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1.
Isabela Resende Pereira Glaucia Vilar-Pereira Virgínia Marques Andrea Alice da Silva Bráulia Caetano Otacilio Cruz Moreira Alexandre Vieira Machado Oscar Bruna-Romero Maurício Martins Rodrigues Ricardo Tostes Gazzinelli Joseli Lannes-Vieira 《PLoS pathogens》2015,11(1)
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naïve C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)γ-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNγ-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNγ+ cells, increased the expression of IFNγ mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas’ heart disease. 相似文献
2.
Rafael Rodrigues Silva Rafael M. Mariante Andrea Alice Silva Ana Luiza Barbosa dos Santos Ester Roffê Helton Santiago Ricardo Tostes Gazzinelli Joseli Lannes-Vieira 《PloS one》2015,10(2)
The inflammatory cytokine interferon-gamma (IFNγ) is crucial for immunity against intracellular pathogens such as the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (CD). IFNγ is a pleiotropic cytokine which regulates activation of immune and non-immune cells; however, the effect of IFNγ in the central nervous system (CNS) and astrocytes during CD is unknown. Here we show that parasite persists in the CNS of C3H/He mice chronically infected with the Colombian T. cruzi strain despite the increased expression of IFNγ mRNA. Furthermore, most of the T. cruzi-bearing cells were astrocytes located near IFNγ+ cells. Surprisingly, in vitro experiments revealed that pretreatment with IFNγ promoted the infection of astrocytes by T. cruzi increasing uptake and proliferation of intracellular forms, despite inducing increased production of nitric oxide (NO). Importantly, the effect of IFNγ on T. cruzi uptake and growth is completely blocked by the anti-tumor necrosis factor (TNF) antibody Infliximab and partially blocked by the inhibitor of nitric oxide synthesis L-NAME. These data support that IFNγ fuels astrocyte infection by T. cruzi and critically implicate IFNγ-stimulated T. cruzi-infected astrocytes as sources of TNF and NO, which may contribute to parasite persistence and CNS pathology in CD. 相似文献
3.
Rodrigo Nunes Rodrigues-da-Silva Jo?o Hermínio Martins da Silva Balwan Singh Jianlin Jiang Esmeralda V. S. Meyer Fátima Santos Dalma Maria Banic Alberto Moreno Mary R. Galinski Joseli Oliveira-Ferreira Josué da Costa Lima-Junior 《PloS one》2016,11(1)
Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and experimentally confirmed the potential of PvMSP9E795-A808 as an immunogenic linear B cell epitope within the P. vivax malaria vaccine candidate PvMSP9 and support its inclusion in future subunit vaccines. 相似文献
4.
Kroll-Palhares K Silvério JC Silva AA Michailowsky V Marino AP Silva NM Carvalho CM Pinto LM Gazzinelli RT Lannes-Vieira J 《Memórias do Instituto Oswaldo Cruz》2008,103(4):375-385
In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-alpha levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-alpha, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-alpha+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy. 相似文献
5.
The participation of cell adhesion molecules (CAMs) in the establishment of autoimmune and infectious myocarditis is an important matter of investigation and may have therapeutic implication. Trypanosoma cruzi infection induces a CD8-mediated myocarditis in patients with severe cardiomyopathy and experimental animals. Previously, we have proposed that this predominance of CD8+ T-cells is, at least in part, consequence of the differential expression of CAMs on circulating CD8+ lymphocytes. In the present study we investigated the participation of CAMs in shaping the phenotypic nature of the autoimmune CD4-mediated myosin-induced and the CD8-mediated T. cruzi-elicited myocarditis. We provide evidence that the prevalence of a certain T-cell subset inside the inflamed heart reflects the differential profile of the adhesion molecules VLA-4, LFA-1, and ICAM-1 displayed on a large proportion of this particular T-cell population in peripheral blood during the early phase of inflammation. Further, the expression of VCAM-1, ligand for VLA-4, and ICAM-1, counter-receptor for LFA-1, was up-regulated on vascular endothelium and paralleled the entrance of inflammatory cells into the cardiac tissue. Thus, this up-regulated expression of receptors-counter-receptors that regulate T-cell transmigration through the vascular endothelium may have an important role in the pathogenesis of the early phase of both autoimmune and infectious myocarditis. 相似文献
6.
Isabela Resende Pereira Glaucia Vilar-Pereira Otacilio Cruz Moreira Isalira Peroba Ramos Daniel Gibaldi Constan?a Britto Milton Ozório Moraes Joseli Lannes-Vieira 《PLoS neglected tropical diseases》2015,9(3)
BackgroundChronic chagasic cardiomyopathy (CCC), the main clinical sign of Chagas disease, is associated with systemic CD8+ T-cell abnormalities and CD8-enriched myocarditis occurring in an inflammatory milieu. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has immunoregulatory and cardioprotective properties. Here, we tested PTX effects on CD8+ T-cell abnormalities and cardiac alterations using a model of experimental Chagas’ heart disease.Conclusions/SignificancePTX therapy ameliorates critical aspects of CCC and repositioned CD8+ T-cell response towards homeostasis, reinforcing that immunological abnormalities are crucially linked, as cause or effect, to CCC. Therefore, PTX emerges as a candidate to treat the non-beneficial immune deregulation associated with chronic Chagas'' heart disease and to improve prognosis. 相似文献
7.
Marino AP Silva AA Santos PV Pinto LM Gazinelli RT Teixeira MM Lannes-Vieira J 《Memórias do Instituto Oswaldo Cruz》2005,100(Z1):93-96
The comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate new therapeutic strategies aiming to ameliorate the inflammation that leads to heart dysfunction, without hampering parasite control. The augmented expression of CCL5/RANTES and CCL3/MIP-1alpha, and their receptor CCR5, in the heart of T. cruzi-infected mice suggests a role for CC-chemokines and their receptors in the pathogenesis of T. cruzi-elicited myocarditis. Herein, we discuss our recent results using a CC-chemokine receptor inhibitor (Met-RANTES), showing the participation of CC-chemokines in T. cruzi infection and unraveling CC-chemokine receptors as an attractive therapeutic target for further evaluation in Chagas disease. 相似文献
8.
Isabela Resende Pereira Glaucia Vilar-Pereira Andrea Alice da Silva Joseli Lannes-Vieira 《Memórias do Instituto Oswaldo Cruz》2014,109(3):289-298
Heart tissue inflammation, progressive fibrosis and electrocardiographic alterations
occur in approximately 30% of patients infected by Trypanosoma
cruzi, 10-30 years after infection. Further, plasma levels of tumour
necrosis factor (TNF) and nitric oxide (NO) are associated with the degree of heart
dysfunction in chronic chagasic cardiomyopathy (CCC). Thus, our aim was to establish
experimental models that mimic a range of parasitological, pathological and cardiac
alterations described in patients with chronic Chagas’ heart disease and evaluate
whether heart disease severity was associated with increased TNF and NO levels in the
serum. Our results show that C3H/He mice chronically infected with the Colombian
T. cruzi strain have more severe cardiac parasitism and
inflammation than C57BL/6 mice. In addition, connexin 43 disorganisation and
fibronectin deposition in the heart tissue, increased levels of creatine kinase
cardiac MB isoenzyme activity in the serum and more severe electrical abnormalities
were observed in T. cruzi-infected C3H/He mice compared to C57BL/6
mice. Therefore, T. cruzi-infected C3H/He and C57BL/6 mice represent
severe and mild models of CCC, respectively. Moreover, the CCC severity paralleled
the TNF and NO levels in the serum. Therefore, these models are appropriate for
studying the pathophysiology and biomarkers of CCC progression, as well as for
testing therapeutic agents for patients with Chagas’ heart disease. 相似文献
9.
Anielle de Pina-Costa Patrícia Brasil Sílvia Maria Di Santi Mariana Pereira de Araujo Martha Cecilia Suárez-Mutis Ana Carolina Faria e Silva Santelli Joseli Oliveira-Ferreira Ricardo Louren?o-de-Oliveira Cláudio Tadeu Daniel-Ribeiro 《Memórias do Instituto Oswaldo Cruz》2014,109(5):618-633
Brazil, a country of continental proportions, presents three profiles of malaria
transmission. The first and most important numerically, occurs inside the Amazon. The
Amazon accounts for approximately 60% of the nation’s territory and approximately 13%
of the Brazilian population. This region hosts 99.5% of the nation’s malaria cases,
which are predominantly caused by Plasmodium vivax (i.e., 82% of
cases in 2013). The second involves imported malaria, which corresponds to malaria
cases acquired outside the region where the individuals live or the diagnosis was
made. These cases are imported from endemic regions of Brazil (i.e., the Amazon) or
from other countries in South and Central America, Africa and Asia. Imported malaria
comprised 89% of the cases found outside the area of active transmission in Brazil in
2013. These cases highlight an important question with respect to both therapeutic
and epidemiological issues because patients, especially those with falciparum
malaria, arriving in a region where the health professionals may not have experience
with the clinical manifestations of malaria and its diagnosis could suffer dramatic
consequences associated with a potential delay in treatment. Additionally, because
the Anopheles vectors exist in most of the country, even a single
case of malaria, if not diagnosed and treated immediately, may result in introduced
cases, causing outbreaks and even introducing or reintroducing the disease to a
non-endemic, receptive region. Cases introduced outside the Amazon usually occur in
areas in which malaria was formerly endemic and are transmitted by competent vectors
belonging to the subgenus Nyssorhynchus (i.e., Anopheles
darlingi, Anopheles aquasalis and species of the Albitarsis complex). The
third type of transmission accounts for only 0.05% of all cases and is caused by
autochthonous malaria in the Atlantic Forest, located primarily along the
southeastern Atlantic Coast. They are caused by parasites that seem to be (or to be
very close to) P. vivax and, in a less extent, by Plasmodium
malariae and it is transmitted by the bromeliad mosquito
Anopheles (Kerteszia) cruzii. This paper deals mainly with the two
profiles of malaria found outside the Amazon: the imported and ensuing introduced
cases and the autochthonous cases. We also provide an update regarding the situation
in Brazil and the Brazilian endemic Amazon. 相似文献
10.
Michailowsky V Celes MR Marino AP Silva AA Vieira LQ Rossi MA Gazzinelli RT Lannes-Vieira J Silva JS 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(1):463-470
In this study, we investigated the involvement of Th1 cytokines in the expression of cell adhesion molecules (CAM) and recruitment of inflammatory cells to the heart of mice infected with Trypanosoma cruzi. Our results show that endogenously produced IFN-gamma is essential to induce optimal expression of VCAM-1 and ICAM-1 on the cardiac vascular endothelium of infected mice. Furthermore, the influx of inflammatory cells into the cardiac tissue was impaired in Th1 cytokine-deficient infected mice, paralleling the intensity of VCAM-1 and ICAM-1 expression on the vascular endothelium. Consistent with the importance of ICAM-1 in host resistance, ICAM-1 knockout (KO) mice were highly susceptible to T. cruzi infection, as assessed by mortality rate, parasitemia, and heart tissue parasitism. The enhanced parasitism was associated with a decrease in the numbers of CD4(+) and CD8(+) T lymphocytes in the heart tissue of ICAM-1 KO mice. Additionally, ICAM-1 KO mice mounted an unimpaired IFN-gamma response and IFN-gamma-dependent production of reactive nitrogen intermediates and parasite- specific IgG2a. Supporting the participation of ICAM-1 in cell migration during T. cruzi infection, the entrance of adoptively transferred PBL from T. cruzi-infected wild-type C57BL/6 mice into the cardiac tissue of ICAM-1 KO mice was significantly abrogated. Therefore, we favor the hypothesis that ICAM-1 plays a crucial role in T lymphocyte recruitment to the cardiac tissue and host susceptibility during T. cruzi infection. 相似文献