MAPK/ERK activation in macrophages promotes Leishmania internalization and pathogenesis

Area of Science:

• Immunology
• Cell Biology
• Parasitology

Background:

• Leishmania parasites cause leishmaniasis through uptake by phagocytic cells.
• Host cell signaling pathways are crucial for Leishmania infection establishment and persistence.
• Understanding the host machinery for parasite uptake is key to developing new therapies.

Purpose of the Study:

• To investigate the role of Mitogen-activated protein/Extracellular signal regulated kinases (MAPK/ERK) signaling in Leishmania amazonensis uptake by macrophages.
• To identify host cellular kinases involved in Leishmania internalization.
• To evaluate the therapeutic potential of targeting MAPK/ERK signaling in leishmaniasis.

Main Methods:

• Utilized small molecule inhibitors of MAPK/ERK pathway components (MEK1/2, ERK1/2).
• Employed macrophages with genetic deficiencies in spleen tyrosine kinase (SYK) and Abl family kinases.
• Assessed Leishmania amazonensis promastigote and amastigote uptake by macrophages.
• Evaluated the efficacy of trametinib (a MEK1/2 inhibitor) in a mouse model of leishmaniasis.

Main Results:

• ERK1/2 signaling is essential for Leishmania amazonensis uptake by macrophages.
• Inhibition of MEK1/2 or ERK1/2 significantly reduces Leishmania amastigote internalization.
• SYK and Abl family kinases are upstream regulators of Raf, MEK, and ERK1/2 activity, mediating parasite uptake.
• Trametinib treatment reduced leishmaniasis disease severity and parasite burden in infected mice, even when initiated post-lesion development.

Conclusions:

• Maximal Leishmania infection relies on MAPK/ERK signaling pathways.
• Targeting MAPK/ERK-mediated signaling represents a promising therapeutic strategy for leishmaniasis.
• Inhibiting MEK/ERK signaling can reduce parasite burden and disease progression.