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Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection

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 mechan...

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Bibliographic Details
Published in:International immunopharmacology 2024-06, Vol.134, p.112100, Article 112100
Main Authors: Kumari, Sangeeta, Bodhale, Neelam, Sarode, Aditya, Jha, Mukesh Kumar, Bhadange, Sagar, Pandey, Surya Prakash, Selvaraj, Sathishkumar, Chande, Ajit G., Mukhopadhyaya, Robin, Ghosh, Soumya Kanti, Singh, Shailza, Mukherjee, Debasri, Duffin, Rebekah, Andrews, Philip, Saha, Bhaskar
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Language:English
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Summary: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.
ISSN:1567-5769
1878-1705
1878-1705
DOI:10.1016/j.intimp.2024.112100