A pH-dependent protein kinase cascade regulates divergent differentiation of Leishmania in the sand fly.

Leishmania parasites must rapidly adapt to changing environments to survive and transmit. Acidic pH within the sand fly vector is a known trigger for their developmental response, but the underlying mechanisms are not fully understood. Researchers screened a library of protein kinases to identify those involved in acid adaptation in Leishmania mexicana. They discovered nine protein kinases that affect survival at low pH, including a protein kinase called HDRK1.

Null mutants lacking HDRK1 (Delta hdrk1) were more likely to differentiate into haptomonad-like forms at low pH. While these mutants could still infect the sand fly midgut, they were unable to colonize the stomodeal valve, which hinders transmission to the mammalian host. Transcriptomic and proteomic analyses revealed that under low pH conditions, Delta hdrk1 mutants enter a low-energy state similar to AMPK-activated cells.

Another protein kinase, HDRK2, was identified, establishing a pH-dependent signaling pathway that determines the parasite's developmental fate, leading to either the mammalian-infective metacyclic or vector-attached haptomonad stages.

The study also found that phosphoinositide balance, regulated by lipid kinases PI4K and PI4P5K, is crucial for acid adaptation. Two STE transmembrane kinases were identified as potential pH sensors. These findings provide a framework for understanding how Leishmania detects and survives acid stress to coordinate its life cycle.