Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Abstract

The presence of the endogenous Leishmania RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured Leishmania guyanensis (LgyLRV1 − ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing (LgyLRV1 + ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with L. guyanensis and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of L. guyanensis infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the LgyLRV1 + metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from L. guyanensis infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World Leishmania parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.Leishmania RNA virus 1 | Totiviridae | arboviruses | trypanosomatid protozoan parasite | Leishmania subgenus Viannia

Neutrophil elastase promotes Leishmania donovani infection via interferon‐β

“…It would be interesting to investigate whether the NE-induced IFN-b requirement for intracellular growth is a common trait for other L. donovani strains, including the reference strain in which the ISP2 gene is truncated. Recently, a role for IFN-b in promoting metastatic spread of L. guyanensis and relapse of infection was reported, associating antiviral responses to disease sustenance and severity (41). It is tempting to speculate that production of IFN-b is a common trait between Leishmania sp.…”

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis

“…Examination of mRNA isolated from peripheral blood mononuclear cells (PBMCs) from VL patients before and after drug treatment, and ECs showed increased IFNA1, IFNB1, IFNAR1, and IFNAR2 transcripts in VL patient cells before drug treatment relative to post-treatment and EC samples (Figures 2A and 2B). Furthermore, expression of IFNA1 and IFNB1 was highest in CD1c + DCs relative to B cells (CD19 + ) and monocytes (CD14 + ) ( Figure 2C), other likely cellular sources of these cytokines in experimental leishmaniasis (Rossi et al, 2017; Silva-Barrios (C) The type I interferon (IFN) signaling pathway was identified as a canonical pathway (Z score of 2.828, p = 1.38 3 10 À4 ) in CD4 + T cells from VL patients by Ingenuity Pathways Analysis. The pathway visualization shows upregulated (red) and downregulated (green) genes within the dataset, relative to CD4 + T cells (legend continued on next page) et al, 2016).…”

A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

“…A notable difference is that LRV is an endogenous viral element of the parasite itself while LDV is an exogenous mouse-specific virus that is co-hosted in Plasmodium-parasitized blood. Nevertheless, it was observed that the aggravation and metastasis of Leishmania lesions were not exclusively associated with LRV and that they could also be enhanced by co-infection with exogenous viruses 76 .…”