gathers the previously mentioned variable surface glycoprotein (VSG) coat. In fact, for almost all trypanosomes, infectivity from the insect vector to the mammal host correlates with the expression of a dense VSG coat.

Once within the host, T. brucei undergoes several morphological and enzymatic changes to facilitate inter-host transfer of the parasite to various organ systems including the lymphatic system and the central nervous system. Each of these transfers are facilitated in different ways and the timing and the severity of the infection vary depending on which subspecies of T. brucei are causing the infection. Subspecies rhodesiense is a form of the disease categorized by an acute onset of neurological complications and requires treatment within days of infection before the disease becomes fatal. Subspecies gambiense is a much more chronic form of the disease with cyclical infective patterns marked by a rapid change in the VSG coat of the parasite. While there is not a complete understanding of the methods by which each of these subspecies function, researchers have been collecting a vast amount of information regarding the developmental cycles of T. brucei in order to effectively combat the disease.

Antigenic Variation


Trypanosomes in general exist in a very exposed and vulnerable ecological niche within their human hosts: the bloodstream. In this environment most pathogens would be susceptible to not only the damaging effects of the innate immune response (inflammation, leukocytes, etc) but also the adaptive immune response (antibodies, killer T cells, etc.). Some hemolytic bacteria and protists have developed methods to avoid the innate immune response through the expression of a lipo-polysaccharide coat (gram-negative bacteria only) or even thick cellular walls, but it is difficult for either of these methods to avoid the specific targeting mechanisms of the adaptive immune system.


Trypanosomes have evolved to thwart the adaptive immune response of the host by maintaining a variant surface glycoprotein (VSG) coat which expresses one of ~1500 surface glycoprotein genes. A new set of surface glycoproteins are expressed in T. brucei outer membranes in approximately 1 out of every 100 cell divisions. This ensures that once the host mounts an effective complementary immune response to the predominantly expressed VSG variant, the infection will persist into the next generation until the host mounts another complementary response. This variable expressive pattern is the main reason patients with chronic trypanosomiasis show cyclical bouts of infection followed by a period of relative latency. By the time the host’s immune system identifies and synthesizes antibodies to combat certain trypanosomes, a percentage of the total trypanosome population has evaded detection and continued the infection.


For each trypanosome organism, only one VSG gene is expressed at a time. Genomic research has identified ~20 VSG expression sites (ES) along a telomere where VSG mRNA is transcribed. Each ES is a polycistronic unit where 13 different genes are expressed including the VSG gene. Further analysis of the trypanosome genome has shown that there are upwards of 1500 “silent” VSG genes that are not associated with the polycistronic ES. 1250 of these silent genes are hidden on subtelomeres with several silent genes located on the same chromosome. These subtelomeres exist in close proximity to the. ~150 of these silent genes are found in the telomeres of tightly packed 80-100kb minichromosomes. These minichromosomes contain only one actual coding gene on an inactive polycistronic ES unit while most of the minichromosome consists of non-coding palindrome sequences. The particular mechanisms of VSG gene switching can vary depending on the source of the VSG gene itself. VSG genes associated with a VSG ES, but are not expressed may simply be preferentially activated by the cell during cell replication. For a silent VSG gene found on a minichromosome, the typical method of activation is to actually transfer an entire coding sequence from an inactive telomere to a telomere containing a promoter sequence replacing the VSG gene that was previously located there. Silent genes found on the subtelomeres also transfer through this method, but these complexes transfer only one particular VSG gene rather than an entire ES from one telomere to another.


These advantageous VSG coats are only found within the metacyclic stages of the trypanosomes life cycle which exist only in the salivary gland of the Tsetse fly and in the mammalian host bloodstream. Within the midgut of the tsetse fly, a separate series of cell surface molecules known as procyclins dominate the cell membrane.

Development within Insect Vector

Different Life Cycle Stages of T. brucei and their respective cell coats. a)Procyclic form in fly midgut. b)Long trypomastigote in fly proventriculus c)Asymmetric dividing epimastigote in fly proventriculus. d)short epimastigote in fly proventriculus. e)attached epimastigotes in fly salivary gland. f) metacyclic trypanosome in salivary gland, prepared for host inoculation. Note the different cell coats the trypanosome maintains throughout its fly life cycle.(Roditi et al.,2008)

Pathogenicity within Host

Conclusion

References

Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.


1. Krafsur, K. "Tsetse flies: Genetics, evolution, and role as vectors" Infection, Genetics and Evolution 2009. Volume 9 p.124-141
2. Taylor, J. Rudenko, G. "Switching trypanosome coats: what's in the wardrobe?" Trends in Genetics. 2006. Volume 22 No. 11
p.614-621
3. Donelson, J. "Antigenic variation and the African trypanosome genome" Acta Tropica. 2003. Volume 85 p.391-404
4. Nikolskala, O. Lima, A. Kim, Y. Lonsdale-Eccles, J. Fukuma, T. Scharfstein, J. Grab, D. "Blood-brain barrier traversal by
African trypanosomes requires calcium signaling induced by parasite cysteine protease" The Journal of Clinical Investigation.
2006. Volume 116 No. 10 p.2739-2747
5.

Edited by student of Joan Slonczewski for BIOL 238 Microbiology, 2009, Kenyon College.