GSE162760
Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-g signature
Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-g within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-g which triggers their ability to kill the intracellular parasites. Consistent with this, a transcriptional analysis of lesions from patients identified the presence of a strong interferon stimulated gene (ISG) signature. To determine what systemic responses are occurring that might influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients, as well as healthy controls. Functional enrichment analysis identified a transcriptional ISG signature as the dominant response in the blood of patients. An increase in monocytes and macrophages in the blood, estimated from our RNA-seq dataset, was positively correlated with this ISG signature. Consistent with this result, patients had circulating IFN-g in their serum. A cytotoxicity signature, which is a dominant feature in the lesions, was also found in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis – another localized infection – but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria.  Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests that when these cells enter lesions they may already be primed to control the parasites. Overall design: Whole blood samples from patients infected with Leishmania braziliensis (n=50) and from not-infected individuals (n=14)