Leishmania RNA virus: when the host pays the toll

Abstract

The presence of an RNA virus in a South American subgenus of the Leishmania parasite, L. (Viannia), was detected several decades ago but its role in leishmanial virulence and metastasis was only recently described. In Leishmania guyanensis, the nucleic acid of Leishmania RNA virus (LRV1) acts as a potent innate immunogen, eliciting a hyper-inflammatory immune response through toll-like receptor 3 (TLR3). The resultant inflammatory cascade has been shown to increase disease severity, parasite persistence, and perhaps even resistance to anti-leishmanial drugs. Curiously, LRVs were found mostly in clinical isolates prone to infectious metastasis in both their human source and experimental animal model, suggesting an association between the viral hyperpathogen and metastatic complications such as mucocutaneous leishmaniasis (MCL). MCL presents as chronic secondary lesions in the mucosa of the mouth and nose, debilitatingly inflamed and notoriously refractory to treatment. Immunologically, this outcome has many of the same hallmarks associated with the reaction to LRV: production of type 1 interferons, bias toward a chronic Th1 inflammatory state and an impaired ability of host cells to eliminate parasites through oxidative stress. More intriguing, is that the risk of developing MCL is found almost exclusively in infections of the L. (Viannia) subtype, further indication that leishmanial metastasis is caused, at least in part, by a parasitic component. LRV present in this subgenus may contribute to the destructive inflammation of metastatic disease either by acting in concert with other intrinsic “metastatic factors” or by independently preying on host TLR3 hypersensitivity. Because LRV amplifies parasite virulence, its presence may provide a unique target for diagnostic and clinical intervention of metastatic leishmaniasis. Taking examples from other members of the Totiviridae virus family, this paper reviews the benefits and costs of endosymbiosis, specifically for the maintenance of LRV infection in Leishmania parasites, which is often at the expense of its human host.

Correlation between presence of Leishmania RNA virus 1 and clinical characteristics of nasal mucosal leishmaniosis

“…The exaggeration in Th1 response causes destruction of soft tissues where the antigenic particles are located. 14,18,19 Recently, Ives et al demonstrated that the parasitism of Leishmania by the Leishmania RNA virus 1 (LRV1), a double-stranded RNA virus of Totviridae family, increases the concentration of cytokines and chemokines (TNF-␣, CXCL10, CCL5, IL-6) in TLR3/TRIF-mediated macrophages of L. guyanensis clones. In this study there was a high potential for metastasis in guinea pigs, indicating that the nucleic acids of the endosymbiotic virus function as strong immunogens, and cause destructive mucosal inflammation.…”

“…In the assessment of the genetic evolution among LRV types and among Leishmania species infected with these viruses, there is evidence of a parallelism in the evolution of Leishmania and LRV. 19,20 The model suggests that innate recognition of LRV1 occurs in the first hours of infection. Viral dsRNA release occurs from dead parasites; then the particle binds to the Toll-like receptor 3 (TLR3) and triggers the inflammatory cascade that aggravates the disease, perhaps representing the main determinant of its severity.…”

“…21 Thus, the detection of LRV can have clinical importance, guiding therapy and prognosis. 13,16,19,21 Despite the detection of LRV1 in large metastatic strains of L. braziliensis and L. guyanensis, metastases may occur in its absence. 19,22 LRV discovery as an innate immunogen, changing the course of leishmaniosis, should motivate further research on such viral hyperpathogens in other infections.…”

“…13,16,19,21 Despite the detection of LRV1 in large metastatic strains of L. braziliensis and L. guyanensis, metastases may occur in its absence. 19,22 LRV discovery as an innate immunogen, changing the course of leishmaniosis, should motivate further research on such viral hyperpathogens in other infections. 19 The methods routinely used in the diagnosis of cutaneous leishmaniosis are limited for mucosal lesions.…”

Antileishmanial effects of the alkaloid-rich fraction of Quassia amara L.

“…They are considered endemic in 98 countries and have a broad spectrum of clinical manifestations ranging from disfiguring skin lesions, known as tegumentary leishmaniasis (TL) to the visceral form of the disease, visceral leishmaniasis (VL) or kala-azar, that can lead to death (Hartley et al, 2012;Rebbestad et al, 2012). Brazil possesses the highest incidence of TL and VL with 26,008 and 3,481 cases reported, respectively (Roqueline et al, 2014).…”