---
title: "pH-dependent protein kinase cascade controls Leishmania differentiation in the sand fly"
id: "biorxiv-0-a-ph-dependent-protein-kinase-cascade-regulates-divergent-differentiation-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-a-ph-dependent-protein-kinase-cascade-regulates-divergent-differentiation-of"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.15.751656v1?rss=1"
published_at: "2026-09-16T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# pH-dependent protein kinase cascade controls Leishmania differentiation in the sand fly
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-a-ph-dependent-protein-kinase-cascade-regulates-divergent-differentiation-of
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.15.751656v1?rss=1)
- **Published At:** 2026-09-16T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Leishmania must adapt rapidly to changing environments to survive and transmit between insect vector and mammalian host. Acidic pH in the sand fly is a conserved developmental trigger but the sensing mechanisms were unclear. - A barcoded **protein kinase** library screen in Leishmania mexicana identified nine kinases that influence survival at low pH, including a haptomonad differentiation regulator kinase named **HDRK1**. - HDRK1 null mutants (Δhdrk1) show increased propensity to differentiate into **haptomonad-like** forms when exposed to low pH. - Although Δhdrk1 mutants infect the sand fly midgut, they fail to colonise the stomodeal valve, which impairs transmission potential. - Transcriptomic and proteomic integration indicates that at low pH Δhdrk1 parasites enter a **low energy state** similar to cells with **AMPK** activation. - A second kinase, **HDRK2**, was identified and appears to function in the same pH-dependent signalling pathway that determines whether parasites differentiate into **metacyclic** (mammalian-infective) or **haptomonad** (vector-attached) stages. - The screen also highlighted the importance of **phosphoinositide** balance for acid adaptation: lipid kinases **PI4K** and **PI4P5K** are required for survival at low pH. - Two STE family transmembrane kinases emerged as candidate pH sensors. - These results provide a framework for how Leishmania detects and responds to acid stress to coordinate life-cycle transitions; specific experimental and mechanistic details are reported in the preprint but were not all reproduced in this summary.
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[ View ORCID Profile](http://orcid.org/0000-0003-4748-2855)Laryssa Vanessa de Liz, Jovana Sadlova, Barbora Becvarova, [ View ORCID Profile](http://orcid.org/0000-0001-6597-8972)James A Brannigan, [ View ORCID Profile](http://orcid.org/0000-0001-8332-7196)Sarah Forrester, [ View ORCID Profile](http://orcid.org/0000-0002-7944-9948)Charlotte McNiven, [ View ORCID Profile](http://orcid.org/0000-0002-6501-5444)Adam Dowle, chris Taylor, [ View ORCID Profile](http://orcid.org/0000-0003-4577-9479)Anthony J. Wilkinson, [ View ORCID Profile](http://orcid.org/0000-0003-1790-1123)Petr Volf, [ View ORCID Profile](http://orcid.org/0000-0001-5574-3766)Jeremy C Mottram, [ View ORCID Profile](http://orcid.org/0000-0002-6193-9818)Nicola Baker doi: https://doi.org/10.64898/2026.09.15.751656 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Laryssa Vanessa de Liz 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Laryssa%2BVanessa%2Bde%2BLiz%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=de%20Liz%20LV&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALaryssa%2BVanessa%2Bde%2BLiz%2B) * [ORCID record for Laryssa Vanessa de Liz](http://orcid.org/0000-0003-4748-2855 "Open in new tab") Jovana Sadlova 2 Charles University * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Jovana%2BSadlova%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Sadlova%20J&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJovana%2BSadlova%2B) Barbora Becvarova 2 Charles University * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Barbora%2BBecvarova%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Becvarova%20B&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ABarbora%2BBecvarova%2B) James A Brannigan 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=James%2BA%2BBrannigan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Brannigan%20JA&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJames%2BA%2BBrannigan%2B) * [ORCID record for James A Brannigan](http://orcid.org/0000-0001-6597-8972 "Open in new tab") Sarah Forrester 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Sarah%2BForrester%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Forrester%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASarah%2BForrester%2B) * [ORCID record for Sarah Forrester](http://orcid.org/0000-0001-8332-7196 "Open in new tab") Charlotte McNiven 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Charlotte%2BMcNiven%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=McNiven%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ACharlotte%2BMcNiven%2B) * [ORCID record for Charlotte McNiven](http://orcid.org/0000-0002-7944-9948 "Open in new tab") Adam Dowle 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Adam%2BDowle%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Dowle%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAdam%2BDowle%2B) * [ORCID record for Adam Dowle](http://orcid.org/0000-0002-6501-5444 "Open in new tab") chris Taylor 1 University of York; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=chris%2BTaylor%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Taylor%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3Achris%2BTaylor%2B) Anthony J. 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While acidic pH in the sand fly vector is a conserved developmental trigger, sensing mechanisms remain poorly understood. Using a barcoded protein kinase library, we screened for regulators of acid adaptation in _Leishmania mexicana_ , identifying nine protein kinases influencing survival at low pH, including a haptomonad differentiation regulator protein kinase (HDRK1). We demonstrate that HDRK1 null mutants (Δ _hdrk1_) are predisposed to differentiate to haptomonad-like forms at low pH. While Δ _hdrk1_ mutants successfully infect the sand fly midgut, they fail to colonise the stomodeal valve, compromising transmission. Integrated transcriptomic and proteomic analyses revealed that at low pH, Δ _hdrk1_ mutants enter a low energy state reminiscent of AMPK-activated cells. We identified a second protein kinase, HDRK2, establishing a pH-dependent signalling pathway that governs the developmental fate of the parasite, directing differentiation towards either mammalian-infective metacyclic or vector-attached haptomonad stages. Finally, our screen revealed that phosphoinositide balance, regulated by the lipid kinases PI4K and PI4P5K, is vital for acid adaptation, and identified two STE transmembrane kinases as potential pH sensors. Together these findings provide a framework for how _Leishmania_ detects and survives acid stress to coordinate its life cycle. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared Wellcome Trust, https://ror.org/029chgv08, 223045/Z/21/Z, 226513/Z/22/Z Czech Science Foundation, GACR 25-15318S ERSRC Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](https://www.zeffy.com/en-US/donation-form/donate-to-make-a-difference-10981) [ Back to top](https://www.biorxiv.org/content/10.64898/2026.09.15.751656v1?rss=1#page) [ Previous](https://www.biorxiv.org/content/10.1101/2025.04.04.647214v2 "Menger_Curvature : a MDAKit implementation to decipher the dynamics, curvatures and flexibilities of polymeric backbones at the residue level") P
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