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Updated: Jun 26, 2025
Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
Published on: October 28, 2022
Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection
Sangeeta Kumari1, Neelam Bodhale1, Aditya Sarode1
1National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
Abstract:
The parasite Leishmania resides as amastigotes within the macrophage parasitophorous vacuoles inflicting the disease Leishmaniasis. Leishmania selectively modulates mitogen-activated protein kinase (MAPK) phosphorylation subverting CD40-triggered anti-leishmanial functions of macrophages. The mechanism of any pathogen-derived molecule induced host MAPK modulation remains poorly understood. Herein, we show that of the fifteen MAPKs, LmjMAPK4 expression is higher in virulent L. major. LmjMAPK4- detected in parasitophorous vacuoles and cytoplasm- binds MEK-1/2, but not MKK-3/6. Lentivirally-overexpressed LmjMAPK4 augments CD40-activated MEK-1/2-ERK-1/2-MKP-1, but inhibits MKK3/6-p38MAPK-MKP-3, phosphorylation. A rationally-identified LmjMAPK4 inhibitor reinstates CD40-activated host-protective anti-leishmanial functions in L. major-infected susceptible BALB/c mice. These results identify LmjMAPK4 as a MAPK modulator at the host-pathogen interface and establish a pathogen-intercepted host receptor signaling as a scientific rationale for identifying drug targets.
Insights
The parasite Leishmania uses LmjMAPK4 to disrupt host macrophage defenses against Leishmaniasis. Inhibiting LmjMAPK4 restores protective functions, offering a new drug target for this disease.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Leishmania parasites infect macrophages, causing Leishmaniasis by altering host cell functions.
- Pathogen-induced modulation of host mitogen-activated protein kinase (MAPK) signaling is crucial but poorly understood.
Purpose of the Study:
- To investigate the role of Leishmania MAPKs in modulating host macrophage responses.
- To identify specific MAPK pathways targeted by Leishmania during infection.
Main Methods:
- Analyzed MAPK expression in virulent Leishmania major (L. major).
- Investigated LmjMAPK4 interactions with host MEK and MKK proteins.
- Utilized lentiviral overexpression of LmjMAPK4 to assess its impact on MAPK phosphorylation.
- Tested a novel LmjMAPK4 inhibitor in infected mice.
Main Results:
- LmjMAPK4 expression is elevated in virulent L. major and localized to host cell compartments.
- LmjMAPK4 binds MEK-1/2 and modulates CD40-activated signaling pathways.
- Overexpression of LmjMAPK4 dysregulates specific MAPK cascades (ERK and p38).
- LmjMAPK4 inhibition restores anti-leishmanial macrophage functions and host protection.
Conclusions:
- LmjMAPK4 is a key parasite effector modulating host MAPK signaling at the host-pathogen interface.
- Targeting LmjMAPK4 offers a promising therapeutic strategy for Leishmaniasis.
- Understanding pathogen-hijacked host signaling provides a rationale for drug development.
