Enhanced replication of Leishmania amazonensis amastigotes in gamma interferon-stimulated murine macrophages: implications for the pathogenesis of cutaneous leishmaniasis.
During Leishmania major infection in mice, gamma interferon (IFN-gamma) plays an essential role in controlling parasite growth and disease progression. In studies designed to ascertain the role of IFN-gamma in Leishmania amazonensis infection, we were surprised to find that IFN-gamma could promote L. amazonensis amastigote replication in macrophages (Mphis), although it activated Mphis to kill promastigotes. The replication-promoting effect of IFN-gamma on amastigotes was independent of the source and genetic background of Mphis, was apparently not affected by surface opsonization of amastigotes, was not mediated by interleukin-10 or transforming growth factor beta, and was observed at different temperatures. Consistent with the different fates of promastigotes and amastigotes in IFN-gamma-stimulated Mphis, L. amazonensis-specific Th1 transfer helped recipient mice control L. amazonensis infection established by promastigotes but not L. amazonensis infection established by amastigotes. On the other hand, IFN-gamma could stimulate Mphis to limit amastigote replication when it was coupled with lipopolysaccharides but not when it was coupled with tumor necrosis factor alpha. Thus, IFN-gamma may play a bidirectional role at the level of parasite-Mphi interactions; when it is optimally coupled with other factors, it has a protective effect against infection, and in the absence of such synergy it promotes amastigote growth. These results reveal a quite unexpected aspect of the L. amazonensis parasite and have important implications for understanding the pathogenesis of the disease and for developing vaccines and immunotherapies.
Qi
Hai
H
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Ji
Jiaxiang
J
Wanasen
Nanchaya
N
Soong
Lynn
L
D000818:Animals; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000502:physiology; D007894:Leishmania mexicana / Q000254:growth & development*; D016773:Leishmaniasis, Cutaneous / Q000209:etiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013696:Temperature; D018417:Th1 Cells / Q000276:immunology
D008070:Lipopolysaccharides; D016753:Interleukin-10; D007371:Interferon-gamma