PhD Candidate, University of Toronto
Leishmaniasis is a parasitic disease that affects 1.5-2 million people globally with 350 million people at risk, particularly in third world settings. American Tegumentary Leishmaniasis (ATL) is a form of Leishmaniasis specific to Central and South America with an annual incidence of 1-135 million cases including 3.3% of tourists infected by the disease. Leishmaniasis is transmitted by female sandflies, resulting in ulcerative lesions on the skin that are generally self-healing. To further perplex the situation, a virus known as Leishmania RNA Virus-1 (LRV-1) has been documented in patients solely from Latin America. LRV-1 is believed to cause severe Leishmaniasis where patients are likely to develop destructive, multiple lesions months to years after the initial infection and often succumb to treatment failure. LRV-1 has been associated with severe disease ever since the first documentation of a patient in 1988 returning from Suriname where LRV-1 was first identified. Since then, a number of studies have attempted to predict the likelihood of developing severe disease, as well as it's role in treatment failure. The focus of my project is understand how LRV-1 influences the overall pathogenesis of ATL. By attempting to understand the baseline prevalence of LRV-1 in an endemic population in Peru, determine how it influences the human immune response as well as the overall effects of the virus on the parasite through key virulence factors, I hope to illuminate the potential role of LRV-1 as a diagnostic biomarker which can inform clinical outcome and prognosis, as well as therapeutic decisions.
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.
Pub.: 01 Jul '15, Pinned: 23 Aug '17
Abstract: Cutaneous leishmaniasis is endemic in the tropics and neotropics. It is often referred to as a group of diseases because of the varied spectrum of clinical manifestations, which range from small cutaneous nodules to gross mucosal tissue destruction. Cutaneous leishmaniasis can be caused by several Leishmania spp and is transmitted to human beings and animals by sandflies. Despite its increasing worldwide incidence, but because it is rarely fatal, cutaneous leishmaniasis has become one of the so-called neglected diseases, with little interest by financial donors, public-health authorities, and professionals to implement activities to research, prevent, or control the disease. In endemic countries, diagnosis is often made clinically and, if possible, by microscopic examination of lesion biopsy smears to visually confirm leishmania parasites as the cause. The use of more sophisticated diagnostic techniques that allow for species identification is usually restricted to research or clinical settings in non-endemic countries. The mainstays of cutaneous leishmaniasis treatment are pentavalent antimonials, with new oral and topical treatment alternatives only becoming available within the past few years; a vaccine currently does not exist. Disease prevention and control are difficult because of the complexity of cutaneous leishmaniasis epizoology, and the few options available for effective vector control.
Pub.: 24 Aug '07, Pinned: 23 Aug '17
Abstract: We present an algorithm based on three PCR assays for Leishmania (Viannia) species identification and assessed its performance using 70 specimens from Peruvian patients. The succession of the assayed targets can be ordered according to species prevalence. Sequential progression through the algorithm reduced the number of samples here studied by approximately 30% after each step.
Pub.: 26 Nov '11, Pinned: 23 Aug '17
Abstract: Mucosal leishmaniasis (ML) is a disfiguring manifestation of Leishmania (Viannia) infection. We evaluated parasite load (PL) over time as a potential biomarker of treatment outcome in ML. PL was assessed with kinetoplast DNA quantitative real-time polymerase chain reaction (kDNA-qPCR) at enrollment, days 14 and 21-28 of therapy and 3, 6, 12-18, and 18-24 months after treatment of ML and correlated to demographic, clinical, and parasitologic factors. Forty-four patients were enrolled: 30 men and 14 women. Enrollment PL differed significantly by causative species (P < 0.001), and was higher in patients with severe ML (nasal and laryngeal involvement) compared with those with only isolated nasal involvement (median = 1,285 versus 51.5 parasites/μg tissue DNA; P = 0.005). Two patterns of PL emerged: pattern 1 (N = 23) was characterized by a sequential decline in PL during and after therapy until kDNA was undetectable. Pattern 2 (N = 18) was characterized by clearance of detectable kDNA during treatment, followed by an increased PL thereafter. All patients who failed treatment (N = 4) demonstrated pattern 1. Leishmania (Viannia) braziliensis was overrepresented among those with pattern 2 (P = 0.019). PL can be quantified by cytology brush qPCR during and after treatment in ML. We demonstrate that treatment failure was associated with undetectable PL, and L. (V.) braziliensis infection was overrepresented in those with rebounding PL.
Pub.: 21 Oct '15, Pinned: 23 Aug '17