A systemic inflammatory response primes blood monocytes in cutaneous leishmaniasis

Abstract

Abstract Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-y within lesions. Phagocytic cells recruited to lesions are exposed to IFN-y which triggers their ability to kill the intracellular parasites. To determine what systemic responses are occurring that might influence the disease, we performed RNA sequencing (RNA-seq) on the blood of 50 L. braziliensis-infected patients, as well as 14 healthy controls. Genes reflecting Interferon downstream activation such as GBP1-6, STAT1, IDO1, AIM2, BATF2, SOCS1 and FCGR-related genes, were upregulated in patients and functional enrichment analysis identified a transcriptional type II Interferon-stimulated gene (ISG) signature as the dominant response. An increase in monocytes and macrophages in the blood, estimated from our RNA-seq dataset, was positively correlated with this type II ISG signature. Consistent with this result, patients had circulating IFN-y in their serum. Monocytes in the bone marrow and circulating in the blood of mice infected with leishmania exhibited increased expression of Class II, further supporting the premise that there is a systemic response to infection. Together, these results suggest that there is a mechanism to limit systemic spread of the parasites, as well as enhance parasite control by pre-activating cells prior to lesion entry.