NETs Tangle with HIV
2012; Cell Press; Volume: 12; Issue: 1 Linguagem: Inglês
10.1016/j.chom.2012.07.002
ISSN1934-6069
Autores Tópico(s)Blood disorders and treatments
ResumoNeutrophil extracellular traps (NETs) are comprised of extracellular DNA coated in cytotoxic proteins capable of ensnaring and killing bacteria. Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar expand our understanding of NETs into antiviral immunity by demonstrating that HIV induces the formation of NETs, which can bind and neutralize viral particles. Neutrophil extracellular traps (NETs) are comprised of extracellular DNA coated in cytotoxic proteins capable of ensnaring and killing bacteria. Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar expand our understanding of NETs into antiviral immunity by demonstrating that HIV induces the formation of NETs, which can bind and neutralize viral particles. Neutrophils are the foot soldiers of the innate immune response. These cells are often the first to respond to pathogens, arriving rapidly and deploying a vast array of antimicrobial agents in an effort to control the early phases of infection. This arsenal of effector mechanisms include the ability to phagocytose pathogens and the release of large numbers of antimicrobial peptides, cytokines, and reactive oxygen species (ROS). More recently, a novel effector mechanism has been described whereby in response to a pathogen, the nuclear DNA of the neutrophil decondenses and is released from the cell to form a large sticky web. These Neutrophil extracellular traps (NETs) are decorated with histones—and antimicrobial proteins such as neutrophil elastase, myeloperoxidase (MPO), and α-defensin (Brinkmann et al., 2004Brinkmann V. Reichard U. Goosmann C. Fauler B. Uhlemann Y. Weiss D.S. Weinrauch Y. Zychlinsky A. Science. 2004; 303: 1532-1535Crossref PubMed Scopus (6167) Google Scholar). Furthermore, NETs have been demonstrated to both ensnare and directly kill a number of different bacteria. Although viral infection has classically been studied in the context of the adaptive immune response, a significant amount of evidence exists to suggest a critical role for the innate immune system in the host antiviral immune response. The innate immune system detects viral pathogen-associated molecular patterns (PAMPs) through a diverse array of pattern recognition receptors (PRR), including Toll-like receptor (TLR)-3, 7, and 8, as well as RIG-I and MDA5, suggesting the evolution of an antiviral response within this arm of the immune system. Furthermore, neutrophils themselves have been demonstrated to be essential for the early control of highly pathogenic influenza infections; however, the specific mechanisms involved in this antiviral response remained unclear (Tate et al., 2009Tate M.D. Deng Y.M. Jones J.E. Anderson G.P. Brooks A.G. Reading P.C. J. Immunol. 2009; 183: 7441-7450Crossref PubMed Scopus (245) Google Scholar). In this issue, Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar link the production of NETs by human neutrophils, previously thought of as an antibacterial effector mechanism, to the host antiviral response. In a series of elegant experiments, Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar are able to demonstrate that neutrophils release NETs in response to exposure to HIV virions alone, and that these extracellular DNA structures are able to bind and, more importantly, directly inactivate the HIV virus. This viral neutralization was dependent on the presence of MPO and α-defensin within the NET structure, as destruction of NETs with DNase, inhibition of MPO, or blocking antibodies against α-defensin abrogated the ability of the neutrophils to neutralize HIV. Using superresolution structured illumination microscopy (SR-SIM), Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar were able to capture striking 3D images of NETs at a much higher resolution than is possible with conventional fluorescence microscopy. The images reveal sheets of DNA rather than the previously reported strands or strings. Moreover, these studies clearly illustrate the intricacy of the extracellular DNA structures and directly visualize the capture of intact virus particles by NETs. Through the use of a series of chemical and protein inhibitors, Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar further demonstrate the ability of HIV to induce NET production by neutrophils is dependent on TLR-7, TLR-8, and the generation of ROS (Figure 1). These findings are particularly interesting, as the initiation of NET release by bacteria or bacterial ligands is also dependent on ROS production (Fuchs et al., 2007Fuchs T.A. Abed U. Goosmann C. Hurwitz R. Schulze I. Wahn V. Weinrauch Y. Brinkmann V. Zychlinsky A. J. Cell Biol. 2007; 176: 231-241Crossref PubMed Scopus (2175) Google Scholar). These findings suggest that regardless of the specific nature of the pathogen (bacterial versus viral), stimulation of neutrophils through one of a number of different PRR can result in the activation of a common innate effector response, culminating in the dissolution of the neutrophil's nuclei and the release of NETs in an effort to ensnare and neutralize the invading pathogen. It remains unclear from this study whether this NET production actually led to neutrophil death or whether neutrophils maintained viability and helped to eliminate NET caught pathogens. This interaction between the neutrophil and the virus is not a one-way street whereby the neutrophil simply reacts to the pathogen but rather a complex and dynamic relationship in which the pathogen attempts to modulate the neutrophil's response. As with most host-effector processes, pathogens have evolved strategies and mechanisms to escape NETs. The best characterized of these strategies is the production of nucleases by some bacterial strains to digest NET structures (Buchanan et al., 2006Buchanan J.T. Simpson A.J. Aziz R.K. Liu G.Y. Kristian S.A. Kotb M. Feramisco J. Nizet V. Curr. Biol. 2006; 16: 396-400Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar). The expression of these nucleases contributes to bacterial virulence and facilitates the evasion of the host innate immune response. Importantly, in the current study the authors also identified a means by which HIV is able to regulate NET production by neutrophils; however, rather than targeting the neutrophil or NETs directly, HIV modulates the local immune microenvironment. Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar demonstrate that HIV is able to bind to the surface of dendritic cells (DC) via CD209 (DC-SIGN), a C-type lectin receptor, and induce the production of IL-10, a potent anti-inflammatory cytokine. Treatment of activated neutrophils with supernatants from HIV-treated DC or with purified IL-10 attenuated NET production and significantly reduced the virucidal capacity of human neutrophils. It is important to note that these studies were carried out using an in vitro cell-culture system. Although the work by Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar beautifully characterize the antiviral potential of NETs and the complex dynamic that exists between HIV, DC, and neutrophils, it will be important to understand how these mechanisms function within the context of the host immune response to viruses in vivo. The authors propose that this interaction could occur in the mucosa, but one could also imagine NETs being formed in blood as was reported by Clark et al., 2007Clark S.R. Ma A.C. Tavener S.A. McDonald B. Goodarzi Z. Kelly M.M. Patel K.D. Chakrabarti S. McAvoy E. Sinclair G.D. et al.Nat. Med. 2007; 13: 463-469Crossref PubMed Scopus (1612) Google Scholar. In fact, trying to catch viruses under flow conditions could be quite difficult, but the release of NETs could facilitate the capture of many viral particles by a single cell. Moreover, the efficacy of this novel antiviral response is dependent on the ability of neutrophils to deploy their NETs in such a manner that they are able to ensnare free virus. This mechanism has great potential in limiting viral dissemination but may be of limited value in dealing with virally infected host cells. Furthermore, as indicated by the authors, some viral infections induce neutropenia and, as such, these viruses may be able to limit the antiviral potential of the neutrophil response. Regardless of the potential complexities of the in vivo response, the study by Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar represents a de facto antiviral response and, as suggested by the authors, also represents an exciting opportunity for the development of new therapeutic approaches to viral infections. Strategies targeting neutrophils, and specifically the generation of NETs, may prove to be important tools in limiting viral replication and spread. However, one must be cautious in developing NETs as an antiviral therapy. NETs, like most immune effector mechanisms, are only effective if they are a component of a balanced response. Recent studies have indicated excess NET formation can result in host tissue damage and may be associated with a number of human disease states (Clark et al., 2007Clark S.R. Ma A.C. Tavener S.A. McDonald B. Goodarzi Z. Kelly M.M. Patel K.D. Chakrabarti S. McAvoy E. Sinclair G.D. et al.Nat. Med. 2007; 13: 463-469Crossref PubMed Scopus (1612) Google Scholar; Narasaraju et al., 2011Narasaraju T. Yang E. Samy R.P. Ng H.H. Poh W.P. Liew A.A. Phoon M.C. van Rooijen N. Chow V.T. Am. J. Pathol. 2011; 179: 199-210Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar; Thomas et al., 2012Thomas G.M. Carbo C. Curtis B.R. Martinod K. Mazo I.B. Schatzberg D. Cifuni S.M. Fuchs T.A. von Andrian U.H. Hartwig J.H. et al.Blood. 2012; 119: 6335-6343Crossref PubMed Scopus (230) Google Scholar; Leffler et al., 2012Leffler J. Martin M. Gullstrand B. Tydén H. Lood C. Truedsson L. Bengtsson A.A. Blom A.M. J. Immunol. 2012; 188: 3522-3531Crossref PubMed Scopus (352) Google Scholar). Future immunotherapies directed at controlling viral infections through the generation of NETs will have to strike a balance between viral neutralization and host tissue damage. These findings by Saitoh et al., 2012Saitoh T. Komano J. Saitoh Y. Misawa T. Takahama M. Kozaki T. Uehata T. Iwasaki H. Omori H. Yamaoka S. Yamamoto N. Akira S. Cell Host & Microbe. 2012; 12 (this issue): 109-116Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar open an entirely new chapter in our understanding of the innate immune response to viruses and blur the lines between antiviral and antimicrobial immunity. Furthermore, this study represents a unique opportunity for the development of antiviral therapies, particularly when viral infections are found in the context of neutrophilic inflammation. We thank H. Neto, B. Petri, and C.H. Wong for their critical review of this manuscript. C.N.J. is supported by Alberta Innovates Health Solutions. Neutrophil Extracellular Traps Mediate a Host Defense Response to Human Immunodeficiency Virus-1Saitoh et al.Cell Host & MicrobeJuly 19, 2012In BriefNeutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Full-Text PDF Open Archive
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