MyD88-dependent signaling influences fibrosis and alternative macrophage activation during Staphylococcus aureus biofilm infection
Mark L Hanke, Amanda Angle, Tammy Kielian, Mark L Hanke, Amanda Angle, Tammy Kielian
Abstract
Bacterial biofilms represent a significant therapeutic challenge based on their ability to evade host immune and antibiotic-mediated clearance. Recent studies have implicated IL-1β in biofilm containment, whereas Toll-like receptors (TLRs) had no effect. This is intriguing, since both the IL-1 receptor (IL-1R) and most TLRs impinge on MyD88-dependent signaling pathways, yet the role of this key adaptor in modulating the host response to biofilm growth is unknown. Therefore, we examined the course of S. aureus catheter-associated biofilm infection in MyD88 knockout (KO) mice. MyD88 KO animals displayed significantly increased bacterial burdens on catheters and surrounding tissues during early infection, which coincided with enhanced dissemination to the heart and kidney compared to wild type (WT) mice. The expression of several proinflammatory mediators, including IL-6, IFN-γ, and CXCL1 was significantly reduced in MyD88 KO mice, primarily at the later stages of infection. Interestingly, immunofluorescence staining of biofilm-infected tissues revealed increased fibrosis in MyD88 KO mice concomitant with enhanced recruitment of alternatively activated M2 macrophages. Taken in the context of previous studies with IL-1β, TLR2, and TLR9 KO mice, the current report reveals that MyD88 signaling is a major effector pathway regulating fibrosis and macrophage polarization during biofilm formation. Together these findings represent a novel example of the divergence between TLR and MyD88 action in the context of S. aureus biofilm infection.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Drago L, DeVecchi E, Nicola L, Gismondo MR (2007) In vitro evaluation of antibiotic combinations for empirical therapy of suspected methicillin resistant Staphylococcus aureus severe respiratory infections. BMC Infect Dis 7.
- Fowler VG, Olsen MK, Corey GR, Woods CW, Cabell CH, et al. (2003) Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 163: 2066–2072.
- Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15: 167–193.
- Fitzpatrick F, Humphreys H, O’Gara JP (2005) The genetics of staphylococcal biofilm formation–will a greater understanding of pathogenesis lead to better management of device-related infection? Clin Microbiol Infect 11: 967–973.
- Otto M (2008) Staphylococcal biofilms. Curr Top Microbiol Immunol 322: 207–228.
- Rice KC, Mann EE, Endres JL, Weiss EC, Cassat JE, et al. (2007) The cidA murein hydrolase regulator contributes to DNA release and biofilm development in Staphylococcus aureus. Proc Natl Acad Sci U S A 104: 8113–8118.
- Whitchurch CB, Tolker-Nielsen T, Ragas PC, Mattick JS (2002) Extracellular DNA required for bacterial biofilm formation. Science. 1487.
- Allesen-Holm M, Barken KB, Yang L, Klausen M, Webb JS, et al. (2006) A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms. Mol Microbiol 59: 1114–1128.
- Mann EE, Rice KC, Boles BR, Endres JL, Ranjit D, et al. (2009) Modulation of eDNA release and degradation affects Staphylococcus aureus biofilm maturation. PLoS One 4: e5822.
- Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell Microbiol 124: 783–801.
- Jones BW, Means TK, Heldwein KA, Keen MA, Hill PJ, et al. (2001) Different Toll-like receptor agonists induce distinct macrophage responses. J Leukoc Biol 69: 1036–1044.
- Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, et al. (1999) Differential roles of TLR2 and TLR4 in recognition of gramnegative and gram-positive bacterial cell wall components. Immunity 11: 443–451.
- Thurlow LR, Hanke ML, Fritz T, Angle A, Williams SH, et al. (2011) Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo . J Immunol 186: 6585–6596.
- Bernthal NM, Pribaz JR, Stavrakis A, Billi F, Cho JS, et al. (2011 ) Protective role of IL-1β against post-arthroplasty Staphylococcus aureus infection. J Orthop Res 29: 1621–1626.
- Varin A GS (2009) Alternative activation of macrophages: immune function and cellular biology. Immunobiology 214: 630–664.
- Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953–964.
- Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199–210.
- Curran JN, Winter DC, Bouchier-Hayes D (2006) Biological fate and clinical implications of arginine metabolism in tissue healing. Wound Repair Regen 14: 376–386.
- Garvin KL, Hanssen AD (1995) Infection after total hip arthroplasty. J Bone Joint Surg Am 77: 1576–1588.
- Lew DP, Waldvogel FA (1997) Osteomyelitis. N Engl J Med 326: 999–1007.
- NIH CDPoTHR (1995) Total hip replacement. JAMA 273: 1950–1956.
- Buret A, Ward KH, Olson ME, Costerton JW (1991) An in vivo model to study the pathobiology of infectious biofilms on biomaterial surfaces. J Biomed Mater Res 25: 865–874.
- Duch JM, Yee J (2001) Successful use of recombinant tissue plasminogen activator in a patient with relapsing peritonitis. Am J Kidney Dis 37: 149–153.
- Pickering SJ, Fleming SJ, Bowley JA, Sissons P, Oppenheim BA, et al. (1989) Urokinase: a treatment for relapsing peritonitis due to coagulase-negative staphylococci. Nephrol Dial Transplant 4: 62–65.
- Bergmann S, Hammerschmidt S (2007) Fibrinolysis and host response in bacterial infections. Thromb Haemost 98: 512–520.
- Rivera J, Vannakambadi G, Höök M, Speziale P (2007) Fibrinogen-binding proteins of Gram-positive bacteria. Thromb Haemost 98: 503–511.
- Wagner C, Aytac S, Hänsch GM (2011) Biofilm growth on implants: bacteria prefer plasma coats. Int J Artif Organs 34: 811–817.
- Lupher ML, Gallatin WM (2006) Regulation of fibrosis by the immune system. Adv Immunol 89: 245–288.
- Mauviel A (2005) Transforming growth factor-beta: a key mediator of fibrosis. Methods Mol Med 117: 69–80.
- Barron L, Wynn TA (2011) Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. Eur J Immunol 41: 2509–2514.
- Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, et al. (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6: 137–143.
- Gallardo-Soler A, Gómez-Nieto C, Campo ML, Marathe C, Tontonoz P, et al. (2008) Arginase I Induction by Modified Lipoproteins in Macrophages: A Peroxisome Proliferator-Activated Receptor-{gamma}/{delta}-Mediated Effect that Links Lipid Metabolism and Immunity. Mol Endocrinol 22: 1394–1402.
- He X, Mekasha S, Mavrogiorgos N, Fitzgerald KA, Lien E, et al. (2010) Inflammation and fibrosis during Chlamydia pneumoniae infection is regulated by IL-1 and the NLRP3/ASC inflammasome. J Immunol 184: 5743–5754.
- Hanke ML, Kielian T (2012) Deciphering mechanisms of staphylococcal biofilm evasion of host immunity. Front Cell Inf Microbio 2. doi: .
- Fremond CM, Yeremeev V, Nicolle DM, Jacobs M, Quesniaux VF, et al. (2004) Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114: 1790–1799.
- Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11: 115–122.
- Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, et al. (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143–150.
- Rupp ME, Ulphani JS, Fey PD, Bartscht K, Mack D (1999) Characterization of the importance of polysaccharide intercellular adhesin/hemagglutinin of Staphylococcus epidermidis in the pathogenesis of biomaterial-based infection in a mouse foreign body infection model. Infect Immun 67: 2627–2632.
- Cassat JE, Lee CY, Smeltzer MS (2007) Investigation of biofilm formation in clinical isolates of Staphylococcus aureus. Methods Mol Biol 391: 127–144.
- Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11: 723–737.
- Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164: 6166–6173.
- Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181: 3733–3739.
- Longbrake EE, Lai W, Ankeny DP, Popovich PG (2007) Characterization and modeling of monocyte-derived macrophages after spinal cord injury. J Neurochem 102: 1083–1094.
- Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, et al. (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29: 13435–13444.
Source: PubMed