Trypanosoma cruzi co-opts myocardial neurotrophin receptors for invasion and cardiotrophism.
cruzi is an obligate intracellular parasite and the causative agent of Chagas disease. A
leading cause of heart failure in the Western Hemisphere, T cruzi invasion of myocardial
cells drives disease progression. Overt disease occurs only in ~30% of infected
individuals, however, and even then it takes decades before symptoms appear. T cruzi
exploits neurotrophin receptors ... read moreTrkA and TrkC for invasion via binding of its parasite
derived neurotrophic factor (PDNF), yet these receptors were not known to be expressed
by adult cardiomyocytes until recently. We demonstrate that in addition to
cardiomyocytes, cardiac fibroblasts express TrkA and TrkC. The TrkA ligand nerve growth
factor (NGF) is also expressed by both cell types, representing a potential paracrine
signaling pathway. The slow progression of Chagas heart disease implies that T cruzi
engages protective signals within its myocardial niche. We demonstrate that T cruzi
elicits NGF expression specifically from cardiac fibroblasts and not cardiomyocytes, in
vitro and in vivo. NGF induction is mediated by surface PDNF, and can be inhibited by
blockade of TrkA by antibodies, chemical inhibition, or shRNA knockdown. Recombinant
PDNF recapitulates the NGF induction and represents a novel therapeutic option for
cardiomyopathy, as NGF from cardiac fibroblasts rescues cardiomyocytes from lethal
oxidative stress. In contrast to induction of NGF via TrkA, we find that TrkC
preferentially mediates T cruzi invasion. Invasion of either cardiac fibroblasts or
cardiomyocytes can be inhibited by TrkC- but not TrkA-blocking agents, establishing for
the first time that T cruzi invasion favors TrkC over TrkA. Direct T cruzi or PDNF
activation of TrkA on cardiomyocytes, meanwhile, protects against oxidative stress,
highlighting a dichotomy of Trk receptor utilization. We also find homology between PDNF
and NGF which corresponds to PDNF's Asp-boxes, a conserved β-turn of unknown
function. By mutating PDNF Asp-boxes, we can enhance or reduce its ability to block
invasion or induce trophic signals, creating tailored molecules for specific
applications. T cruzi interacts with myocardial Trk receptors in multiple ways during
infection. Mechanistic and molecular understanding of these interactions should provide
therapeutic opportunities for Chagasic and perhaps other cardiomyopathies as
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Immunology.
Advisor: Mercio PereiraPerrin.
Committee: Alexander Poltorak, Honorine Ward, Joan Mecsas, and Marc-Jan Gubbels.
Keyword: Immunology.read less