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

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 (IFNgamma) 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 IFNgamma-primed conditions to study internalization and intracellular killing of bacteria and cytokine responses of huAM.

RESULTS:

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.

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

• Authors: Melita A Gordon, Stephen B Gordon, Lisa Musaya, Eduard E Zijlstra, Malcolm E Molyneux, Robert C Read
• Journal: AIDS (London, England) (AIDS) Vol. 21 Issue 18 Pg. 2399-408 (Nov 30 2007) ISSN: 1473-5571 [Electronic] England
• PMID: 18025876 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Recombinant Proteins
• Interferon-gamma

Topics

• AIDS-Related Opportunistic Infections (immunology)
• Adolescent
• Adult
• CD4 Lymphocyte Count
• Case-Control Studies
• Cells, Cultured
• Cytokines (biosynthesis)
• HIV Infections (immunology, virology)
• Humans
• Interferon-gamma (immunology)
• Macrophages, Alveolar (immunology, microbiology)
• Middle Aged
• Recombinant Proteins
• Salmonella Infections (immunology)
• Salmonella typhimurium (growth & development, immunology)
• Viral Load