Primary macrophages from HIV-infected adults show dysregulated cytokine responses to Salmonella, but normal internalization and killing

Abstract

Adults with advanced HIV are susceptible to invasive and recrudescent infections with nontyphoidal salmonellae. To examine whether persistence and recurrence of salmonella infection results from HIV-related defects in macrophage internalization and intracellular killing or from ineffective type 1 cytokine responses. Such defects could be a direct consequence of macrophage HIV infection or secondary to reduced enhancement of macrophage effector functions by interferon-gamma (IFNgamma) as CD4 cell count falls. Ex-vivo scientific case-control study. Primary ex-vivo human alveolar macrophages (huAM) from HIV-negative and HIV-positive subjects were challenged with Salmonella typhimurium under unprimed and IFNgamma-primed conditions to study internalization and intracellular killing of bacteria and cytokine responses of huAM. Priming of huAM with IFNgamma reduced bacterial internalization but enhanced microbicidal activity against intracellular salmonellae. HuAM from HIV-positive subjects showed unimpaired internalization and intracellular killing of salmonellae, with and without IFNgamma priming. Opsonic and mannose receptor (CD206)-mediated entry was not required for optimal internalization. HuAM from HIV-positive subjects, however, exhibited increased secretion of tumour necrosis factor alpha (TNFalpha), interleukin (IL)-10 and IL-12 in response to S. typhimurium challenge, regardless of IFNgamma priming. This cytokine dysregulation showed a trend to a curvilinear relationship with peripheral CD4 cell count, with marked decline at values < 250 cell/mul. Dysregulation of proinflammatory cytokine release, including IL-12, by macrophages during salmonella infection may underlie the susceptibility to severe salmonellosis in patients with AIDS. This defect was not reversed by IFNgamma and may represent a proinflammatory effect of HIV infection upon the macrophage or the alveolar milieu.