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MRSA Infections in HIV-Infected People Are Associated with Decreased MRSA-Specific Th1 Immunity.

Utay NS, Roque A, Timmer JK, Morcock DR, DeLeage C, Somasunderam A, Weintrob AC, Agan BK, Estes JD, Crum-Cianflone NF, Douek DC - PLoS Pathog. (2016)

Bottom Line: Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified.These IFNγ+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs.Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
People with HIV infection are at increased risk for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFNγ+ CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFNγ+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFNγ responses to cytomegalovirus and Mycobacterium avium antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFNγ production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of Staphylococcus aureus. Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFNγ+ CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people.

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MRSA-specific memory CD4 T cells.Flow cytometry analysis of MRSA-specific memory (CD27+CD45RO+ or CD27-) CD4 T-cell responses in HIV-infected or HIV-uninfected participants with MRSA SSTI, colonization or neither. Frequency of memory CD4 T cells producing (A) IFNγ, (B) IL-17, (C) TNF and (D) CD40L. For all figures, horizontal lines indicate medians. P-values were calculated using the Mann-Whitney U test.
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ppat.1005580.g001: MRSA-specific memory CD4 T cells.Flow cytometry analysis of MRSA-specific memory (CD27+CD45RO+ or CD27-) CD4 T-cell responses in HIV-infected or HIV-uninfected participants with MRSA SSTI, colonization or neither. Frequency of memory CD4 T cells producing (A) IFNγ, (B) IL-17, (C) TNF and (D) CD40L. For all figures, horizontal lines indicate medians. P-values were calculated using the Mann-Whitney U test.

Mentions: Next, we measured MRSA-specific CD4 T-cell responses. Among HIV-infected participants, the frequencies of MRSA-specific IFNγ+, IL-17+, CD40L+, TNF+, IL-2+ or IL-22+ memory CD4 T cells did not differ significantly between MRSA SSTI and MRSA-negative groups (Fig 1). HIV-infected participants with MRSA SSTIs had lower MRSA-specific IFNγ+ memory CD4 T-cell frequencies compared to MRSA-colonized participants (0.007% vs 0.03%, P = 0.04; Fig 1A). Among HIV-uninfected participants, the MRSA SSTI group had higher MRSA-specific IL-17+ (0.08% vs. 0.02%, P = 0.004, Fig 1B), TNF+ (0.13% vs 0.03%, P = 0.02, Fig 1C) and CD40L+ (0.09% vs. 0.03%, P = 0.04, Fig 1D) memory CD4 T-cell frequencies than MRSA-negative participants. The MRSA-specific IFNγ+ (0.07% vs. 0.02%, P = 0.14; Fig 1A), IL-2+ (0.08% vs. 0.01%, P = 0.05) and IL-22+ (0.04% vs. 0.001%, P = 0.12) CD4 T-cell frequencies were not significantly higher in HIV-uninfected participants with MRSA SSTIs than MRSA-negative participants. However, HIV-infected participants with MRSA SSTIs had significantly lower MRSA-specific IFNγ+ memory CD4 T-cell frequencies compared to HIV-uninfected participants with MRSA SSTIs (0.007% vs 0.07%, P = 0.03, Fig 1A). The frequencies of other cytokine-producing MRSA-specific memory CD4 T cells or memory CD8 T cells did not differ significantly. Thus, HIV-infected participants with MRSA SSTIs had deficient MRSA-specific IFNγ+ memory CD4 T-cell responses.


MRSA Infections in HIV-Infected People Are Associated with Decreased MRSA-Specific Th1 Immunity.

Utay NS, Roque A, Timmer JK, Morcock DR, DeLeage C, Somasunderam A, Weintrob AC, Agan BK, Estes JD, Crum-Cianflone NF, Douek DC - PLoS Pathog. (2016)

MRSA-specific memory CD4 T cells.Flow cytometry analysis of MRSA-specific memory (CD27+CD45RO+ or CD27-) CD4 T-cell responses in HIV-infected or HIV-uninfected participants with MRSA SSTI, colonization or neither. Frequency of memory CD4 T cells producing (A) IFNγ, (B) IL-17, (C) TNF and (D) CD40L. For all figures, horizontal lines indicate medians. P-values were calculated using the Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836670&req=5

ppat.1005580.g001: MRSA-specific memory CD4 T cells.Flow cytometry analysis of MRSA-specific memory (CD27+CD45RO+ or CD27-) CD4 T-cell responses in HIV-infected or HIV-uninfected participants with MRSA SSTI, colonization or neither. Frequency of memory CD4 T cells producing (A) IFNγ, (B) IL-17, (C) TNF and (D) CD40L. For all figures, horizontal lines indicate medians. P-values were calculated using the Mann-Whitney U test.
Mentions: Next, we measured MRSA-specific CD4 T-cell responses. Among HIV-infected participants, the frequencies of MRSA-specific IFNγ+, IL-17+, CD40L+, TNF+, IL-2+ or IL-22+ memory CD4 T cells did not differ significantly between MRSA SSTI and MRSA-negative groups (Fig 1). HIV-infected participants with MRSA SSTIs had lower MRSA-specific IFNγ+ memory CD4 T-cell frequencies compared to MRSA-colonized participants (0.007% vs 0.03%, P = 0.04; Fig 1A). Among HIV-uninfected participants, the MRSA SSTI group had higher MRSA-specific IL-17+ (0.08% vs. 0.02%, P = 0.004, Fig 1B), TNF+ (0.13% vs 0.03%, P = 0.02, Fig 1C) and CD40L+ (0.09% vs. 0.03%, P = 0.04, Fig 1D) memory CD4 T-cell frequencies than MRSA-negative participants. The MRSA-specific IFNγ+ (0.07% vs. 0.02%, P = 0.14; Fig 1A), IL-2+ (0.08% vs. 0.01%, P = 0.05) and IL-22+ (0.04% vs. 0.001%, P = 0.12) CD4 T-cell frequencies were not significantly higher in HIV-uninfected participants with MRSA SSTIs than MRSA-negative participants. However, HIV-infected participants with MRSA SSTIs had significantly lower MRSA-specific IFNγ+ memory CD4 T-cell frequencies compared to HIV-uninfected participants with MRSA SSTIs (0.007% vs 0.07%, P = 0.03, Fig 1A). The frequencies of other cytokine-producing MRSA-specific memory CD4 T cells or memory CD8 T cells did not differ significantly. Thus, HIV-infected participants with MRSA SSTIs had deficient MRSA-specific IFNγ+ memory CD4 T-cell responses.

Bottom Line: Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified.These IFNγ+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs.Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
People with HIV infection are at increased risk for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFNγ+ CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFNγ+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFNγ responses to cytomegalovirus and Mycobacterium avium antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFNγ production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of Staphylococcus aureus. Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFNγ+ CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people.

Show MeSH
Related in: MedlinePlus