Abstract
The various symptomatic outcomes of cutaneous leishmaniasis relates to the type and potency of its underlying inflammatory responses. Presence of the cytoplasmic Leishmania RNA virus-1 (LRV1) within Leishmania guyanensis, worsens lesional inflammation and parasite burden, as the viral dsRNA genome acts as a potent innate immunogen stimulating Toll-Like-Receptor-3 (TLR3). Here we investigated other innate pattern recognition receptors capable of reacting to dsRNA and potentially contributing to LRV1-mediated inflammatory pathology. We included the cytoplasmic dsRNA sensors, namely, the RIG-like receptors (RLRs) and the inflammasome-dependent and -independent Nod-like-receptors (NLRs). Our study found no role for RLRs or inflammasome-dependent NLRs in the pathology of L. guyanensis infection irrespective of its LRV1-status. Further, neither LRV1-bearing L. guyanensis (LgyLRV1+) nor LRV1-negative L. guyanensis (LgyLRV1-) activated the inflammasome in vitro. Interestingly, similarly to L. donovani, L. guyanensis infection induced the up-regulation of the A20 protein, known to be involved in the evasion of inflammasome activation. Moreover, we observed that LgyLRV1+ promoted the transcription of inflammasome-independent NLRC2 (also called NOD2) and NLRC5. However, only NLRC2 showed some contribution to LRV1-dependent pathology. These data confirmed that the endosomal TLR3 pathway is the dominant route of LRV1-dependent signalling, thus excluding the cytosolic and inflammasome pathways. We postulate that avoidance of the inflammasome pathways is likely an important mechanism of virulence in Leishmania infection irrespective of the LRV1-status.
Highlights
The human protozoan parasite Leishmania is highly immuno-stimulatory, presenting to the host cell a variety of potent pathogen-associated molecular patterns (PAMPs) that shape the outcome of the inflammatory skin disease known as cutaneous leishmaniasis (CL) [1]
We previously revealed that the dsRNA genome of an endosymbiotic virus within virulent Leishmania species is able to act as a potent innate immunogen that worsens the outcome of cutaneous disease [5]
We showed the essential role of TLR3, we could not formally exclude the role of other pattern recognition receptor (PRR) in leishmaniasis such as the RIG-like receptors (RLRs) and various members of the NOD-like receptors (NLRs)
Summary
The human protozoan parasite Leishmania is highly immuno-stimulatory, presenting to the host cell a variety of potent pathogen-associated molecular patterns (PAMPs) that shape the outcome of the inflammatory skin disease known as cutaneous leishmaniasis (CL) [1]. The various symptomatic outcomes of CL can be categorised by the type and potency of its underlying inflammatory response: ranging from a single, self-healing lesion at the site of inoculation to chronic hyper-inflammatory tissue destruction and the establishment of disfiguring metastatic lesions that are refractory to routine therapies [2]. These inflammatory responses have a high-degree of species-specificity, where metastatic and chronic complications occur mainly in infections of the Leishmania Viannia subgenus found in Central and South America [3] [4]. The presence of LRV1 in L. guyanensis and L. braziliensis negatively affects the patients response to anti-Leishmania drugs, as it is predictive of treatment failure and symptomatic relapses [8, 9], and potentially worsens the disease outcome in patients coinfected with HIV [10]
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