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Trichinella: Potential Supplier of Paraceuticals


Eukaryotic parasites co-evolve with their hosts, and are thus selected for life in a wide variety of complex physiological and biochemical environments. Successful agents that infect mammals live in a microcosm dominated by host-based complex cellular and humoral immune responses These protective mechanisms were selected specifically to thwart potential pathogens, and in large measure do just that throughout the life of the animal. Helminth parasites are equally complex critters, and because of their long-term associations with mammals, many have elaborated a wide variety of secreted molecules that are central to their ability to survive within them. Many of these molecules are proteins and function by altering normal host functions, particularly those related to resistance. In a real sense, all successful eukaryotic parasites behave just like pharmacologists, synthesizing bioactive molecules, enriching their own lives and making ours quite miserable, at times!

A well-characterized example is the family of anti-coagulant peptides produced by hookworms. Both Necator spp. and Ancylostoma spp. secrete these highly active substances directly into the gut tissue at the site of feeding to prevent blood from clotting while they merrily go about sucking it out of the host’s small intestinal tissue. The genes for these anti-coagulants have been identified, their cDNAs cloned and sequenced, and the active peptides expressed. Schistosome spp. secrete hydrolases that allow them to enter the skin of the host, and once inside, they secrete other molecules that alter cellular immune responses favoring the parasite’s long-term survival. Brugia spp. secrete a molecule(s) that alters the pattern of mitosis of lymphatic endothelial cells, causing those cells to arrest. As the result, the vessel remains patent. Upon the death of the parasite, the host resumes normal cellular replication and immune functions, "killing" the dead parasite with a set of reactions that end up harming the host by occluding the vessel.

Trichinella spp. are quintessential chemists, producing some 350+ proteins that are deployed at various times during the parenteral and enteral phases of their life. The 2-D gel shows the general pattern of peptides secreted by the infectious L1 larva. Note the wide range of molecular weights and isoelectric points. The precise function of each of these peptides remains unknown. This is due to the fragmentary nature of information that presently exists regarding:
1. the time during infection at which each is released into the host;
2. the sub-cellular compartment(s) that each translocates to within the Nurse cell or enterocyte, and;
3. the amino acid sequence and putative function of each molecule.
Trichinella has accomplished something unequalled in eukaryotic parasite evolution; namely, it has maintained a long-term relationship with its host, lasting in some cases for up to 30 years. The most likely explanation as to how it achieves this feat is that It does so with the help of its secreted molecules. Therefore, discovering the true meaning of Trichinella’s molecular treasures will provide humankind with the next generation of bioactive molecules, "paraceuticals".

We have expended much energy exploiting the world’s soils looking for new anti-microbial agents. We have extended the quest to include the world’s rain forests, coral reefs, and numerous other ecological settings. The breadth and depth of the search now encompasses the need for solutions to medical problems associated with all aspects of modern life on earth. We may be looking too far afield. The answer to many of our needs may lie within ourselves in the form of the numerous protozoan and helminth invaders that have already solved those puzzles. Exploitation of these untapped resources, paraceuticals, may prove to be the richest yet for pharmacologically useful agents. A partial list of altered host activities for which Trichinella is responsible is listed below.

HOST ACTIVITY INDUCED OR MODIFIED BY THE PRESENCE OF THE PARASITE

  1. Immunosuppression
  2. Induction of host DNA synthesis
  3. Karyokinesis in the developing Nurse cell
  4. Induction of overall growth of the Nurse cell
  5. Possible alteration of the myogenic program in satellite cells, thus preventing them from repairing damage after the newborn larva penetrates the muscle cell.
  6. Up regulation of two families of collagen genes; type IV and type VI.
  7. Up regulation of synthesis of smooth membranes in the Nurse cell
  8. Induction of an anaerobic intracellular environment by damaging mitochondria
  9. Up regulation of vascular endothelial growth factor, probably by a mechanism not used by the host.

As alluded to, it is not known which secreted peptides from the L1 larva interact with normal host cellular processes. With a seemingly imposing list of some 350+ peptides to choose from for each alteration in host cellular function, the most reasonable approach to characterizing them would be first to clone and sequence all relevant cDNAs. After that, one could then begin to sort out the peptide sequences into families according to their functional motifs. In this way, the "dictionary" of Trichinella could then be written. Fortunately, this task is relatively straight-forward and should take a maximum of three years to complete if a well-equipped laboratory worked full time only on this project. Alternatively, by distributing the sequencing work among the world’s Trichinella labs, it would go even faster, especially if a robust cDNA expression library were available to all of them.

How Trichinella uses its words in "sentences", and what they mean can only be determined after these data are in hand. It is highly likely that at least some of them function by mimicking host molecules that it uses to communicate with other parts of itself. I have coined the term "parakine" to accommodate the possibility that the parasite is able to "speak" in host dialects using "look-a-like" molecules. Immunosuppression, as well as angiogenesis (circulatory rete formation), and even perhaps collagen gene up regulation are likely to be induced by parakine peptides. Finally, using in situ hybridization and immuno-cytochemistry, one could determine when the worm "speaks" to the host, and thus learn specifically what it is saying. When this is known, we will approach knowing the rudiments of the function of the stichosome of the L1 larva while it is in its parenteral niche.

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