AI Article Synopsis
- The parasite Leishmania causes Leishmaniasis by residing in macrophage vacuoles and manipulating host cell signaling pathways.
- The study finds that LmjMAPK4, a specific mitogen-activated protein kinase, is overexpressed in virulent L. major and affects macrophage responses by selectively interacting with certain MAPKs.
- Targeting LmjMAPK4 with a specific inhibitor can restore protective immune functions in infected mice, highlighting its potential as a drug target for treating Leishmaniasis.
Article 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.intimp.2024.112100 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!