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

Gordon, M. A., Gordon, Stephen ORCID: https://orcid.org/0000-0001-6576-1116, Musaya, L., Zijlstra, E. E., Molyneux, Malcolm E and Read, R. C. (2007) 'Primary macrophages from HIV-infected adults show dysregulated cytokine responses to Salmonella, but normal internalization and killing'. AIDS, Vol 21, Issue 18, pp. 2399-2408.

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Abstract

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-gamma (IFN gamma) 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 IFN gamma-primed conditions to study internalization and intracellular killing of bacteria and cytokine responses of huAM.
Results: Priming of huAM with IFN gamma 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 IFN gamma 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 a (TNF alpha), interleukin (IL)-10 and IL-12 in response to S. typhimurium challenge, regardless of IFN gamma priming. This cytokine dysregulation showed a trend to a curvilinear relationship with peripheral CD4 cell count, with marked decline at values < 250cell/mu l.
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 IFN gamma and may represent a proinflammatory effect of HIV infection upon the macrophage or the alveolar milieu. 2007 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Item Type:	Article
Subjects:	WC Communicable Diseases > Infection. Bacterial Infections > Enteric Infections > WC 269 Salmonella infections WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.5 Complications
Digital Object Identifer (DOI):	https://doi.org/10.1097/QAD.0b013e3282f25107
Depositing User:	Ms Julia Martin
Date Deposited:	13 Sep 2010 10:12
Last Modified:	17 Aug 2022 08:56
URI:	https://archive.lstmed.ac.uk/id/eprint/1356

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