Insights from Leishmania (Viannia) guyanensis in vitro behavior and intercellular communication.
2021
Background: Pentavalent antimonial-based chemotherapy is the first-line approach for leishmaniasis treatment and
disease control. Nevertheless antimony-resistant parasites have been reported in some endemic regions. Treatment
refractoriness is complex and is associated with patient- and parasite-related variables. Although amastigotes are
the parasite stage in the vertebrate host and, thus, exposed to the drug, the stress caused by trivalent antimony in
promastigotes has been shown to promote significant modification in expression of several genes involved in various
biological processes, which will ultimately affect parasite behavior. Leishmania (Viannia) guyanensis is one of the main
etiological agents in the Amazon Basin region, with a high relapse rate (approximately 25%).
Methods: Herein, we conducted several in vitro analyses with L. (V.) guyanensis strains derived from cured and
refractory patients after treatment with standardized antimonial therapeutic schemes, in addition to a drug-resistant
in vitro-selected strain. Drug sensitivity assessed through Sb(III) half-maximal inhibitory concentration (
IC50) assays,
growth patterns (with and without drug pressure) and metacyclic-like percentages were determined for all strains
and compared to treatment outcomes. Finally, co-cultivation without intercellular contact was followed by parasitic
density and Sb(III) IC50
measurements.
Results: Poor treatment response was correlated with increased Sb(III) IC50
values. The decrease in drug sensitivity
was associated with a reduced cell replication rate, increased in vitro growth ability, and higher metacyclic-like
proportion. Additionally, in vitro co-cultivation assays demonstrated that intercellular communication enabled lower
drug sensitivity and enhanced in vitro growth ability, regardless of direct cell contact.
Conclusions: Data concerning drug sensitivity in the Viannia subgenus are emerging, and L. (V.) guyanensis plays
a pivotal epidemiological role in Latin America. Therefore, investigating the parasitic features potentially related to
relapses is urgent. Altogether, the data presented here indicate that all tested strains of L. (V.) guyanensis displayed an
association between treatment outcome and in vitro parameters, especially the drug sensitivity. Remarkably, sharing
enhanced growth ability and decreased drug sensitivity, without intercellular communication, were demonstrated.
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