Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature

Abstract

Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed 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 a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry.

Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology

“…The top 12 overrepresented SASP genes were associated with recruitment of inflammatory immune cells (CCL3, CCL8, CXCL1, CXCL11, CXCL13, CXCL8); metalloproteinases (MMP1, MMP10 and MMP3) and inflammatory cytokines (IL‐6, IL‐15 and IL‐1β) (Figure 3b, c and Figure ). In addition, other non‐SASP inflammatory cytokines, chemokines and their receptors such as IFN‐γ ( IFNG ), TNF‐α ( TNF ), IL‐23 ( IL23A ), IL‐15 receptor ( IL15RA ), CXCL10, CXCL9, CCL4 and CCR5 were overrepresented in CL lesions (Figure 3C and Figures ), supporting previous findings [13,14,29,37,39]. As expected, most of the DEGs positively correlated with the predicted relative proportions of analysed cell subsets (Figure 3C).…”

“…Although there are few parasites, their presence in the skin tissue is not correlated to the size of the lesions observed in patients. Recent data show that the lesional parasite load directly correlates with the transcriptional signature of inflammatory, cytotoxic mediators and accumulation of cytotoxic CD8 + T cells [61], and these are the main responsible for the tissue pathology [14,29]. The accumulation of senescent and non‐senescent cells in the cellular infiltrate as well as local inflammation may clarify the correlation observed between the parasites and senescence signature.…”

“…This was observed in skin lesions of patients with MCL and CL that demonstrated the enrichment of cytotoxic and pro‐inflammatory cells with a conspicuous capacity to mediate tissue destruction [5,6,9]. Moreover, both cytotoxicity and inflammatory‐related genes are overexpressed in the lesional environment of CL patients that positively correlated with extensive necrosis and lesion size [11–16].…”

Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis

“…In contrast, no DEGs were identified by RNA-seq in whole blood ( Supplemental Figure 4 and Supplemental Table 2 ), suggesting that unlike CL caused by L . braziliensis ( 21 ), CL due to L . donovani in Sri Lanka is not accompanied by an overt systemic immune response.…”

In vivo reprogramming of murine host immune response genes following Leishmania major infection

“…A recent study comparing the gene expression profile of primary cutaneous lesions from L. braziliensis-infected patients with or without pentavalent antimony treatment revealed most of the differentially expressed transcripts were correlated with components of cytotoxicity related pathways and parasite load in the skin (39). While another study using RNA-Seq from the same group revealed a consistent and significant myeloid interferon stimulated gene (ISG) signature in skin lesions from L. braziliensis-infected patients (43). Altogether, these studies revealed that the host immune response upregulates transcripts related to both pro-inflammatory and antiinflammatory responses during leishmaniasis (44,45).…”