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

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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: DRM: Leidos Biomedical Research, Inc (employment); JDE: Leidos Biomedical Research, Inc (employment); NSU: Tobira Therapeutics, Inc (scientific advisory board, research funds, travel); EnteraHealth, Inc (research funds); Gilead Sciences, Inc (travel funds).

Figures

Fig 1. 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.

Fig 2. Cytokine concentrations released into supernatant.

Supernatant concentrations of IFNγ (A) and drivers of IFNγ production, IL-12 (B) and IL-15 (C), after MRSA stimulation of PBMCs were assayed using the Luminex platform. P-values were calculated using the Mann-Whitney U test.

Fig 3. 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.