RESUMO
Cerebral malaria (CM) is a neurological complication derived from the Plasmodium falciparum infection in humans. The mechanisms involved in the disease progression are still not fully understood, but both the sequestration of infected red blood cells (iRBC) and leukocytes and an exacerbated host inflammatory immune response are significant factors. In this study, we investigated the effect of Monocyte Locomotion Inhibitory Factor (MLIF), an anti-inflammatory peptide, in a well-characterized murine model of CM. Our data showed that the administration of MLIF increased the survival and avoided the neurological signs of CM in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. MLIF administration down-regulated systemic inflammatory mediators such as IFN-γ, TNF-α, IL-6, CXCL2, and CCL2, as well as the in situ expression of TNF-α in the brain. In the same way, MLIF reduced the expression of CD31, CD36, CD54, and CD106 in the cerebral endothelium of infected animals and prevented the sequestration of iRBC and leucocytes in the brain microvasculature. Furthermore, MLIF inhibited the activation of astrocytes and microglia and preserved the integrity of the blood-brain barrier (BBB). In conclusion, our results demonstrated that the administration of MLIF increased survival and conferred neuroprotection by decreasing neuroinflammation in murine CM.
Assuntos
Anti-Inflamatórios/administração & dosagem , Malária Cerebral/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Oligopeptídeos/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Malária Cerebral/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Plasmodium berghei/imunologiaRESUMO
The host response against Mycobacterium tuberculosis show a wide spectrum of clinical manifestations in those patients who fail to control the infection. The course of the infection and its epidemiological consequences depend upon a complex interplay of host, environmental and bacterial factors. Experimental animal models have helped to define the influence of bacterial genetic diversity on virulence and on the immune response that is induced. For this purpose, experimental animals such as mice, guinea pigs and rabbits have been infected with selected clinical isolates obtained from outbreaks or from clinical epidemiology settings. Here we review the contribution of mouse models to defining the variability in virulence and immune response in relation to mycobacterial genetic diversity. Low dose aerosol infection in C57Bl mice or high dose intratracheal infection in BALB/c mice have demonstrated wide variability in virulence and immune responses induced by different bacterial genotypes, and each genotype has different phenotypes, with high and low virulence variants. In general, these studies have shown that high prevalent strains from big clusters are more virulent than low prevalent sporadic clinical isolates, and highly virulent strains induce non-protective immune responses with some correlation with clinical-epidemiological data. In the future selected strains from these types of studies should be analyzed with molecular technologies. These kinds of study will contribute to the identification of mycobacterial genes associated with virulence and immunogenicity.