Replication of Leishmania inside phagolysome (top) fails when LIT1 is deleted (bottom).

Leishmania parasites that lack an essential iron transporter lose the ability to replicate within macrophages. These parasites persist but do not lead to host pathology, report Chau Huynh et al. (page 2363). Targeting the newly identified LIT1 pathway could be a potential route to leishmaniasis therapy.

Intracellular parasites need iron to grow and multiply, but within the phagolysosome compartment, which such parasites inhabit, the supply of iron is limited. Specialized iron transporters had been identified in other intracellular pathogens, but none had been found in Leishmania, until now. Huynh and colleagues searched the Leishmania genome for sequences with similarity to known iron transporters and found a novel gene they call Leishmania iron transporter 1 (LIT1).

Having confirmed that LIT1 behaved as an iron transporter in yeast, the team deleted the gene from Leishmania to see how the bugs would fare in mouse macrophages. By 48 to 72 hours, the number of wild-type Leishmania per phagolysome compartment had significantly increased. LIT1−/− Leishmania, on the other hand, failed to multiply. Their phagolysosome homes appeared smaller, and the bugs themselves showed signs of degeneration. Whether these bugs would be eventually cleared from the cells is unknown, as macrophages do not survive well in culture beyond 72 hours.

Mice infected with wild-type Leishmania developed skin lesions indicative of cutaneous leishmaniasis. However, when infected with LIT1−/− Leishmania, no lesions appeared. Interestingly, samples from the mice injected with LIT1−/− bugs still contained live Leishmania up to 6 months later, despite the pathology-free status of these mice. Removal of the iron transporter LIT1, thus, obliterates Leishmania's virulence and renders the bug incapable of replication, yet does not kill it. The team is currently interested in determining the intracellular location of the surviving LIT1−/− bugs and in seeing whether this location allows them to acquire iron by an alternative route. This is an important question—if answered, it could lead to new treatments capable of completely eliminating the parasites from their infected hosts.