Transcriptional profiling of the spleen in progressive visceral leishmaniasis reveals mixed expression of type 1 and type 2 cytokine-responsive genes

BMC Immunology

Peter C Melby⁷  Andrew Pekosz¹  Michael Cappello⁵  Audrie A Medina⁶  Mandakini J Patel²  Mark Band⁸  Alvaro Hernandez⁸  E Yaneth Osorio⁴  Bruno L Travi³  Omar A Saldarriaga⁴  Claudia M Espitia² 

[1] Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, Maryland, USA;Department of Medicine, Cancer Therapy and Research Center, Institute for Drug Development, The University of Texas Health Science Center, San Antonio, Texas, USA;Center for Tropical Diseases and Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, USA;Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA;Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA;Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA;Roy J. Carver Biotechnology Center, University of Illinois, Urbana, Illinois, USA

关键词: Interleukin-4;    Interferon-gamma;    Microarray;    Transcriptional profiling;    Visceral leishmaniasis;    Leishmania donovani;    Hamster;   

Others  :  1089867
DOI  :  10.1186/s12865-014-0038-z

 received in 2014-04-09, accepted in 2014-09-15,  发布年份 2014

【 摘 要 】

Background

The Syrian golden hamster (Mesocricetus aureus) has been used as a model to study infections caused by a number of human pathogens. Studies of immunopathogenesis in hamster infection models are challenging because of the limited availability of reagents needed to define cellular and molecular determinants.

Results

We sequenced a hamster cDNA library and developed a first-generation custom cDNA microarray that included 5131 unique cDNAs enriched for immune response genes. We used this microarray to interrogate the hamster spleen response to Leishmania donovani, an intracellular protozoan that causes visceral leishmaniasis. The hamster model of visceral leishmaniasis is of particular interest because it recapitulates clinical and immunopathological features of human disease, including cachexia, massive splenomegaly, pancytopenia, immunosuppression, and ultimately death. In the microarray a differentially expressed transcript was identified as having at least a 2-fold change in expression between uninfected and infected groups and a False Discovery Rate of <5%. Following a relatively silent early phase of infection (at 7 and 14 days post-infection only 8 and 24 genes, respectively, were differentially expressed), there was dramatic upregulation of inflammatory and immune-related genes in the spleen (708 differentially expressed genes were evident at 28 days post-infection). The differentially expressed transcripts included genes involved in inflammation, immunity, and immune cell trafficking. Of particular interest there was concomitant upregulation of the IFN-γ and interleukin (IL)-4 signaling pathways, with increased expression of a battery of IFN-γ- and IL-4-responsive genes. The latter included genes characteristic of alternatively activated macrophages.

Conclusions

Transcriptional profiling was accomplished in the Syrian golden hamster, for which a fully annotated genome is not available. In the hamster model of visceral leishmaniasis, a robust and functional IFN-γ response did not restrain parasite load and progression of disease. This supports the accumulating evidence that macrophages are ineffectively activated to kill the parasite. The concomitant expression of IL-4/IL-13 and their downstream target genes, some of which were characteristic of alternative macrophage activation, are likely to contribute to this. Further dissection of mechanisms that lead to polarization of macrophages toward a permissive state is needed to fully understand the pathogenesis of visceral leishmaniasis.

【 授权许可】

   
2014 Espitia et al.; licensee BioMed Central Ltd.

【 图 表 】

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