Trypanosoma cruzi Neuraminidase/sialidase is an Immunomodulator
and a Mimic of Mammalian Host Cell Survival Factors in the Nervous System

There are obvious differences and similarities in the organization of the nervous and immune systems, as both relay information across short and long distances. The nervous system depends on axons, dendrites, and synapses to communicate across short and long distances, while the immune system uses ordered and guided migration of immune cells and soluble factors (antibodies, cytokines, and chemokines) for long-range networking, and immunological synapses for short-range communication. These similarities in intercellular communications are complemented by many factors that induce cell growth and differentiation: In the nervous system, these are called neurotrophic factors and in the immune system, cytokines.

Neither neurotrophic factors nor cytokines are exclusive to each system, as the former react with cells of the immune system and the latter activate most cells of nervous tissue. For example, two of the most potent members of the neurotrophin family, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), can be produced by immune cells and promote repair and survival of neurons. It is this cross-talk that forms the basis for vaccine therapeutics (glatiramer acetate, Copaxone) that target multiple sclerosis. Classical immune mediators, like the cytokines interleukin-6 (IL-6) and interferon-γ, react with neurons to promote survival and differentiation and with glial cells (astrocytes and microglia) to induce de novo synthesis of MHC class I molecules.

Our results suggest that T. cruzi shrewdly exploits the interplay between the nervous and immune systems to promote long-lasting parasitism. T. cruzi is the agent of Chagas' disease, a chronic debilitating illness affecting millions of people in the Americas . The parasite encodes a family of proteins capable of catalyzing the release of sialic acid from glycoconjugates into water (neuraminidase) and the transfer of released sialic acid to β-Gal acceptors (sialyl-transferase). Hence, the neuraminidase, discovered in our lab, is also a trans-sialidase.

The N-terminal region of the trans-sialidase molecule mediates trypanosome attachment to and entry into fibroblasts and other cells. What's more, the N-terminus may prolong intracellular parasitism by protecting infected cells from apoptotic death. Such survival action is caused, in part, by the specific binding and activation of the neurotrophic receptor tyrosine kinase TrkA, whose primary ligand is NGF. Hence, the trans-sialidase is also known as a parasite-derived mimic of neurotrophic factors (PDNF).

Structure of PDNF Based on its 3-D and DNA Structure. The N terminus is composed of a catalytic domain (residues 1-271), an α helix, and a lectin-like domain (residues 395-632). The C terminus contains a long terminal repeat (LTR) of 12 amino acids. The red dot in the lectin-like domain (residues 425-445) represents a 21-mer that reproduces the neurotrophic action of the intact molecule.

The C-terminal region of PDNF, made up of tandem repeats of 12 amino acids, is an immunomodulator and can trigger polyclonal B lymphocyte activation, secretion of non-specific immunoglobulin, IL-6, and other cytokines. These actions may result in reduced and/or delayed specific anti- T. cruzi immune responses in acute Chagas' disease, thereby indirectly enhancing parasite invasion of tissues.

The survival actions of PDNF may very well prevent or reduce damage of peripheral and central nervous systems of patients infected with T. cruzi , which would provide one logical explanation for the pathogenesis of Chagas' disease. If this hypothesis is true, PDNF and other parasitokines may very well be a potential therapeutic to treat infectious diseases and unrelated disorders such as Parkinson's disease.

The illustration below depicts the different cellular interactions that occur following infection.

Novel Neuroprotective and Infection-blocking Autoantibodies
Specific for Neurotrophic Factor Receptors in Patients with Chagas' Disease

Induction of autoantibodies that react selectively with the extracellular domain of neurotrophic receptor tyrosine kinases may be another important feature in the game T. cruzi plays with the nervous and immune systems of man. Some of the autoantibodies, rather than being detrimental, appear to promote survival of neuronal cells infected or not with T. cruzi, either by themselves or in synergy with neurotrophic factors. These findings reinforce the new concept of neuroprotective autoimmunity put forward by Michal Schwartz and her colleagues from the Weizmann Institute, Israel . In addition, the neurotrophic receptor autoantibodies block infection of neurons and glial cells in vitro and in vivo .

Thus, and perhaps analogous to microbe-based PDNF, these novel host-specified autoantibodies may be mutually beneficial to the host (enhanced host cell survival and tissue healing) and parasite (low level and long-lasting infection).