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Compare and contrast the mechanism and consequences of antigenic variation in a named

protozoan parasite and named virus.

David Burke
Oxford

Just as the immune system has evolved to combat external pathogens, certain pathogens employ
methods to combat the immune system. A major mechanism of pathogenic subversion of the
immune system is the process of antigenic variation. The adaptive immune system works by
detecting a pathogen through specific antigen binding. Antigenic variation is the process by which a
pathogen is able to alter its antigens so that they are less detectable to the adaptive immune system
and thus the immune response to that pathogen is weakened. Different mechanisms of antigenic
variation can be exemplified by the protozoan trypanosoma brucei and by the influenza virus.

Trypanosoma Brucei

This parasite is the major cause of East and West African trypanosomiasis more commonly known
as 'Sleeping Sickness'. This disease is rife in sub-Saharan Africa most recently causing a 2008
epidemic in Uganda. This disease causes fever and extreme lethargy. It is characterised by
Winterbottom's sign of swollen neck lymph nodes as well as night-time insomnia and daytime
sleepiness. Although treatable it can be fatal and is a serious health risk with over 300 000 new
cases per annum.

The life-cycle of trypanosoma brucei involves a human stage as well as a stage in a tsetse fly vector.

Tsetse Fly:
bloodstream trypomastigotes
‫׀‬
procyclic trypomastigotes
‫׀‬
epimastigotes
‫׀‬
metacyclic trypomastigotes

Human:
metacyclic trypomastigotes
‫׀‬
bloodstream trypomastigotes

While the parasite is within the bloodstream and the lymphatics it is prone to antigen detection. As
the trypanosoma brucei is always extracellular, its surface antigens are detected by B lymphocytes
of the humeral system and also by MHC class II presentation of their antigens to CD4+ T
lymphocytes. The main surface protein Variant-Specific Glycoprotein (VSG) is readily detectable
by the adaptive immune system in this way. The humeral system then produces antibodies that are
in theory very effective at destroying the parasite. However, this is halted by deliberate antigenic
variation within the trypanosoma brucei genome.

Trypanosoma brucei contains around 1000 VSG genes but only one expression site in which a VSG
gene can produce the VSG protein. By gene rearrangement the parasite periodically alters its VSG
expression to a form that isn't recognised by the host. So as the immune response is responding to
the trypanosome infection effectively a new strain is produced from the same infection that can then
proliferate. This cycle of relapse and remission keeps occurring until the overactive immune system
leads to immune-complex damage and chronic inflammation eventually causing neurological
damage and inducing a coma. Thus trypanosoma brucei hides in plain-slight from the immune
system through its clever evolution of antigenic variation.

Influenza Virus

Influenza is currently an ineradicable disease due to its antigenic variation. The influenza virus is
the cause of each wave of seasonal flu. It causes usually non-fatal symptoms of fever and malaise.
However in the elderly and immunocompromised people influenza can indeed be fatal accounting
for 40 000 deaths per annum in the USA.

It is an airborne virus transmitted from person to person. In the mucosa the virus invades cells
through its haemagglutinin binding to sialic acid residues. For successful release from the cell the
viral protein neuraminidase is required. It is these two protein that are mainly detected by the
immune system. This occurs through MHC class I presentation of these antigens on the infected cell
surface along with IFNγ signals released. This activates CD8+ T lymphocytes which cause
destruction of the infected cells. However these two viral proteins are also undergo antigenic
variation.

This antigenic variation is unlike that of trypanosoma brucei in that it is not a set mechanism
employed deliberately by the virus. It also occurs between infections not during a current infection.
For this reason a person can recover fully from an influenza infection, yet still be susceptible to a
future infection as they only have memory T lymphocytes for the antigens of the virus before
variation. There are two types of influenza antigenic variation; drift and shift.

Antigenic drift is by far more common and occurs on an annual basic producing seasonal flu. It
involves point mutations in genes encoding the haemagglutinin and neuraminidase proteins causing
slight changes in their structure that spare their function. This means that neutralising antibodies can
no longer bind and the person becomes re-infected. However as the mutation is mild there is cross-
reaction between memory T lymphocytes and antibodies from previous infections. This means that
once infected only a mild disease will ensue due to a second infection after antigenic drift.

Antigenic shift on the other hand is much more severe. This involves a major change in the viral
proteins meaning that the new proteins are not recognised at all by the immune system. This is due
to reassortment of segmented RNA genomes of human and animal influenza viruses within an
animal host (i.e. animal haemagglutinin or neuraminidase genes within a human virus). This
extreme antigenic variation can lead to a global pandemic as no human population has any level of
immunity. The occurrence of this is roughly every 30-40 years.

Conclusion

In conclusion antigenic variation is a very efficient way for a pathogen to evade surveillance and
antigen specific destruction by the adaptive immune system. It can be a deliberate mechanism that
occurs during a single infection as seen in trypanosoma brucei or a mutation driven process that
occurs between infections seen in the influenza virus. Antigenic variation in also an extremely
important process to consider when developing treatment and vaccines against pathogens as a
current effective treatment can be rendered completely useless by it.