Skip Navigation LinksHome > November 30, 2007 - Volume 21 - Issue 18 > Primary macrophages from HIV-infected adults show dysregulat...
doi: 10.1097/QAD.0b013e3282f25107
Basic Science

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

Gordon, Melita Aa,d; Gordon, Stephen Ba,e; Musaya, Lisaa; Zijlstra, Eduard Eb; Molyneux, Malcolm Ea,e; Read, Robert Cc

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Background: Adults with advanced HIV are susceptible to invasive and recrudescent infections with nontyphoidal salmonellae.

Objectives: 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-γ (IFNγ) as CD4 cell count falls.

Design: Ex-vivo scientific case–control study.

Methods: Primary ex-vivo human alveolar macrophages (huAM) from HIV-negative and HIV-positive subjects were challenged with Salmonella typhimurium under unprimed and IFNγ-primed conditions to study internalization and intracellular killing of bacteria and cytokine responses of huAM.

Results: Priming of huAM with IFNγ 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 IFNγ 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 α (TNFα), interleukin (IL)-10 and IL-12 in response to S. typhimurium challenge, regardless of IFNγ priming. This cytokine dysregulation showed a trend to a curvilinear relationship with peripheral CD4 cell count, with marked decline at values < 250 cell/μl.

Conclusions: 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 IFNγ and may represent a proinflammatory effect of HIV infection upon the macrophage or the alveolar milieu.

© 2007 Lippincott Williams & Wilkins, Inc.


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