Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for Human Leishmaniasis Caused byLeishmania braziliensisin Peru and Bolivia

Abstract

Cutaneous and mucosal leishmaniasis, caused in South America by Leishmania braziliensis, is difficult to cure by chemotherapy (primarily pentavalent antimonials [Sb(V)]). Treatment failure does not correlate well with resistance in vitro, and the factors responsible for treatment failure in patients are not well understood. Many isolates of L. braziliensis (>25%) contain a double-stranded RNA virus named Leishmaniavirus 1 (LRV1), which has also been reported in Leishmania guyanensis, for which an association with increased pathology, metastasis, and parasite replication was found in murine models. Here we probed the relationship of LRV1 to drug treatment success and disease in 97 L. braziliensis-infected patients from Peru and Bolivia. In vitro cultures were established, parasites were typed as L. braziliensis, and the presence of LRV1 was determined by reverse transcription-polymerase chain reaction, followed by sequence analysis. LRV1 was associated significantly with an increased risk of treatment failure (odds ratio, 3.99; P = .04). There was no significant association with intrinsic Sb(V) resistance among parasites, suggesting that treatment failure arises from LRV1-mediated effects on host metabolism and/or parasite survival. The association of LRV1 with clinical drug treatment failure could serve to guide more-effective treatment of tegumentary disease caused by L. braziliensis.

Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response

“…Our studies extend the generality of LRV1-dependent virulence to Lbr because LRV1 + Lbr likewise induces strong TLR3-dependent cytokine responses. These findings are especially important in light of published work on the association of LRV1 with MCL, with mixed results depending on the geographic region and methods used (6,(16)(17)(18)(19). Our data show that, in in vitro infections, LRV1 contributes strongly to the proinflammatory phenotype associated with elevated pathogenicity, as seen in Lgy, which suggests that, in human infections, it may be informative to seek for correlations between LRV1 and the severity of CL in Lbr infections.…”

“…Although in some studies LRV1 was not correlated with MCL (16,17), in others there was a strong association (6,18,19). Recent studies show that LRV1 in Lbr and Lgy clinical isolates correlates with drug treatment failure (16,20). Thus, although other parasite or host factors may play a significant role in the development of MCL (21,22), current data support a role for LRV1 in exacerbating the pathogenesis of human leishmaniasis caused by Lbr and Lgy.…”

“…Although in some studies LRV1 was not correlated with MCL (16,17), in others there was a strong association (6,18,19). Recent studies show that LRV1 in Lbr and Lgy clinical isolates correlates with drug treatment failure (16,20).…”

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

“…These findings may explain why the tight correlation between disease severity and metastasis with LgyLRV1 + in animal models (5) may be more variable in humans (13,17,47,48). Potentially, coinfection with viruses or other pathogens inducing a sufficient amount of type I IFNs could increase the severity of Lgy infection, contributing to the development of more severe disease manifestations.…”

“…These latter, more severe, forms of the disease are characterized by the dissemination of the parasites from the primary infection site. Another complication of Lgy or Lbr infection can be relapse, which may occur months to years after the healing of the primary lesion, or after a first-line drug treatment (3,4). Recently, we correlated the development of these more severe forms of leishmaniasis with the presence of Leishmania RNA virus (LRV1) within different species of Leishmania (3-6).…”