Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection

• DOI: 10.1016/j.intimp.2024.112100
• Publication Date: 2024-05-09T11:29:31Z
• Authors: Sangeeta Kumari; Neelam Bodhale; Aditya Sarode; Mukesh Kumar Jha; Sagar Bhadange; Surya Prakash Pandey; Sathishkumar Selv...; Ajit G. Chande; Robin Mukhopadhyaya; Soumya Kanti Ghosh; Shailza Singh; Debasri Mukherjee; Rebekah Duffin; Philip Andrews; Bhaskar Saha
• Keywords: Mice, Inbred BALB C; Mice; MAP Kinase Signaling System; Macrophages; Animals; Leishmaniasis, Cutaneous; Humans; Female; CD40 Antigens; Phosphorylation; Leishmania major; Signal Transduction; Host-Parasite Interactions

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.