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

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

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.

AIDS-Related Opportunistic Infections, Adolescent, Adult, CD4 Lymphocyte Count, Case-Control Studies, Cells, Cultured, Cytokines, HIV Infections, Humans, Interferon-gamma, Macrophages, Alveolar, Middle Aged, Recombinant Proteins, Salmonella Infections, Salmonella typhimurium, Viral Load, Journal Article, Research Support, Non-U.S. Gov't
0269-9370
2399-2408
Gordon, Melita A.
d63b6bc8-5b49-4848-9910-35885e6bc563
Gordon, Stephen B.
e1d3f391-d2b9-4a4f-b7af-ad91cd29d48e
Musaya, Lisa
5d34c2a6-4b44-4978-9574-8c1931230c53
Zijlstra, Eduard E.
6a049b30-e92d-4ff0-b40f-56ec64979ea6
Molyneux, Malcolm E.
2da5a12a-1c16-49bc-9b13-c068029e9676
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Gordon, Melita A.
d63b6bc8-5b49-4848-9910-35885e6bc563
Gordon, Stephen B.
e1d3f391-d2b9-4a4f-b7af-ad91cd29d48e
Musaya, Lisa
5d34c2a6-4b44-4978-9574-8c1931230c53
Zijlstra, Eduard E.
6a049b30-e92d-4ff0-b40f-56ec64979ea6
Molyneux, Malcolm E.
2da5a12a-1c16-49bc-9b13-c068029e9676
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51

Gordon, Melita A., Gordon, Stephen B., Musaya, Lisa, Zijlstra, Eduard E., Molyneux, Malcolm E. and Read, Robert C. (2007) Primary macrophages from HIV-infected adults show dysregulated cytokine responses to Salmonella, but normal internalization and killing. AIDS, 21 (18), 2399-2408. (doi:10.1097/QAD.0b013e3282f25107).

Record type: Article

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.

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More information

Accepted/In Press date: 14 September 2007
e-pub ahead of print date: 30 November 2007
Published date: 30 November 2007
Keywords: AIDS-Related Opportunistic Infections, Adolescent, Adult, CD4 Lymphocyte Count, Case-Control Studies, Cells, Cultured, Cytokines, HIV Infections, Humans, Interferon-gamma, Macrophages, Alveolar, Middle Aged, Recombinant Proteins, Salmonella Infections, Salmonella typhimurium, Viral Load, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416237
URI: https://eprints.soton.ac.uk/id/eprint/416237
ISSN: 0269-9370
PURE UUID: b678ca22-719a-4280-ba7c-764dc23a260e
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 08 Dec 2017 17:30
Last modified: 14 Mar 2019 01:36

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