Impact of Staphylococcus aureus USA300 Colonization and Skin Infections on Systemic Immune Responses in Humans This information is current as Maria-Luisa Alegre, Luqiu Chen, Michael Z. David, of September 24, 2021. Caroline Bartman, Susan Boyle-Vavra, Neha Kumar, Anita S. Chong and Robert S. Daum J Immunol 2016; 197:1118-1126; Prepublished online 11 July 2016; doi: 10.4049/jimmunol.1600549 Downloaded from http://www.jimmunol.org/content/197/4/1118 Supplementary http://www.jimmunol.org/content/suppl/2016/07/11/jimmunol.160054 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 39 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/197/4/1118.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Impact of Staphylococcus aureus USA300 Colonization and Skin Infections on Systemic Immune Responses in Humans Maria-Luisa Alegre,*,1 Luqiu Chen,*,1 Michael Z. David,*,† Caroline Bartman,‡ Susan Boyle-Vavra,† Neha Kumar,† Anita S. Chong,x and Robert S. Daum†,x Staphylococcus aureus is both a commensal and a pathogen, and USA300, a strain that is usually methicillin-resistant but can sometimes be methicillin-susceptible, has been causing skin and soft tissue infections (SSTIs) in epidemic proportions among otherwise healthy individuals. Although many people are colonized with S. aureus strains, including some with USA300, few of these colonized individuals develop SSTIs. This prompts the hypothesis that infections may develop in individuals with somewhat reduced innate and/or adaptive immune responses to S. aureus, either because prior S. aureus colonization has dampened such responses selectively, or because of more globally reduced immune reactivity. In this study, we analyzed the S. aureus colonization status and PBMC responses to innate and adaptive stimuli in 72 patients with SSTIs and 143 uninfected demographically matched Downloaded from controls. Contrary to the hypothesis formulated, PBMCs from infected patients obtained at the time of infection displayed enhanced innate cytokine production upon restimulation compared with PBMCs from controls, a difference that disappeared after infection resolution. Notably, PBMCs from patients infected with a documented USA300 SSTI displayed greater innate cytokine production than did those from patients infected with documented non-USA300 genotypes. Moreover, colonization with USA300 in infected patients, regardless of their infecting strain, correlated with increased production of IL-10, IL-17A, and IL-22 compared with patients colonized with non-USA300 subtypes. Thus, our results demonstrate that infected patients associated with http://www.jimmunol.org/ USA300 either as an infecting strain, or as a colonizing strain, have systemic immune responses of greater magnitude than do those associated with other S. aureus subtypes. The Journal of Immunology, 2016, 197: 1118–1126. he Gram-positive bacterium S. aureus is a frequent com- the community, although methicillin-susceptible S. aureus (MSSA) mensal of the human skin and mucosal areas, but it is also strains sharing many genetic characteristics of USA300 also exist T the most commonly isolated human bacterial pathogen (2, 3). and an important cause of skin and soft tissue infections (SSTIs) It is often cited that 20% of the human population is persistently (1). Since the mid-1990s, there has been a sharp increase in the colonized with S. aureus (4), although the prevalence is likely by guest on September 24, 2021 incidence of S. aureus SSTIs in community-dwelling populations higher (5). Aside from patients with immune genetic defects known in the absence of frequent exposure to the healthcare system. This to be associated with recurrent S. aureus infections (6), it is not clear increase has coincided with the identification of new, virulent why some seemingly healthy individuals develop S. aureus S. aureus strain types that are usually resistant to nearly all b-lactam SSTIs and others do not. One possibility is that individuals antibiotics (methicillin-resistant S. aureus [MRSA]). Such community- with slightly lower immune responses (toward the left of the associated MRSA strains can be distinguished molecularly from Gaussian distribution of normal immune responses) are the ones health care–associated strains and appear to cause infections in who develop SSTIs. Indeed, polymorphisms in the cytokine genes otherwise healthy individuals. Since 2001, in the United States, IL6, TNF, IL10, IL17A,andIFNG, as well as in the innate immune USA300 MRSA has been the dominant strain causing infections in modulating gene TLR10, have been linked to susceptibility to complicated SSTIs, although how these polymorphisms affect cy- tokine levels has not been resolved (7, 8). An alternative possibility is † *Department of Medicine, University of Chicago, Chicago, IL 60637; Department of that colonization with S. aureus may tolerize the immune system to Pediatrics, University of Chicago, Chicago, IL 60637; ‡University of Pennsylvania, Philadelphia, PA 19104; and xDepartment of Surgery, University of Chicago, Chicago, S. aureus Ags or microbial products, as such predisposing an indi- IL 60637 vidual to subsequent infections by any S. aureus strain. This is 1M.-L.A. and L.C. contributed equally to this work. conceivable, as the superantigen properties of S. aureus can result in ORCIDs: 0000-0001-5707-6194 (M.-L.A.); 0000-0001-8537-6071 (L.C.); 0000- deletion or anergy of an entire Vb family of T cells (9), and de- 0002-1926-7800 (M.Z.D.). sensitization of pattern-recognition receptors can occur in innate cells Received for publication March 29, 2016. Accepted for publication June 13, 2016. following exposure to certain microbial products (10). This work was supported by National Institutes of Health Grant AR059414 (to R.S.D. S. aureus infections can activate both innate and adaptive and M.-L.A.). immune cells. The cell surface TLR2 and the cytosolic nucleotide- Address correspondence and reprint requests to Dr. Maria-Luisa Alegre, University binding oligodimerization domain 2 are the main microbial mo- of Chicago, 924 E. 57th Street, JFK R-312, Chicago, IL 60637. E-mail address: [email protected] lecular pattern-recognition receptors known to signal immune The online version of this article contains supplemental material. cells during S. aureus infection (11). Activated innate cells pro- Abbreviations used in this article: D0, day 0; D40, day 40; ED, emergency depart- duce inflammatory cytokines, including IL-6, that promote pro- ment; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin- duction of C-reactive protein, a primitive opsonin and an activator sensitive Staphylococcus aureus; PVL, Panton–Valentine leukocidin; SSTI, skin of complement (12). An association between the presence of and soft tissue infection. neutralizing anti-IL-6 Abs in the serum, low C-reactive protein, Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 and recurrent S. aureus infection has been reported (13), empha- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600549 The Journal of Immunology 1119 sizing the importance of this cytokine in anti–S. aureus immunity. of .38.5˚C), receipt of immunosuppressive medications, presence of a T cell responses have received less attention, but emerging data comorbid condition such as diabetes or chronic renal failure, morbid . 2 support their role in protection against S. aureus infections. For obesity (body mass index of 40 kg/m ), or antibacterial therapy with anti-staphylococcal activity within the prior 14 d. All inclusion/exclusion instance, T cells, but not Abs, were shown to mediate protection criteria were as described previously (27, 28). Patients were randomized to against S. aureus lethality, following vaccination in mice (14, 15). receive either trimethoprim/sulfamethoxazole or clindamycin (or a placebo A link between T cell IL-17 and IL-22 and protection against in cases of a single abscess ,5 cm in diameter). Surgical incision and SSTIs caused by S. aureus has emerged both in rodents and hu- drainage were performed when an abscess was present, and purulent ma- terial was cultured. Blood was drawn on the day of the infected patients’ mans (16–19), and our group has shown that Th17 cells can confer first visit (day 0, D0) and at day 40 (D40) after enrollment. partial protection that limits the size of dermonecrotic lesions Uninfected controls enrolled were adults presenting to the ED during the upon secondary skin infection in mice (20). Notably, patients with same time period with minor, noninfectious complaints without comor- mutations in the STAT3 gene