This study aims to characterize the intra-specific variability of virulence in Leishmania infantum zymodeme MON-1 strains isolated from dogs and immunocompetent and immunosuppressed patients through the evaluation of growth pattern, infective ability and immunopathogenicity. Two of the strains, classified as the most virulent, presented higher levels of macrophage infection, increased promastigote replication in culture medium and as well as amastigote multiplication within macrophages. These strains caused the most pathogenic infection inducing splenomegalia and maximum parasite loads in spleen and liver of BALB/c mice. The other strains exhibited either low virulence, with reduced infective capability and low replication levels, or an intermediate virulent phenotype showing mixed features similar to low and high virulent phenotypes. A correlation between the infectivity, growth dynamics and pathogenicity of each strain and the humoral and cellular immune response was demonstrated. Strains with accentuated virulent phenotype induced higher levels of anti-Leishmania IgG1 antibodies and TGF-beta but reduced production of IFN-gamma. Virulence phenotype seems to be a characteristic of each strain regardless of the host (dog or human) from which it was firstly isolated.
"According to Maia et al. , dermotropic and viscerotropic L. infantum strains modulate the sand fly biting time on the host leading to the delivery, respectively, of a high or low dose of metacyclic promastigotes into the skin which will impact on the parasite tropism and manifestation of the disease. Even strains belonging to the same zymodeme have been associated to differential infectivity . "
[Show abstract][Hide abstract] ABSTRACT: Background
Leishmaniasis is a group of diseases with a variety of clinical manifestations. The form of the disease is highly dependent on the infective Leishmania species and the immunological status of the host. The infectivity of the parasite strain also plays an important role in the progression of the infection. The aim of this work is to understand the influence of the natural infectivity of Leishmania strains in the outcome of visceral leishmaniasis.
In this study we have characterized four strains of L. infantum in terms of molecular typing, in vitro cultivation and differentiation. Two strains were isolated from HIV+ patients with visceral leishmaniasis (Bibiano and E390M), one strain was isolated from a cutaneous lesion in an immunocompetent patient (HL) and another internal reference strain causative of visceral leishmaniasis (ST) also from an immunocompetent patient was used for comparison. For this objective, we have compared their virulence by in vitro and in vivo infectivity in a murine model of visceral leishmaniasis.
Molecular typing unraveled a new k26 sequence attributed to MON-284 zymodeme and allowed the generation of a molecular signature for the identification of each strain. In vitro cultivation enabled the production of promastigotes with comparable growth curves and metacyclogenesis development. The HL strain was the most infective, showing the highest parasite loads in vitro that were corroborated with the in vivo assays, 6 weeks post-infection in BALB/c mice. The two strains isolated from HIV+ patients, both belonging to two different zymodemes, revealed different kinetics of infection.
Differences in in vitro and in vivo infectivity found in the murine model were then attributed to intrinsic characteristics of each strain. This work is supported by other studies that present the parasite’s inherent features as factors for the multiplicity of clinical manifestations and severity of leishmaniasis.
"Among the escape mechanisms present in the genus Leishmania, is its ability to release cathepsin B, a protease able to cleave the latent form of TGF-β into its active form, which has immunosuppressive properties, helping to prolong the survival of the parasite in macrophages (Wilson et al. 2005). Besides the escape mechanisms of the parasite, other factors could contribute to the maintenance of infection such as different virulence strains (Baptista-Fernandes et al. 2007), genetic background of the host (Fowell and Locksley 1999; Lipoldová et al. 2000), concomitant infections (Barral-Netto et al. 1995; Hassan et al. 2006; Rodríguez-Sosa et al. 2006), the number of bites and effect of the saliva of infected sand flies (Mbow et al. 1998; De Moura et al. 2007; Oliveira et al. 2008), and also by nutritional factors (Anstead et al. 2001). "
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO), the product of the nitric oxide synthase enzymes has been detected in Leishmania-infected animals. Besides its role on the immunity to infection, the role of NO and the inducible nitric oxide synthase (iNOS) in the pathogenesis of canine visceral leishmaniasis (CVL) is not well understood. This study aimed at evaluating immunohistochemically the iNOS expression in the spleen of dogs naturally infected (ID) with Leishmania (L.) chagasi compared with non-infected dogs (NID). The ID was grouped according to the clinical form and the parasite load. Symptomatic dogs (SD) presented higher parasite load in relation to oligosymptomatic (OD) and asymptomatic (AD). The qualitative expression of iNOS was observed only in ID. SD presented strong and prominent labeling of iNOS, followed by OD and AD. Quantitatively, the results showed that the median expression of iNOS was higher in SD and OD compared to NID. Also, dog spleens with high parasitism load showed marked iNOS expression. Taken together, the results suggest that the expression of iNOS in the spleen of infected dogs with CVL was associated with clinical worsening of the disease and with high parasitism.
Parasitology Research 12/2010; 108(6):1397-403. DOI:10.1007/s00436-010-2183-5 · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This work aims to study the influence of H-2 locus in the control of Leishmania infantum infection by evaluating whether cytokine responses by host macrophages of different H-2 haplotype are differentially regulated, either induced or actively impaired during parasite growth and replication. This study shows that macrophages of "non-cure" phenotype (H-2(d)) are more susceptible to infection with virulent L. infantum promastigotes. Virulent parasites lead to impaired IL-12 and inhibited TNF-alpha expression. The degree of parasite virulence is an important contributing factor to differences detected in cytokine expression. Virulent parasites also induced TGF-beta, a deactivating cytokine that is known to suppress Th-1 type responses, thus allowing the parasite to subvert antimicrobial activity and increase its chances of survival. Depending on specific host haplotype, cells differentially respond to infection since TNF-alpha expression is inhibited and TGF-beta is enhanced by macrophages of "non-cure" phenotype, thus perhaps determining their degree of susceptibility in this strain of mice.
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