Heme limitation induces LHR2, an essential gene for Leishmania pathogenesis

TL;DR

A gene called LHR2 is essential for Leishmania survival and disease progression, especially under low heme conditions, and could be a new target for treating leishmaniasis.

Contribution

LHR2 is a novel gene in Leishmania that is essential for pathogenesis and distinct from human proteins, making it a promising drug target.

Findings

LHR2 is the most upregulated gene in Leishmania under heme limitation and is essential for intracellular replication.

LHR2 is a mitochondrial hemoprotein that protects against reactive oxygen species and is critical for disease progression in mice.

LHR2 shares functional similarities with yeast Dap1p but has distinct heme-binding properties and structural differences from human proteins.

Abstract

Leishmania spp. are intracellular parasites that cause leishmaniasis, a devastating disease with no effective treatment. These parasites are heme auxotrophs and must scavenge this essential cofactor from the host. Transcriptomic analysis of Leishmania
major promastigotes cultured in the presence or absence of heme revealed numerous differentially expressed genes. Among those of unknown function, LHR2 (Leishmania Heme Response-2) was the most upregulated gene in response to heme limitation. LHR2 encodes a mitochondrial hemoprotein that likely protects this organelle from elevated levels of reactive oxygen species. It is essential during the promastigote stage, and loss of a single LHR2 allele severely compromises intracellular replication and prevents the development of cutaneous leishmaniasis in mice. This essential function depends on LHR2’s ability to bind heme. Complementation studies in Saccharomyces cerevisiae revealed that LHR2 is an analogue of the yeast Dap1p, although it binds heme in a distinct manner. Importantly, LHR2 displays key structural differences from the most closely related human proteins. These findings highlight LHR2 as a critical factor in parasite survival and pathogenesis, and suggest it as a promising new target for antileishmanial drug development.

Leishmaniasis is a life-threatening tropical disease for which there is no adequate treatment. It is caused by Leishmania parasites, which require heme—an essential molecule they cannot produce themselves—to survive. We investigated how the parasite responds to low heme conditions and discovered a gene called LHR2, which is upregulated when heme is scarce. We found that LHR2 encodes a previously unknown protein located in the parasite’s mitochondrion that is essential for parasite survival and disease progression. Disrupting just one copy of the LHR2 gene severely impaired the parasite’s ability to multiply inside host cells and to cause disease in mice. Interestingly, LHR2 shares some functional similarities with the yeast protein Dap1p but binds heme in a different way. Moreover, its structure shows important differences from related human proteins, making it a promising new candidate for drug development. Our findings shed light on how Leishmania copes with heme limitation and identify a potential new target to combat leishmaniasis.

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