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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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Histological evaluation of skin biopsies.Skin biopsies were obtained from MRSA SSTI participants at the infection site (SSTI lesion) or a distant site (SSTI Not Lesion), or MRSA-negative participants (-). (A) Abundance of CD3. (B) Abundance of CD4. (C) Abundance of IL-17. (D) Abundance of neutrophils (myeloperoxidase+ [MPO]). (E) Abundance of macrophage/myeloid cells (CD68+ and/or CD163+). P-values were calculated using the Mann-Whitney U test.
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ppat.1005580.g003: Histological evaluation of skin biopsies.Skin biopsies were obtained from MRSA SSTI participants at the infection site (SSTI lesion) or a distant site (SSTI Not Lesion), or MRSA-negative participants (-). (A) Abundance of CD3. (B) Abundance of CD4. (C) Abundance of IL-17. (D) Abundance of neutrophils (myeloperoxidase+ [MPO]). (E) Abundance of macrophage/myeloid cells (CD68+ and/or CD163+). P-values were calculated using the Mann-Whitney U test.

Mentions: Because peripheral blood may not reflect the immunological perturbations in tissue, we evaluated T-cell abundance in skin biopsies. CD3+ T-cell abundance was significantly higher in lesional sites from HIV-infected participants compared to non-lesional sites (5.78% vs. 0.36%, P = 0.01) and to biopsies from HIV-infected MRSA-negative participants (5.78% vs. 0.33%, P = 0.006). CD3+ T-cell abundance did not differ between the non-lesional sites and biopsies from HIV-infected MRSA-negative participants (Fig 3A). Similarly, among HIV-uninfected participants with MRSA SSTI, CD3+ T-cell abundance was significantly higher in lesional compared to non-lesional sites (2.11% vs. 0.34%, P<0.0001) and to biopsies from MRSA-negative participants (2.11% vs. 0.43%, P = 0.001), but CD3+ T-cell abundance did not differ between the non-lesional sites and biopsies from HIV-uninfected MRSA-negative participants. Among HIV-infected participants, CD4+ T-cell abundance did not differ significantly among lesional and non-lesional biopsies and MRSA-negative participants (Fig 3B). In contrast, in HIV-uninfected participants, CD4+ T-cell abundance was significantly higher in lesional sites compared to non-lesional sites (0.90% vs. 0.26%, P = 0.0005) and to biopsies from MRSA-negative participants (0.90% vs. 0.52%, P = 0.03). IL-17+-cell abundance was significantly higher in lesional sites of HIV-uninfected participants with MRSA SSTIs compared to biopsies from MRSA-negative participants (1.25% vs. 0.38%, P = 0.02) (Fig 3C). IL-17+-cell abundance was also higher in lesional sites of HIV-infected participants with MRSA SSTIs compared to biopsies from MRSA-negative participants, but this finding did not reach statistical significance. No significant differences in CD3, CD4 or IL-17 abundance were observed between HIV-infected and HIV-uninfected participants. In sum, lesional sites had more lymphocyte, CD4 and IL-17 infiltration compared to non-lesional sites and biopsies from MRSA-uninfected participants.


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)

Histological evaluation of skin biopsies.Skin biopsies were obtained from MRSA SSTI participants at the infection site (SSTI lesion) or a distant site (SSTI Not Lesion), or MRSA-negative participants (-). (A) Abundance of CD3. (B) Abundance of CD4. (C) Abundance of IL-17. (D) Abundance of neutrophils (myeloperoxidase+ [MPO]). (E) Abundance of macrophage/myeloid cells (CD68+ and/or CD163+). P-values were calculated using the Mann-Whitney U test.
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Related In: Results  -  Collection

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ppat.1005580.g003: Histological evaluation of skin biopsies.Skin biopsies were obtained from MRSA SSTI participants at the infection site (SSTI lesion) or a distant site (SSTI Not Lesion), or MRSA-negative participants (-). (A) Abundance of CD3. (B) Abundance of CD4. (C) Abundance of IL-17. (D) Abundance of neutrophils (myeloperoxidase+ [MPO]). (E) Abundance of macrophage/myeloid cells (CD68+ and/or CD163+). P-values were calculated using the Mann-Whitney U test.
Mentions: Because peripheral blood may not reflect the immunological perturbations in tissue, we evaluated T-cell abundance in skin biopsies. CD3+ T-cell abundance was significantly higher in lesional sites from HIV-infected participants compared to non-lesional sites (5.78% vs. 0.36%, P = 0.01) and to biopsies from HIV-infected MRSA-negative participants (5.78% vs. 0.33%, P = 0.006). CD3+ T-cell abundance did not differ between the non-lesional sites and biopsies from HIV-infected MRSA-negative participants (Fig 3A). Similarly, among HIV-uninfected participants with MRSA SSTI, CD3+ T-cell abundance was significantly higher in lesional compared to non-lesional sites (2.11% vs. 0.34%, P<0.0001) and to biopsies from MRSA-negative participants (2.11% vs. 0.43%, P = 0.001), but CD3+ T-cell abundance did not differ between the non-lesional sites and biopsies from HIV-uninfected MRSA-negative participants. Among HIV-infected participants, CD4+ T-cell abundance did not differ significantly among lesional and non-lesional biopsies and MRSA-negative participants (Fig 3B). In contrast, in HIV-uninfected participants, CD4+ T-cell abundance was significantly higher in lesional sites compared to non-lesional sites (0.90% vs. 0.26%, P = 0.0005) and to biopsies from MRSA-negative participants (0.90% vs. 0.52%, P = 0.03). IL-17+-cell abundance was significantly higher in lesional sites of HIV-uninfected participants with MRSA SSTIs compared to biopsies from MRSA-negative participants (1.25% vs. 0.38%, P = 0.02) (Fig 3C). IL-17+-cell abundance was also higher in lesional sites of HIV-infected participants with MRSA SSTIs compared to biopsies from MRSA-negative participants, but this finding did not reach statistical significance. No significant differences in CD3, CD4 or IL-17 abundance were observed between HIV-infected and HIV-uninfected participants. In sum, lesional sites had more lymphocyte, CD4 and IL-17 infiltration compared to non-lesional sites and biopsies from MRSA-uninfected participants.

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