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Diego M Santos,
Marcia W Carneiro,
Tatiana R de Moura,
Manuel Soto, Nívea F Luz,
Deboraci B Prates,
Juan Manuel Irache,
Claudia Brodskyn,
Aldina Barral,
Manoel Barral-Netto,
Socorro Espuelas,
Valéria M Borges,
Camila I de Oliveira
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ABSTRACT: We recently demonstrated that immunization with polyester poly (lactide-co-glycolide acid) (PLGA) nanoparticles loaded with the 11 kDa Leishmania vaccine candidate Kinetoplastid Membrane Protein 11 (KMP-11) significantly reduced parasite load in vivo. Presently, we explored the ability of the recombinant PLGA nanoparticles to stimulate innate responses in macrophages and the outcome of infection with L. braziliensis in vitro. Incubation of macrophages with KMP-11-loaded PLGA nanoparticles significantly decreased parasite load. In parallel, we observed augmented production of nitric oxide, superoxide, TNF-α and IL-6. An increased release of CCL2/MCP-1 and CXCL1/KC was also observed, resulting in macrophage and neutrophil recruitment in vitro. Lastly, the incubation of macrophages with KMP-11-loaded PLGA nanoparticles triggered activation of caspase-1 and the secretion of IL-1β and IL-18, suggesting inflammasome participation. Inhibition of caspase-1 significantly increased the parasite load. We conclude that KMP-11-loaded PLGA nanoparticles promote the killing of intracellular Leishmania parasites through the induction of potent innate responses.
Nanomedicine: nanotechnology, biology, and medicine 04/2013; · 5.44 Impact Factor
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Nívea F Luz,
Bruno B Andrade,
Daniel F Feijó,
Théo Araújo-Santos,
Graziele Q Carvalho,
Daniela Andrade,
Daniel R Abánades,
Enaldo V Melo,
Angela M Silva,
Cláudia I Brodskyn,
Manoel Barral-Netto,
Aldina Barral,
Rodrigo P Soares,
Roque P Almeida,
Marcelo T Bozza,
Valéria M Borges
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ABSTRACT: Visceral leishmaniasis (VL) remains a major public health problem worldwide. This disease is highly associated with chronic inflammation and a lack of the cellular immune responses against Leishmania. It is important to identify major factors driving the successful establishment of the Leishmania infection to develop better tools for the disease control. Heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, and its role in VL has not been investigated. In this study, we evaluated the role of HO-1 in the infection by Leishmania infantum chagasi, the causative agent of VL cases in Brazil. We found that L. chagasi infection or lipophosphoglycan isolated from promastigotes triggered HO-1 production by murine macrophages. Interestingly, cobalt protoporphyrin IX, an HO-1 inductor, increased the parasite burden in both mouse and human-derived macrophages. Upon L. chagasi infection, macrophages from Hmox1 knockout mice presented significantly lower parasite loads when compared with those from wild-type mice. Furthermore, upregulation of HO-1 by cobalt protoporphyrin IX diminished the production of TNF-α and reactive oxygen species by infected murine macrophages and increased Cu/Zn superoxide dismutase expression in human monocytes. Finally, patients with VL presented higher systemic concentrations of HO-1 than healthy individuals, and this increase of HO-1 was reduced after antileishmanial treatment, suggesting that HO-1 is associated with disease susceptibility. Our data argue that HO-1 has a critical role in the L. chagasi infection and is strongly associated with the inflammatory imbalance during VL. Manipulation of HO-1 pathways during VL could serve as an adjunctive therapeutic approach.
The Journal of Immunology 03/2012; 188(9):4460-7. · 5.79 Impact Factor
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ABSTRACT: Intravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of the HMOX1 and Hp genes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)n repeats in the microsatellite polymorphism region of the HMOX1 gene, the Hp2 allele, and the Hp2.2 genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria.
Infection and immunity 01/2012; 80(4):1445-54. · 4.21 Impact Factor
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Bruno B Andrade,
Cristiane J N Santos,
Luís M Camargo,
Sebastião M Souza-Neto,
Antonio Reis-Filho,
Jorge Clarêncio,
Vitor R R Mendonça, Nívea F Luz,
Erney P Camargo,
Aldina Barral,
Antônio A M Silva,
Manoel Barral-Netto
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ABSTRACT: Areas that are endemic for malaria are also highly endemic for hepatitis B virus (HBV) infection. Nevertheless, it is unknown whether HBV infection modifies the clinical presentation of malaria. This study aimed to address this question.
An observational study of 636 individuals was performed in Rondônia, western Amazon, Brazil between 2006 and 2007. Active and passive case detections identified Plasmodium infection by field microscopy and nested Polymerase Chain Reaction (PCR). HBV infections were identified by serology and confirmed by real-time PCR. Epidemiological information and plasma cytokine profiles were studied. The data were analyzed using adjusted multinomial logistic regression. Plasmodium-infected individuals with active HBV infection were more likely to be asymptomatic (OR: 120.13, P<0.0001), present with lower levels of parasitemia and demonstrate a decreased inflammatory cytokine profile. Nevertheless, co-infected individuals presented higher HBV viremia. Plasmodium parasitemia inversely correlated with plasma HBV DNA levels (r = -0.6; P = 0.0003).
HBV infection diminishes the intensity of malaria infection in individuals from this endemic area. This effect seems related to cytokine balance and control of inflammatory responses. These findings add important insights to the understanding of the factors affecting the clinical outcomes of malaria in endemic regions.
PLoS ONE 01/2011; 6(5):e19841. · 4.09 Impact Factor
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ABSTRACT: In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE(2) and TGF-beta in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE(2) and TGF-beta than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-alpha. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE(2) and TGF-beta increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE(2) and TGF-beta partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches.
The Journal of Immunology 07/2010; 185(2):1196-204. · 5.79 Impact Factor
