Date Published: April 19, 2016
Publisher: Public Library of Science
Author(s): Netanya S. Utay, Annelys Roque, J. Katherina Timmer, David R. Morcock, Claire DeLeage, Anoma Somasunderam, Amy C. Weintrob, Brian K. Agan, Jacob D. Estes, Nancy F. Crum-Cianflone, Daniel C. Douek, Guido Silvestri.
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.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) emerged as a major cause of skin and soft tissue infections (SSTIs) in the 1990s. SSTIs manifest as cellulitis, abscesses, folliculitis, furuncles and carbuncles . MRSA colonizes 8.8% of HIV-infected persons in North America . HIV-infected people are 18-fold more likely to have CA-MRSA infections than HIV-uninfected people and twice as likely to have recurrences . Risk factors for CA-MRSA infection include higher peak HIV RNA levels, lower nadir and current CD4 T-cell counts, no antiretroviral therapy, same-sex intercourse among men, multiple sexual partners, recent sexually transmitted infections, close contact with MRSA-infected persons and injection drug use . However, CA-MRSA SSTIs still affect HIV-infected participants with relatively high CD4 T-cell counts (mean 430 cells/mm3) , suggesting an antigen-specific rather than global immune defect.
The factors determining increased susceptibility of HIV-infected people to MRSA SSTIs have been unclear with no specific immune defect identified to date. Studies of other human immunodeficiency states and of animal models suggest that deficiencies in IFNγ or IL-17 may predispose to S. aureus infections. Here, we show that HIV-infected participants who developed MRSA SSTIs had a lower frequency of IFNγ+ producing CD4 memory T cells compared to HIV-uninfected participants with MRSA SSTIs, and these IFNγ+ cells were less polyfunctional. We found that PBMC production of IFNγ and IL-12, which contributes to IFNγ feed-forward signaling, was lower in participants with MRSA SSTIs compared to subjects with MRSA colonization. Together, these data suggest that defective production of IFNγ, not IL-17, is the key determinant of increased susceptibility to MRSA SSTIs in HIV-infected people.