TAK1 Deficiency in Macrophages Increases Host Susceptibility to Leishmania Infection

Leishmania parasites mainly infect macrophages and may cause severe immunopathologies in their host,which are called leishman-iases.In the current work,we infected human and mouse macrophages in vitro with Leishmania major,an etiological agent of cu-taneous leishmaniasis,and found that inhibition or deletion of the transforming growth factorβ–activated kinase 1(TAK1)gene re-sulted in increased parasite loads.In vivo,following a challenge with L.major,mice with a macrophage-specific deletion of TAK1 showed increased clinical signs and higher parasite loads compared with wild-type controls.TAK1 deficiency in mouse macro-phages led to biased Th2 cell responses during the acute stage of infection,characterized by a decrease in interferon-γexpression,and increased expression of IL-4,IL-5 and IL-10.Finally,we found that,in the late stage of L.major infection,excessive Th2-related cytokines led to high arginase 1 expression in mouse tissues and a significant reduction of NO production both locally and system-ically,resulting in compromised control of Leishmania.These findings suggest that TAK1 plays a vital role in host resistance to Leish-mania infection.