Innate Immunity in Chagas Heart Disease: The Role of Cathelicidin
stem/progenitor cells (CPCs) can repair the injured heart by replacing dead cells and/or
secreting paracrine factors that trigger cell survival. Whether CPCs also work to
prevent myocardial injury is less appreciated. We observed that CPCs, unlike cardiac
myocytes and fibroblasts, are resistant to infection by the obligate intracellular
parasite Trypanosoma cruzi, which caus... read morees Chagas disease. We determined that the observed
resistance is due to a soluble factor secreted by CPCs because CPC conditioned media
prevents T. cruzi from invading otherwise permissive cardiac cells. RNA-Seq, real-time
PCR and ELISA revealed that mouse CPCs constitutively secrete cathelicidin-related
antimicrobial peptide (CRAMP), and indicated that this CPC-secreted peptide is one of
the factors which inhibits T. cruzi invasion of cardiac cells. Indeed, CRAMP antibodies
specifically eliminate the infection-inhibitory activity of CPC conditioned media,
allowing for T. cruzi to invade the otherwise protected cardiac cells despite being
exposed to the conditioned media. Furthermore, synthetic CRAMP peptide and human
counterpart cathelicidin LL-37, but not the scrambled control peptide, potently inhibit
T. cruzi invasion of permissive cardiac cells. Cathelicidins are known for their broad
range of antibacterial and antifungal activities, and CPCs likely utilize this
antimicrobial agent for immune surveillance of other pathogens besides T. cruzi. Thus,
our results suggest that CPCs preemptively act against protozoan pathogens by
constitutively secreting the antimicrobial peptide cathelicidin, highlighting a novel,
stem cell-mediated, innate host defense mechanism against microbial invaders of the
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Immunology.
Advisor: Mercio Perrin.
Committee: Pilar Alcaide, Thereza Imanishi-Kari, and Honorine Ward.
Keyword: Immunology.read less