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Cambridge Infectious Diseases

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Evolutionary Subterfuge

Prof Mark Carrington’s work on trypanosomes is uncovering new insights into these curious creatures’ life cycles, and how they evade our immune response.

Professor Mark Carrington, Department of Biochemistry
African Trypanosomes are tsetse fly transmitted pathogens that can cause severe disease in humans and animals in sub-Saharan Africa. Cases of Human African Trypanosomiasis have dropped considerably in recent years, with fewer than 10,000 cases now identified annually, although this is probably a huge underestimate. The zoonotic form of the disease continues to place a heavy burden, with economic losses measured in billions of dollars. In humans, untreated infection is lethal with death caused by either by the organism crossing blood brain barrier and causing inflammation in the CNS.

 

However, despite their reputation as highly lethal parasites, most trypanosome species do not in fact cause infections in humans. “As primates evolved, they developed an innate immunity to trypanosomes, since when there has been an evolutionary arms race between the two. To date, the vast majority of trypanosomes cannot infect primates, but a few have evolved molecular mechanisms to infect humans, such as T.brucei gambiense and T.brucei rhodesiense”, explains Professor Mark Carrington, whose work in the Department of Biochemistry is focused at understanding the basic biology of the organisms, and the mechanisms associated with immune evasion.  “Trypanosomes diverged from all other eukaryotes at an early point in evolution. As a consequence, they tend to use similar cellular processes, but regulate them in a different way and often with a different emphasis: what can be a minor process in many eukaryotes is the predominant process in trypanosomes.”

As such they offer a number of aspects of unique biology that are not present in other organisms or have been evolutionarily de-emphasised in other microorganisms. The genome organisation in trypanosomes is also unusual, breaking from the eukaryotic paradigm of a single promoter for a single gene. Instead, transcription is polycistronic with processing to monocistronic mRNAs and non-selective  - regulation occurs at a post-transcriptional level. Carrington’s group seeks to understand how the external environment feeds back to regulate gene expression, both the overall rate of transcription when the cells arrest as part of the natural life cycle, and as a response to an external insult.

Structure of T. congolense HpHbR and the conserved three-helical bundle architecture of trypanosome surface proteins
Fig 1. Structure of T. congolense HpHbR and the conserved three-helical bundle architecture of trypanosome surface proteins.

African trypanosomes are protected by a densely packed surface monolayer of variant surface glycoprotein, or VSG. VSG is also responsible for antigenic variation, where genetic variation produces novel variants of VSG at a sufficient rate to continuously evade detection by the immune system. The VSG is a paradigm for conservation of  tertiary structure and sequence variation. “VSG was one of the first examples of where it was experimentally shown that the same protein structure could be the product of incredibly dissimilar genetic sequences. Hundreds of VSG sequences have since been identified, although the final number of functional sequences in the genome is not known. During the evolution of the African Trypanosomes there was an immense selection pressure for an expansion of the number of VSG genes to enable it to form a lifelong infection of the host. Once a genomic reservoir of a few hundred/thousand genes has evolved, some of these could diverge to a different function. At least two of the VSGs have evolved to proteins involved in human infectivity and another has become the transferrin receptors.”

More recently, Prof. Carrington’s group has uncovered the structure of a receptor crucial to human infectvity. The haptoglobin-hemoglobin receptor (HpHbR) within the VSG coat is used by the trypanosome for haem acquisition. This receptor is exploited by a human innate immunity molecule, trypanolytic factor 1 (TLF1), which enters the trypanosome by binding the HpHbR. A collaboration between Mark Carrington’s lab and those of Matt Higgins in Oxford and Jayne Raper in New York has determined the structure of HpHbR, revealing an elongated three α-helical bundle with a small membrane distal head (see Fig 1). The HpHb-binding site has been mapped and a single polymorphism in the receptor unique to human infective T. brucei gambiense has been shown to be sufficient to reduce binding of both HpHb and TLF1, modulating ligand affinity in a delicate balancing act that allows HpHb uptake but avoids TLF1 uptake.