Abstract

Resolution of infection with the pathogenic fungus, Histoplasma capsulatum, requires collaboration among numerous constituents of the host immune response. Although the necessity for particular cytokines has been established, we have examined the contribution of chemokines and their receptors on host defenses to this fungus. Mice lacking the chemokine receptor, CCR2, succumb to an otherwise sublethal infection. The failed immune response is caused by elevated levels of interleukin-4. The absence of CCL7 and CCL2, two ligands for CCR2, is responsible for altered production of interleukin-4. Protective immunity is restored by neutralizing interleukin-4 or by adoptive transfer of antigen-primed dendritic cells plus elimination of CD4+ cells prior to, but not at the time of, infection. Hence, CD4+ cells are deleterious to host defenses in this model. We have also explored how IL-4 modulates host response. In a series of in vitro studies, we demonstrated that activation of macrophages by the cytokine granulocyte-macrophage colony stimulating factor (GN-CSF) inhibits intracellular growth of the fungus by depriving reducing zinc content in both the macrophage and the fungus. Treatment of macrophages exposed to GM-CSF with IL-4 restores intracellular growth in association with an increase in zinc. ਀䤀渀 挀漀渀琀爀愀猀琀 琀漀 琀栀攀 愀漀瘀攀Ⰰ 琀栀攀 愀戀猀攀渀挀攀 漀昀 琀栀攀 挀栀攀洀漀欀椀渀攀 爀攀挀攀瀀琀漀爀 䌀䌀刀㔀 愀挀挀攀氀攀爀愀琀攀猀 挀氀攀愀爀愀渀挀攀 漀昀 椀渀昀攀挀琀椀漀渀⸀ 吀栀攀 椀洀瀀爀漀瘀攀搀 漀甀琀挀漀洀攀 椀猀 愀 爀攀猀甀氀琀 漀昀 愀 猀栀椀昀琀 椀渀 琀栀攀 戀愀氀愀渀挀攀 戀攀琀眀攀攀渀 爀攀最甀氀愀琀漀爀礀 吀 挀攀氀氀猀 愀渀搀 椀渀琀攀爀氀攀甀欀椀渀ⴀ㄀㜀⬀ 䌀䐀㐀⬀ 吀 挀攀氀氀猀⸀ 吀栀攀 氀愀挀欀 漀昀 䌀䌀刀㔀Ⰰ 漀爀 漀渀攀 漀昀 椀琀猀 氀椀最愀渀搀猀Ⰰ 䌀䌀䰀㐀Ⰰ 搀愀洀瀀攀渀猀 洀椀最爀愀琀椀漀渀 漀昀 爀攀最甀氀愀琀漀爀礀 吀 挀攀氀氀猀 昀爀漀洀 琀栀攀 琀栀礀洀甀猀 愀渀搀 椀渀栀椀戀椀琀猀 琀栀攀椀爀 攀砀瀀愀渀猀椀漀渀 椀渀 琀栀攀 氀甀渀最猀Ⰰ 戀甀琀 昀愀挀椀氀椀琀愀琀攀猀 吀栀㄀㜀 挀攀氀氀 攀砀瀀愀渀猀椀漀渀⸀ 吀栀攀 愀戀猀攀渀挀攀 漀昀 䌀䌀刀㔀 愀氀猀漀 洀椀琀椀最愀琀攀猀 琀栀攀 搀攀氀攀琀攀爀椀漀甀猀 攀昀昀攀挀琀猀 漀昀 琀爀攀愀琀洀攀渀琀 眀椀琀栀 愀渀琀椀ⴀ琀甀洀漀爀 渀攀挀爀漀猀椀猀 昀愀挀琀漀爀ⴀ☀⌀㤀㐀㔀㬀 愀渀琀椀戀漀搀礀⸀  吀栀攀猀攀 昀椀渀搀椀渀最猀 栀椀最栀氀椀最栀琀 琀栀攀 挀漀洀瀀氀攀砀 渀愀琀甀爀攀 漀昀 挀栀攀洀漀欀椀渀攀 猀椀最渀愀氀椀渀最 愀渀搀 琀栀攀 椀渀琀攀爀愀挀琀椀漀渀 戀攀琀眀攀攀渀 挀栀攀洀漀欀椀渀攀猀 愀渀搀 挀礀琀漀欀椀渀攀猀 椀渀 琀栀椀猀 椀渀昀攀挀琀椀漀甀猀 搀椀猀攀愀猀攀⸀㰀⼀昀漀渀琀㸀㰀⼀瀀㸀㰀戀爀㸀㰀戀㸀䬀攀礀眀漀爀搀㨀 㰀⼀戀㸀☀渀戀猀瀀㬀䌀栀攀洀漀欀椀渀攀Ⰰ 䘀甀渀最愀氀Ⰰ 䰀甀渀最Ⰰ 刀漀搀攀渀琀Ⰰ 䤀洀洀甀渀椀琀礀㰀⼀琀搀㸀㰀⼀琀爀㸀㰀⼀琀愀戀氀攀㸀㰀⼀琀爀㸀㰀⼀琀搀㸀㰀⼀琀愀戀氀攀㸀㰀⼀戀漀搀礀㸀㰀⼀栀琀洀氀㸀