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- Title
Unveiling the Enigmatic nature of six neglected Amazonian Leishmania (Viannia) species using the hamster model: Virulence, Histopathology and prospection of LRV1.
- Authors
Soares, Rodrigo Pedro; Fontes, Igor Campos; Dutra-Rêgo, Felipe; Rugani, Jeronimo Nunes; Moreira, Paulo Otávio L.; da Matta, Vânia Lúcia Ribeiro; Flores, Gabriela Venícia Araujo; Pacheco, Carmen Maria Sandoval; de Andrade, Andrey José; da Costa-Ribeiro, Magda Clara Vieira; Shaw, Jeffrey Jon; Laurenti, Márcia Dalastra
- Abstract
American tegumentary leishmaniasis (ATL) is highly endemic in the Amazon basin and occurs in all South American countries, except Chile and Uruguay. Most Brazilian ATL cases are due to Leishmania (Viannia) braziliensis, however other neglected Amazonian species are being increasingly reported. They belong to the subgenus L. (Viannia) and information on suitable models to understand immunopathology are scarce. Here, we explored the use of the golden hamster Mesocricetus auratus and its macrophages as a model for L. (Viannia) species. We also studied the interaction of parasite glycoconjugates (LPGs and GIPLs) in murine macrophages. The following strains were used: L. (V.) braziliensis (MHOM/BR/2001/BA788), L. (V.) guyanensis (MHOM/BR/85/M9945), L. (V.) shawi (MHOM/BR/96/M15789), L. (V.) lindenbergi (MHOM/BR/98/M15733) and L. (V.) naiffi (MDAS/BR/79/M5533). In vivo infections were initiated by injecting parasites into the footpad and were followed up at 20- and 40-days PI. Parasites were mixed with salivary gland extract (SGE) from wild-captured Nyssomyia neivai prior to in vivo infections. Animals were euthanized for histopathological evaluation of the footpads, spleen, and liver. The parasite burden was evaluated in the skin and draining lymph nodes. In vitro infections used resident peritoneal macrophages and THP-1 monocytes infected with all species using a MOI (1:10). For biochemical studies, glycoconjugates (LPGs and GIPLs) were extracted, purified, and biochemically characterized using fluorophore-assisted carbohydrate electrophoresis (FACE). They were functionally evaluated after incubation with macrophages from C57BL/6 mice and knockouts (TLR2-/- and TLR4-/-) for nitric oxide (NO) and cytokine/chemokine production. All species, except L. (V.) guyanensis, failed to generate evident macroscopic lesions 40 days PI. The L. (V.) guyanensis lesions were swollen but did not ulcerate and microscopically were characterized by an intense inflammatory exudate. Despite the fact the other species did not produce visible skin lesions there was no or mild pro-inflammatory infiltration at the inoculation site and parasites survived in the hamster skin/lymph nodes and even visceralized. Although none of the species caused severe disease in the hamster, they differentially infected peritoneal macrophages in vitro. LPGs and GIPLs were able to differentially trigger NO and cytokine production via TLR2/TLR4 and TLR4, respectively. The presence of a sidechain in L. (V.) lainsoni LPG (type II) may be responsible for its higher proinflammatory activity. After Principal Component analyses using all phenotypic features, the clustering of L. (V.) lainsoni was separated from all the other L. (Viannia) species. We conclude that M. auratus was a suitable in vivo model for at least four dermotropic L. (Viannia) species. However, in vitro studies using peritoneal cells are a suitable alternative for understanding interactions of the six L. (Viannia) species used here. LRV1 presence was found in L. (V.) guyanensis and L. (V.) shawi with no apparent correlation with virulence in vitro and in vivo. Finally, parasite glycoconjugates were able to functionally trigger various innate immune responses in murine macrophages via TLRs consistent with their inflammatory profile in vivo. Author summary: American Tegumentary Leishmaniasis (ATL) is one of the major neglected diseases occurring in Brazil and the Amazon contributes with a wide range of species that are not completely known. These little-known species are transmitted to rural workers entering the forest during lumbering, mining, and latex extraction activities and rarely in peri domestic situation. Infection occurs by the bite of infected sand flies in different environments and biomes. One of the major constraints in studying L. (Viannia) species is the difficulty of finding suitable animal and cellular models to investigate their biology. The mouse model is not a suitable model for most L. (Viannia) species. However, hamsters were considered a good model for L. (V.) braziliensis. In the search for a better model for some neglected dermotropic Amazonian Leishmania, we evaluated interactions in vivo in the hamster and in vitro in its macrophages. All species infected cells in vitro, but hamsters could only be considered as a suitable in vivo model for L. (V.) guyanensis. Importantly the glycoconjugates of the six L. (Viannia) species were very proinflammatory, showing various levels of macrophage activation. This paper opens possibilities of determining more accurately the taxonomic position of L. (V.) lainsoni within the subgenus L. (Viannia).
- Subjects
GOLDEN hamster; PERITONEAL macrophages; FLIES as carriers of disease; SAND flies; PRINCIPAL components analysis
- Publication
PLoS Neglected Tropical Diseases, 2024, Vol 18, Issue 8, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0012333