Understanding the dual participation of the immune response in controlling the invader and at the same time causing tissue damage might contribute to the design of effective new
vaccines and
therapies for
Chagas disease.
Perforin, a cytolytic
protein product of killer cells, is involved in resistance to acute
Trypanosoma cruzi infection. However, the contribution of
perforin in parasite control and chronic chagasic
cardiomyopathy is unclear.
Perforin-positive cells were detected in the heart tissue during the acute and chronic phases of
infection of C57BL/6 mice inoculated with low dose (10(2) parasites) of the Colombian T. cruzi strain. This protocol led to acute phase survival in both wild-type and
perforin null (pfp(-/-)) mice lineages. During the
chronic infection, parasitism and
inducible nitric oxide synthase (iNOS) as well as
interleukin (IL)-4+ and, mainly,
interferon (IFN)-gamma+ cells were more elevated in the heart tissue of pfp(-/-) mice. Higher levels of circulating NO and anti-parasite
immunoglobulin (Ig)G2c and
IgG3, paralleled by a prominent frequency of IFN-gamma+ and IL-10+ splenocytes, were present in pfp(-/-)-infected mice. Therefore, although the
perforin-dependent pathway plays a role, it is not crucial for
anti-T. cruzi immunity and acute phase survival of mice infected with a low inoculum. Further,
perforin deficiency resulted in lower activity of
creatine kinase-muscle brain
isoform (CK-MB)
isoenzyme in serum and a more restricted
connexin 43 loss, both of which are markers of the cardiomyocyte lesion. Moreover,
perforin deficiency hampered the development of severe electrocardiographic abnormalities. Hence, our results corroborate that
perforin-bearing cytotoxic cells might contribute to cardiomyocyte lesion and heart dysfunction during chronic T. cruzi
infection, shedding light on immunopathogenesis of chronic chagasic
cardiomyopathy.