Different parasite inocula determine the modulation of the immune response and outcome of experimental Trypanosoma cruzi infection

Abstract

SummaryDuring infection, the host response develops effector mechanisms to combat the parasite. However, this response can become uncontrolled or regulated by mechanisms that modulate the inflammatory reaction. The number of parasites that infects the host, such as trypomastigotes in Chagas disease, may also influence immune activation and disease pathology. We evaluated the inflammation and immune regulation that follows Trypanosoma cruzi infection with low (300), intermediate (3000) or high (30 000) parasite loads. Our results showed that the load of parasite inoculum influenced disease outcome: the higher the number of parasites in the inoculum, the lower were the survival rates. There was a strong association between parasitism and inflammatory infiltrate in the heart and the parasite inoculum determined cytokine interplay in this tissue, as shown by increased interferon-c, tumour necrosis factor-a, interleukin-17 (IL-17) and IL-23 in the 300 and 30 000 inoculum groups, higher IL-4 and IL-10 in the intermediate-inoculum mice, and elevated IL-6 production in the heart of mice in the 3000 and 30 000 groups. The number of T cells and antigen-presenting cells was augmented in the infected groups, especially for the splenic CD4 + CD25 + regulatory T cells expressing CD45RB low , GITR, PD-1 and FoxP3 in the group with the highest inoculum. Interestingly, these mice also presented an apparent decrease in CD4 + CD25 + FoxP3 + cells in the cardiac infiltrate, in contrast to the intermediate inoculum group, which showed elevated numbers of these regulatory leucocytes in the heart. Finally, our results demonstrated that parasite load during T. cruzi infection is linked to the response pattern that will result in parasite/inflammation control or tissue damage.

CD8+ T cells in Trypanosoma cruzi infection

“…In mice exposed to a highly virulent challenge, PD-1 expression and/or other signs of T cell exhaustion are evident (27, 28). Such high dose and acutely lethal infections are also associated with other immunological anomalies (29). However high dose infections are not the norm in humans and thus these particular experimental systems do not model well the majority of T. cruzi infections in humans.…”

Chagas disease in solid organ and heart transplantation

“…However, some caution is necessary in interpreting this result, as this study was performed in Brazil and patients who acquire T. cruzi infection in Colombia and Argentina have a 20-fold higher parasite load compared with those acquiring T. cruzi infection in Brazil [22,23]. In animal models, a higher number of T. cruzi organisms in the initial inoculum are associated with more inflammation and lower survival [24].…”

Emprego de métodos de imagem de alta-resolução in vivo para estudo das alterações perfusionais e inflamatórias miocárdicas em modelo experimental de cardiomiopatia chagásica crônica no hamster

“…Dois mecanismos fisiopatogênicos centrais têm sido aventados para explicar o desenvolvimento da miocardite crônica da CCC: agressão miocárdica dependente do parasitismo persistente e de baixa intensidade no tecido cardíaco (BENVENUTI et al, 2008) e lesão miocárdica por resposta inflamatória exacerbada, mediada por mecanismos de autoimunidade, alimentada pelo parasitismo persistente (BORGES et al, 2013).…”