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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

doi: 10.1097/QAD.0b013e3282f25107
Basic Science

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.

From the aMalawi–Liverpool–Wellcome Trust Clinical Research Programme, UK

bDepartment of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi, UK

cUniversity of Sheffield, Sheffield, UK

dUniversity of Liverpool, UK

eLiverpool School of Tropical Medicine, Liverpool, UK.

Received 14 June, 2007

Revised 12 September, 2007

Accepted 14 September, 2007

Correspondence to Dr M.A. Gordon, Division of Gastroenterology, Nuffield Building, Crown Street, Liverpool L69 3GE, UK. E-mail:

© 2007 Lippincott Williams & Wilkins, Inc.