Leishmania heme uptake involves LmFLVCRb, a novel porphyrin transporter essential for the parasite

Leishmaniasis comprises a group of neglected diseases caused by the protozoan parasite Leishmania spp. As is the case
for other trypanosomatid parasites, Leishmania is auxotrophic for heme and must scavenge this essential compound from
its human host. In mammals, the SLC transporter FLVCR2 mediates heme import across the plasma membrane. Herein we
identify and characterize Leishmania major FLVCRb (LmFLVCRb), the first member of the FLVCR family studied in a
non-metazoan organism. This protein localizes to the plasma membrane of the parasite and is able to bind heme. LmFLVCRb
levels in Leishmania, which are modulated by overexpression thereof or the abrogation of an LmFLVCRb allele, correlate
with the ability of the parasite to take up porphyrins. Moreover, injection of LmFLVCRb cRNA to Xenopus laevis oocytes
provides these cells with the ability to take up heme. This process is temperature dependent, requires monovalent ions and
is inhibited at basic pH, characteristics shared by the uptake of heme by Leishmania parasites. Interestingly, LmFLVCRb is
essential as CRISPR/Cas9-mediated knockout parasites were only obtained in the presence of an episomal copy of the gene.
In addition, deletion of just one of the alleles of the LmFLVCRb gene markedly impairs parasite replication as intracellular
amastigotes as well as its virulence in an in vivo model of cutaneous leishmaniasis. Collectively, these results show that
Leishmania parasites can rescue heme through plasma membrane transporter LFLVCRb, which could constitute a novel
target for therapeutic intervention against Leishmania and probably other trypanosomatid parasites in which FLVCR genes
are also present.