Abstract
Leishmania (Viannia) braziliensis is responsible for the largest number of American tegumentary leishmaniasis (ATL) in Brazil. ATL can present several clinical forms including typical (TL) and atypical (AL) cutaneous and mucocutaneous (ML) lesions. To identify parasite and host factors potentially associated with these diverse clinical manifestations, we first surveyed the expression of two virulence-associated glycoconjugates, lipophosphoglycan (LPG) and the metalloprotease GP63 by a panel of promastigotes of Leishmania braziliensis (L. braziliensis) strains isolated from patients with different clinical manifestations of ATL and from the sand fly vector. We observed a diversity of expression patterns for both LPG and GP63, which may be related to strain-specific polymorphisms. Interestingly, we noted that GP63 activity varies from strain to strain, including the ability to cleave host cell molecules. We next evaluated the ability of promastigotes from these L. braziliensis strains to modulate phagolysosome biogenesis in bone marrow-derived macrophages (BMM), by assessing phagosomal recruitment of the lysosome-associated membrane protein 1 (LAMP-1) and intraphagosomal acidification. Whereas, three out of six L. braziliensis strains impaired the phagosomal recruitment of LAMP-1, only the ML strain inhibited phagosome acidification to the same extent as the L. donovani strain that was used as a positive control. While decreased phagosomal recruitment of LAMP-1 correlated with higher LPG levels, decreased phagosomal acidification correlated with higher GP63 levels. Finally, we observed that the ability to infect and replicate within host cells did not fully correlate with the inhibition of phagosome maturation. Collectively, our results revealed a diversity of strain-specific phenotypes among L. braziliensis isolates, consistent with the high genetic diversity within Leishmania populations.
Highlights
The various species of the protozoan parasite Leishmania cause a spectrum of human diseases ranging from a relatively confined cutaneous lesion to a progressive and potentially fatal visceral infection (Alvar et al, 2012)
We sought to determine the relative levels of LPG and GP63 expressed by promastigotes of a panel of L. braziliensis strains differing in their origin (Table 1)
Given the variations in GP63 levels and activity observed among the L. braziliensis isolates, we investigated the impact of these differences on the cleavage of phagosomal host cell proteins known to be targeted by GP63 (Matheoud et al, 2013)
Summary
The various species of the protozoan parasite Leishmania cause a spectrum of human diseases ranging from a relatively confined cutaneous lesion to a progressive and potentially fatal visceral infection (Alvar et al, 2012). Defective synthesis of LPG has no measurable effect on the ability of Leishmania mexicana (L. mexicana), which lives in large communal vacuoles, to replicate in cultured macrophages and cause lesions in mice (Ilg, 2000; Ilg et al, 2001) These findings underline the fact that the relative contribution of a given virulence factor in the ability of promastigotes to colonize mammalian hosts varies among Leishmania species
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