Abstract
Resistance or susceptibility to T. cruzi infection is dependent on the host immunological profile. Innate immune receptors, such as Toll-like receptors (TLRs/TLR2, TLR4, TLR7, and TLR9) and Nod-like receptors (NLRs/NOD1 and NLRP3 inflammasome) are involved with the resistance against acute experimental T. cruzi infection. Here, we evaluated the impact of T. cruzi virulence on the expression of innate immune receptors and its products in mice. For that, we used six T. cruzi strains/isolates that showed low (AM64/TcIV and 3253/Tc-V), medium (PL1.10.14/TcIII and CL/TcVI), or high (Colombian/Tc-I and Y/TcII) virulence and pathogenicity to the vertebrate host and belonging to the six discrete typing units (DTUs)—TcI to TcVI. Parasitemia, mortality, and myocarditis were evaluated and correlated to the expression of TLRs, NLRs, adapter molecules, cytokines, and iNOS in myocardium by real time PCR. Cytokines (IL-1β, IL-12, TNF-α, and IFN-γ) were quantified in sera 15 days after infection. Our data indicate that high virulent strains of T. cruzi, which generate high parasitemia, severe myocarditis, and 100% mortality in infected mice, inhibit the expression of TLR2, TLR4, TLR9, TRIF, and Myd88 transcripts, leading to a low IL-12 production, when compared to medium and low virulent T. cruzi strains. On the other hand, the high virulent T. cruzi strains induce the upregulation of NLRP3, caspase-1, IL-1β, TNF-α, and iNOS mRNA in heart muscle, compared to low and medium virulent strains, which may contribute to myocarditis and death. Moreover, high virulent strains induce higher levels of IL-1β and TNF-α in sera compared to less virulent parasites. Altogether the data indicate that differential TLR and NLR expression in heart muscle is correlated with virulence and pathogenicity of T cruzi strains. A better knowledge of the immunological mechanisms involved in resistance to T. cruzi infection is important to understand the natural history of Chagas disease, can lead to identification of immunological markers and/or to serve as a basis for alternative therapies.
Highlights
The experimental infection of mice with different strains of Trypanosoma cruzi (T. cruzi) can range from asymptomatic to lethal infections
Mice infected with high virulent strains showed high levels of parasitemia and 100% mortality, while the animals infected with medium virulent strains showed intermediate levels of parasitemia and 40% mortality, and low virulent strains (AM64 and 3253) generate low parasitism load and 100% survival in mice (Figures 1A, B)
In an attempt to elucidate if the differential expression of Toll-like receptors (TLRs) and Nod-like receptors (NLRs) is involved in the pathogenicity induced by different strains of the parasite, we evaluated the TLR and NLR mRNA expression in heart tissue from mice infected with high, medium, and low virulent strains of T. cruzi
Summary
The experimental infection of mice with different strains of Trypanosoma cruzi (T. cruzi) can range from asymptomatic to lethal infections. Initial activation of immune response against T. cruzi occurs through the recognition of molecular patterns present in parasites by pattern recognition receptors (PRRs) (Bartholomeu et al, 2008; Oliveira et al, 2010; Rodrigues et al, 2012). Parasite is recognized by different receptors and will be phagocytosed by macrophages, leading to the production of inflammatory cytokines such as interleukin-12 (IL-12) (Silva et al, 1995; Aliberti et al, 1996), which acts on natural killer (NK) cells, activating the production of more IL-12 and IFN-g. Cytokines, such as IL-10 and TGF-b inhibit iNOS, restricting the inflammation but allowing parasite replication (Silva et al, 1991; Holscher et al, 1998)
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