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Early Transcriptional Liver Signatures in Experimental Visceral Leishmaniasis

ABSTRACT: Transcriptional analysis of complex biological scenarios has been used extensively, even though sometimes the results of such analysis may prove imprecise or difficult to interpret due to an overwhelming amount of information. In this study, a large-scale real-time qPCR experiment was coupled to multivariate statistical analysis in order to describe the main immunological events underlying the early L. infantum infection in livers of BALB/c mice. High-throughput qPCR was used to evaluate the expression of 223 genes related to immunological response and metabolism 1, 3, 5, and 10 days post infection. This integrative analysis showed strikingly different gene signatures at 1 and 10 days post infection, revealing the progression of infection in the experimental model based on the upregulation of particular immunological response patterns and mediators. The gene signature 1 day post infection was not only characterized by the upregulation of mediators involved in interferon signaling and cell chemotaxis, but also the upregulation of some inhibitory markers. In contrast, at 10 days post infection, the upregulation of many inflammatory and Th1 markers characterized a more defined gene signature with the upregulation of mediators in the IL-12 signaling pathway. Our results reveal a significant connection between the expression of innate immune response and metabolic and inhibitory markers in early L. infantum infection of the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE159195 | GEO | 2021/07/12

REPOSITORIES: GEO

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Project description:Leishmania spp. is a protozoan parasite that affects millions of people around the world. At present, there is no effective vaccine to prevent leishmaniases in humans. A major limitation in vaccine development is the lack of precise understanding of the particular immunological mechanisms that allow parasite survival in the host. The parasite-host cell interaction induces dramatic changes in transcriptome patterns in both organisms, therefore, a detailed analysis of gene expression in infected tissues will contribute to the evaluation of drug and vaccine candidates, the identification of potential biomarkers, and the understanding of the immunological pathways that lead to protection or progression of disease. High-throughput real-time quantitative PCR is a highly sensitive, and specific technique that allows analysis of gene expression in multiple genes at the same time. Hence, it is an interesting approach that may bring light to this complex topic. In this large-scale analysis, forty-seven BALB/c mice were divided in two groups: control mice and mice infected with L. infantum promastigotes. After infection animals were sacrificed at different timepoints, RNA was purified from spleens and expression of 112 genes related with immune system was determined by high-throughput qPCR. These extensive gene-expression analyses reveal a selective recruitment of lymphocytes to the spleen and an immunosuppressive response, which favors parasite persistence, in early stages of the infection. In later stages of infection, gene-expression patterns suggest an inflammatory process that should resolve infection. Nevertheless, a detailed analysis reveals that L. infantum infection induces a regulatory process that counteracts the Th1/M1 response. Given the results, it seems clear that gene expression signature analysis is a useful tool to identify the mechanisms involved in disease outcome and to establish a rational approach for the identification of potential biomarkers useful for monitoring disease progression, new therapies or vaccine development in Leishmaniases.

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Early Transcriptional Liver Signatures in Experimental Visceral Leishmaniasis

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