Association between an Emerging Disseminated form of Leishmaniasis and Leishmania (Viannia) braziliensis Strain Polymorphisms

Abstract

Leishmaniasis constitutes a spectrum of human diseases caused by protozoa belonging to the genus Leishmania, divided into two subgenera, Leishmania, which is present in both the Old World and the New World, and Viannia, which is restricted to the New World. Productive infections may either be asymptomatic or lead to different clinical syndromes involving internal organs, skin, and/or mucosal surfaces (3). Leishmania (Viannia) braziliensis is endemic in Latin America and causes at least three distinct clinical types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL) (3,4,6,9,29). The most striking feature that differentiates CL from either ML or DL is the degree of metastasis of lesions from the original inoculation site. CL lesions are restricted to the entry site of the parasites, whereas ML is defined by spreading to mucosal surfaces of the upper digestive and airways tracts. DL is characterized by wide dissemination to distant cutaneous sites. Some individuals with DL develop hundreds of lesions throughout their body surfaces.Many reports cite ML as the most common metastatic form of disease caused by L. (V.) braziliensis. It was previously more common, but ML currently develops in 4 to 5% of individuals with CL (2, 7, 17). Recently, in our study area, DL has emerged as the most prevalent metastatic form of L. (V.) braziliensis infection (26). The present study is based on the hypotheses that different strains of L. (V.) braziliensis are prone to cause the different forms of ATL, and it is the spread of a DL-predisposing strain that is responsible for the increasing incidence of this new cutaneous syndrome.Individuals living in the region of Corte de Pedra in the state of Bahia, Northeast Brazil, can be afflicted by any of the three forms of ATL due to L. (V.) braziliensis. However, DL has only recently been recognized in Corte de Pedra (6, 9). Careful longitudinal study of this form of leishmaniasis has revealed a recent increase in the absolute numbers of DL cases, an increase in the relative proportion of DL cases compared to the total number ATL cases, and a pattern of geographic spread of the disease across a wider region of Corte de Pedra over the past 2 decades (16,26,29). Indeed, the geographic distribution of DL cases differs from that of ML in Corte de Pedra, which led us to investigate the regional risks of these two forms of L. (V.) braziliensis disease (26).One of the first clues that different parasite strains may contribute to the different ATL forms was in vitro evidence showing that the total antigen from L. (V.) braziliensis isolated from a DL patient caused peripheral blood mononuclear cells to release larger amounts of the proinflammatory cytokines gamma interferon and tumor necrosis factor alpha than the total antigen of a parasite from a subject with CL (14). Parallel investigations revealed that parasites isolated from ATL patients could be distinguished according to randomly amplified poly...

Atypical Manifestations of Cutaneous Leishmaniasis in a Region Endemic for Leishmania braziliensis: Clinical, Immunological and Parasitological Aspects

“…Genomic DNA was extracted from suspensions containing approximately 10 6 promastigotes as previously described [19, 20] then re-suspended in 100μL of TE (Tris-HCl 10mM, EDTA 1mM pH 8.0) buffer. Long-term storage DNA aliquots were kept at –70°C, while test samples were maintained at –20°C until used.…”

“…(V . ) braziliensis population in Corte de Pedra is complex, and that different parasite strains are associated with distinct clinical presentations of disease [19, 20]. More recently, we described a locus starting at position 425,451 on chromosome 28 of L .…”

“…(V . ) braziliensis (locus CHR28/425451) that is polymorphic among strains of the parasite in the region [19]. We found that certain haplotypes of single-nucleotide polymorphisms (SNP) and insertions-deletions (indel) in CHR28/425451 are associated with increased risk ratios of DL in that sample [19].…”

“…braziliensis (locus CHR28/425451) that is polymorphic among strains of the parasite in the region [19]. We found that certain haplotypes of single-nucleotide polymorphisms (SNP) and insertions-deletions (indel) in CHR28/425451 are associated with increased risk ratios of DL in that sample [19]. Of note, DL itself was considered an atypical manifestation of ATL in the past, but it has steadily increased in prevalence over the decades, reaching a consistent fraction of 4.0% of all ATL in Corte de Pedra [8–10].…”

Age Modifies the Immunologic Response and Clinical Presentation of American Tegumentary Leishmaniasis

“…The outcome of L. braziliensis in Corte de Pedra is polymorphic and there is an association between DL and genotypic characteristics of L. braziliensis isolates. 20,21 Parasites isolated from DL cases also induce a poorer immune response than isolates of CL patients. 22 Therefore, it cannot be ruled out that parasite factors also contribute to the differences observed in the disease in elderly patients.…”