Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi.
Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi.
复制标题
DOI：
10.1371/journal.pntd.0005300
复制
发表时间：
2017-02
影响因子：
3.8
通讯作者：
Malchiodi EL
中科院分区：
文献类型：
--
作者：
Matos MN;Cazorla SI;Schulze K;Ebensen T;Guzmán CA;Malchiodi EL
The development of new adjuvants enables fine modulation of the elicited immune responses. Ideally, the use of one or more adjuvants should result in the induction of a protective immune response against the specific pathogen. We have evaluated the immune response and protection against Trypanosoma cruzi infection in mice vaccinated with recombinant Tc52 or its N- and C-terminal domains (NTc52 and CTc52) adjuvanted either with the STING (Stimulator of Interferon Genes) agonist cyclic di-AMP (c-di-AMP), a pegylated derivative of α-galactosylceramide (αGC-PEG), or oligodeoxynucleotides containing unmethylated CpG motifs (ODN-CpG). All groups immunized with the recombinant proteins plus adjuvant: Tc52+c-di-AMP, NTc52+c-di-AMP, CTc52+c-di-AMP, NTc52+c-di-AMP+αGC-PEG, NTc52+CpG, developed significantly higher anti-Tc52 IgG titers than controls. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 showed the highest Tc52-specific IgA titers in nasal lavages. All groups immunized with the recombinant proteins plus adjuvant developed a strong specific cellular immune response in splenocytes and lymph node cells with significant differences for groups immunized with c-di-AMP and Tc52, NTc52 or CTc52. These groups also showed high levels of Tc52-specific IL-17 and IFN-γ producing cells, while NTc52+CpG group only showed significant difference with control in IFN-γ producing cells. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 developed predominantly a Th17 and Th1immune response, whereas for NTc52+CpG it was a dominant Th1 response. It was previously described that αGC-PEG inhibits Th17 differentiation by activating NKT cells. Thus, in this work we have also included a group immunized with both adjuvants (NTc52+c-di-AMP+αGC-PEG) with the aim to modulate the Th17 response induced by c-di-AMP. This group showed a significant reduction in the number of Tc52-specific IL-17 producing splenocytes, as compared to the group NTc52+c-di-AMP, which has in turn correlated with a reduction in protection against infection. These results suggest that the Th17 immune response developed after immunizing with NTc52+c-di-AMP could have a protective role against T. cruzi infection. Groups NTc52+c-di-AMP, Tc52+c-di-AMP and NTc52PB, were the ones that showed better protection against infection with lower parasitemia and weight loss, and higher survival. Chagas disease is a parasitic disease caused by a protozoan parasite (Trypanosoma cruzi) which has a complex life cycle including insect vector and mammalians. In Latin America, 7–10 million people are infected, 100 million people are at risk of infection, and about 56,000 new infection cases and 12,000 deaths are registered annually. Migration spread the geographic distribution of the disease to North America and Europe. The infection in humans has an initial acute stage followed by a chronic stage where up to 30% of patients develop cardiac alterations and 10% develop digestive, neurological or mixed alterations. The acute infection is hardly detected and there is not drug to treat the chronic infection. Thus, there is an urgent need for prophylactic and therapeutic vaccines development. Several attempts to find a vaccine antigen has been made and the protein Tc52 is a good candidate. In a vaccine composition, as important as the antigen is the adjuvants, which are substances able to increase, improve or modified the immune response. This research provides information about the immune response and protection against Trypanosoma cruzi infection elicited by Tc52 or portions of this molecule using different adjuvants.
