Age-related alterations in immune responses to West Nile virus infection.

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West Nile virus (WNV) is a mosquito‐borne, enveloped, positive‐strand RNA virus belonging to the family Flaviviridae. This virus family is particularly well known for yellow fever, dengue and the recently emerging Zika virus 1. Identified originally in Uganda more than 70 years ago, WNV was first identified in the United States in New York City in 1999 and has now spread across North America, South America and the Caribbean. More than 43 000 cases have been reported in the United States, including 1884 fatalities 2, 3, and the cumulative incidence of WNV infection is estimated to reach 3 million people 4. WNV is the most important causative agent of viral encephalitis worldwide and has become an important public health concern in the United States due to its high prevalence, severe disease in humans and the absence of effective treatments or vaccines 1, 3, 5, 6.

Notably, despite documented presence of WNV in Europe, no cases were noted from 1962 to 1985, and WNV was not considered a public health concern there 6. Europe has seen a rise in the number of cases since 2008, with > 2500 cases in the European Union (EU) (n = 788) and neighbouring countries (n = 1786) between 2011 and 2015, approximately 30% of which were in the Russian Federation 7, 8. WNV is now endemic in northern Italy 9. None the less, the case numbers are considerably lower than in the United States, and indeed no cases were detected, despite surveillance programmes, in the United Kingdom, Germany and Switzerland 6, 10. Lower incidence in Europe may be due in part to the lower density of competent Culex and Aedes species mosquito vectors, in contrast to the abundant presence of these mosquitoes across tropical and subtropical regions 11, 12, 13. Furthermore, as birds are required for the viral life cycle 1, bird population management is a factor in local levels of infection and levels of disease in birds can be used to monitor endemic infection 11, 14. The worldwide variation in incidence and severity of WNV infection highlights the many factors that contribute to infection, including climate, vector prevalence, bird populations, viral strain virulence and exposure history 6, 15.

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The majority of WNV infections are asymptomatic (∼80%); however, some infected patients develop mild symptoms of West Nile fever (∼20%) and a small subset (<1%) develop severe neuroinvasive disease, which may include meningitis, encephalitis, acute flaccid paralysis and death 3. Resistance to infection is multi‐factorial but, notably, age is the most well‐defined risk factor – an approximately 20‐fold increased risk at age > 60 – for susceptibility to neurological involvement and retinopathy associated with severe disease 7, 15, 16, 17, 18, 19. In this study, our understanding is reviewed of risk factors for severe infection with WNV and the effects of ageing on elements of immune responses relevant to those factors are highlighted. Understanding the specific immune parameters and mechanisms that influence susceptibility to symptomatic WNV may lead to a better understanding of increased susceptibility in elderly individuals and could be used to identify potential avenues for therapeutic approaches, an especially relevant goal as the world's populating is ageing 20.

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Beyond risk factors related to exposure to infected mosquitoes, individual host factors have been shown to play a role in susceptibility to WNV infection (Fig. ​(Fig.1a).1a). In particular, increased risk for severe infection has been identified with a history of immunosuppression, cardiovascular disease, chronic renal disease and hepatitis C virus infection 7, 21, 22, 23. Genomic studies of WNV cohorts have identified markers associated with host susceptibility to severe WNV infection, including certain human leucocyte antigen (HLA) types and single nucleotide polymorphisms (SNPs) in immune response genes, e.g. interferon (IFN) response pathway elements oligoadenylate synthetase (OAS), IFN regulatory factor 3 (IRF3), myxovirus resistance 1 (MX)‐1, the chemokine C‐C chemokine receptor type 5 (CCR5) and a replication factor and a sodium channel were associated with severity of infection 5, 24, 25, 26, 27, 28, 29, 30. Recent exome sequencing also identified HLA alleles, as well as ion channels, and immune regulation and IFN responses 31. In addition, studies show that a moderate, not exuberant, early response of type I IFN is crucial to control WNV without severe symptoms 32. Thus it is notable that the IFN‐inducible transcription factor E74‐like ETS transcription factor 4 (ELF4), which up‐regulates and amplifies production of IFN, is elevated in subjects with a history of severe infection with WNV 33, 34. Further, other cytokines are also noted to be elevated in patients with neuroinvasive WNV infection, including elevated numbers of WNV‐specific T lymphocytes which produced both IFN‐γ and interleukin (IL)‐4 35, and a heightened IFN‐γ production in response to WNV in natural killer (NK) cells from symptomatic WNV subjects (Yao Y, Strauss‐Albee DM, Zhou JQ, Malawista A, Garcia MN, Murray KO, Blish CA, Montgomery RR., unpublished article). WNV patients homozygous for high‐expression alleles of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were > 20‐fold more likely to have WNV encephalitis, consistent with a murine model showing that MIF is an important determinant of WNV neuropathogenesis 36, 37.

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Figure 1

Determinants of susceptibility to West Nile Virus (WNV). Resistance and susceptibility to WNV infection result from exposure history and immune status including immunosuppression, cardiovascular disease, chronic renal disease and hepatitis C virus infection 7, 21, 22, 23. Individual susceptibility also derives from host factors such as single nucleotide polymorphisms (SNPs) in immune response genes 5, 24, 25, 26, 27, 28, 29, 30, and control of cytokine responses to infection 32, 33, 34, 35, 36, 37 (a). Increased susceptibility to WNV in the elderly encompasses these determinants as well as impairments of immunity in ageing 38, 39 (b).

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Ageing is a critical risk factor for severe infection with WNV 7, 15, 16, 17, 18, 19. Our understanding of the basis for this increased susceptibility remains incomplete and is being investigated actively (Fig. ​(Fig.1b).1b). Ageing is associated with distinct changes in immune cell populations and a progressive decline in immune function leading to increased susceptibility to infection 38, 39. Age‐related changes in immunity are relevant at each step of WNV infection, from recognition of the virus to dissemination and immune responses (Fig. ​(Fig.2).2). WNV is detected by pathogen recognition receptors including Toll‐like receptors (TLRs), which show reduced expression and functional efficiency in older donors 39. This is particularly relevant in the skin (Fig. ​(Fig.2a)2a) for innate immune cells of the myeloid lineage, monocyte/macrophages and dendritic cells (DCs), which employ TLRs to recognize pathogens 40. In addition, TLR‐7 has been shown to mediate immune cell homing to WNV‐infected cells 41. Many functions of macrophages are known to be diminished with ageing, such as chemotaxis, phagocytosis, intracellular killing, production of reactive oxygen species and cytokines, expression of major histocompatibility complex (MHC) class II and co‐stimulatory molecules. These changes are mediated largely by reductions in signalling mediators such as p38 mitogen‐activated protein kinase (MAPK), nuclear factor kappa B (NF‐κB), myeloid differentiation primary response gene 88 (MyD88) and the phosphorylation capacity of signal transducer and activator of transcription (STAT)‐1α 42, 43. In WNV studies, primary human macrophages showed age‐dependent impairment in TLR‐3‐mediated anti‐WNV responses, leading to an early and sustained elevation of cytokines 44. While cytokine responses are essential to initiate immune responses and viral control, elevated levels of some cytokines have been shown to be detrimental in WNV infection 32, 33, 34, 35, 36, 37. Thus, age‐related over‐exuberant cytokine production that disrupts the balance may be expected to be detrimental to anti‐WNV responses.

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Figure 2

Schematic of key interfaces of West Nile Virus (WNV) susceptibility. Barriers to WNV infection by mosquito vector occur at numerous levels in the host from (a) skin surveillance by innate immune cells which recognize WNV and initiate innate immune responses; (b) blood‐borne or (c) lymphatic dissemination; (d) lymph nodes for priming of adaptive T and B lymphocyte responses; and (e) the blood–brain barrier which protects the brain from infection. Each barrier shows reduced efficiency in ageing that contributes to increased susceptibility to WNV.

DCs also demonstrate an age‐related decline in chemotaxis, endocytosis, a global reduction in expression of expression of TLR‐1, ‐3, ‐5, ‐7 and ‐8, production of IL‐12 and antigen presentation, leading to impaired activation of naive T cells 39. Paradoxically, DCs from elderly individuals also produce a higher basal level of cytokines [e.g. tumour necrosis factor (TNF)‐α, IL‐6 and IL‐2], which can contribute to inflammation. Induction of co‐stimulatory markers (CD80, CD86), TLR‐7 and WNV‐induced type I IFN were significantly lower in dendritic cells (DCs) from older human donors compared to younger donors 45, and older mice showed impaired TLR‐7 signalling following WNV infection 46. Such critical deficits in DC signalling pathways would be expected to contribute to the increased susceptibility to WNV infections in elderly people.

Retinoic acid inducible protein 1 (RIG‐I)‐like receptors (RLRs) are important in the recognition of WNV 47, 48 and have been shown recently in monocytes from older donors to have impaired signalling leading to low induction of IFN and reduced resistance to influenza virus infection 49. RIG‐I activation is regulated by acetylation mediated by histone deactylase 6 50. Notably, histone deactylation contributes to ageing‐related muscle atrophy in a mouse model 51 and may be relevant to RIG‐I activation and the age‐related heightened immune state of ‘inflammageing’ 52. Potential effects of ageing on the viral DNA sensor cGAS, which also plays a role in WNV responses 53, remain to be determined.

Neutrophils, which are the first cells to respond to infection, show impairment with ageing of many functions relevant to anti‐viral responses, including chemotaxis, phagocytosis, superoxide production, neutrophil extracellular traps (NET) formation, TLR expression and apoptosis 54, 55, 56, 57. Although, in the early stages of infection, neutrophils serve as a reservoir for WNV replication and dissemination (Fig. ​(Fig.2b,c),2b,c), they play a role later in WNV clearance 58 and have been noted to play a similar dual role in related arbovirus infections 59. Thus age‐related reduction in functional activity probably contributes to the increased susceptibility to WNV infection in older subjects.

Tissue‐specific IFN signalling pathways and expression of IFN‐induced genes are critical in restricting WNV infection 60, 61. IFNs induce multiple response genes with anti‐viral activity, such as IFN‐response gene (ifit)2 and ifit3 62, 63, and detailed studies have identified IFN‐β promoter stimulator 1 (IPS‐1), working through RIG‐I, to induce IFN in myeloid cells 64. In addition, IFNs are critical for the recruitment and activation of NK cells 65. NK cells have been associated with the control of many viral infections including HIV‐1 and WNV 66, 67, 68, 69, 70. Recent studies have used mass cytometry (CyTOF) to highlight the NK cell repertoire. Notably, increases in diversity of the NK repertoire following infection with either HIV or WNV lead to terminal differentiation and reduced degranulation and an increased risk of viral acquisition 70. In ageing, NK cells show increased levels of a mature phenotype (CD57+) and receptor repertoire co‐ordinated with higher cytokine production, reduced expression of activating receptors DNAX accessory molecule 1 (DNAM‐1) and NKp30 and NKp46, as well as impaired cytotoxicity and decreased production of granzyme A 71, 72, 73. These age‐related changes effect NK function and may contribute to reduced efficiency of anti‐WNV responses.

Although studied in less depth, γδ T cells produce inflammatory cytokines (IL‐17, IL‐10 and TGF‐β) in mouse models of WNV infections and deficient mice [T cell receptor (TCR)δ–/–] show increased susceptibility to WNV 74. The frequency and absolute number of γδ T cells are reduced in ageing, which may contribute to reduced anti‐viral efficiency in WNV infection 75, 76.

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In addition to the reduction in innate recognition and signalling in ageing, age‐related alterations of adaptive immunity compound these reduced efficiencies and play a critical role in increased susceptibility to WNV in elderly people (Fig. ​(Fig.2d).2d). The reduction in naive T and B cells and dysregulated signal transduction and cytokine production, probably unrelated to chronic herpesvirus infection 77, 78, lead to decreased expansion and function of antigen‐specific T and B cells 79. However, production of antibodies to WNV antigens did not differ with disease severity, suggesting that antibody levels do not correlate with susceptibility 80. Both CD4 and CD8 T cells 81, 82 are involved in resistance to WNV, as shown by elevated levels of T cell immunoglobulin and mucin domain‐3 (Tim‐3)+ (inhibitory) T cells in WNV infection 83. Regulatory T cells (Tregs) control acute infection 84 and were elevated in patients with a history of severe disease 34. Although human CD8 T cell responses to WNV are maintained despite ageing phenotypes 85, 86, several studies have shown age‐related dysregulation of responses to WNV in T cells from older mice 46, 87, including an age‐dependent decrease in trafficking of T cells in lymph nodes compounded by deficient cytokine production 88. Moreover, aged mice show lower levels of primary and memory T and B cell responses induced by vaccination with West Nile encephalitis vaccine, and repeated invivo restimulation is needed to generate protective cellular and humoral immunity in older animals 89. It is interesting to speculate whether reduced response to vaccination in ageing may be beneficial overall in infection with WNV, although not for other pathogens, by tempering cytokine production and inflammatory damage. While recent observations suggest that caloric restriction or treatment with rapamycin may be beneficial for longevity, these treatments reduced the function of T cells in infection with WNV with an adverse outcome 90.

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Permeability of the blood–brain barrier, which is enhanced by cytokine responses, has been shown to be critical to susceptibility of neuroinvasive WNV infection (Fig. ​(Fig.2e)2e) 91. The blood–brain barrier is a specialized physiological and functional barrier that separates the nervous system from the circulatory system and is essential to maintain a carefully regulated homeostasis within the brain. The blood–brain barrier has a well‐documented functional decline with ageing leading to increased leakage of soluble factors and immune cell infiltration 92. Elements that decrease the integrity of the blood–brain barrier contribute to entry of WNV into the brain and susceptibility to severe infection with WNV 15. These include cytokines, adhesion molecules, proteases and infected leucocytes 37, 41, 93, 94, 95, 96, 97. TNF‐α may contribute to severe disease by promoting blood–brain barrier permeability 93, and recent studies have identified activity of IFN‐λ at epithelial cell barriers as a critical factor in restricting viral invasion of the brain 98, 99. During infection with WNV, CD8+ T cells expand dramatically and migrate to the site of CNS infection in response to neuronally derived CXCL10 100, 101, 102. Leucocytes crossing the blood–brain barrier may enhance disease by trafficking virus into the brain or increasing inflammation, or alternatively protect from severe disease, by promoting monocyte accumulation, which is critical to anti‐viral activity in the brain or CD8 T cell control of virus 103, 104.

Effects of ageing on these pathways are not defined fully; however, for control of virus in the brain, IL‐1β has been shown to be critically important in resistance to WNV, and animals lacking IL‐1β or inflammasome signalling had elevated viral load and reduced CD8 cell immunity in the central nervous system (CNS) 105. In the brain, IL‐1β and IL‐1R1 signalling restrict WNV 105, 106, as does ifit2 62. Notably, chief among the differences revealed from a systems immunology profile of a stratified cohort of subjects with a history of asymptomatic or severe infection with WNV was decreased IL‐1β production by macrophages and decreased CXCL10 expression from myeloid dendritic cells in response to WNV infection 34. Relevant to these observations is that IL‐1β is also a key factor in neural inflammation in autoimmune disease 38. The IFN‐IL‐1β pathway is closely connected, with myeloid cells exhibiting suppression of IL‐1β transcription upon IFN receptor engagement, perhaps mediated by the IRF8/IRF1 transcription regulation 107, 108. While effects of ageing on these pathways are not defined, these observations may be key to protection from severe disease.

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Several microRNAs, non‐coding short RNAs involved in post‐transcriptional regulation of gene expression, including micro‐RNA (miR)‐196a, ‐202‐3p, ‐449c and ‐125a‐3p, have been shown to be expressed differentially following WNV infection, suggesting their potential role in WNV resistance and pathogenesis 109, 110. Notably, numerous miRNAs are altered with ageing, which may be relevant to deficits noted in age‐related immune responses 111, 112. Specific mechanisms have yet to be elucidated for miRNA regulation in age‐related WNV susceptibility.

The TAM receptors [TYRO3 protein tyrosine kinase (Tyro3), AXL receptor tyrosine kinase (Axl) and MER proto‐oncogene, tyrosine kinase (Mertk)] are a family of homologous receptor‐tyrosine kinases expressed in monocytes and macrophages that suppress TLRs and lead to downstream pathways to control excess stimulation and restore homeostatic balance 113, 114, 115. Mice deficient for the homeostatic regulatory receptors, Mertk and Axl were more susceptible to WNV due to elevations in blood–brain barrier permeability 116. Mertk and type I IFN mediate tightening of tight junctions and reduce blood–brain barrier permeability 116. Recently, another role for these receptors has been recognized, related to identification of a family of receptors including TAMs and CD300a that facilitate viral uptake mediated by phosphatidyl serine, which binds virus and bridges binding to Mertk 117, 118, 119. Age‐related up‐regulation of one TAM receptor, Axl, has been noted previously in human DCs from older donors 45 and might contribute to increased viral uptake.

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WNV gained public attention following its rapid spread throughout the continental United States and neighbouring countries. Thanks to active investigation, we have a good understanding of the ecology of WNV reservoirs and epidemiology of cases. However, unlike other recent dramatic viral epidemics, such as Ebola and Zika viruses, WNV is a particular concern for elderly people. Development of treatments is ongoing, with recent testing in vitro of Parkinson's drugs showing effective reduction of viral reproduction 120; development of some small molecule therapeutics that induce anti‐viral gene transcription relevant against broad viral targets 121; and use of a synthetic TLR‐4 agonist to increase efficacy of a WNV envelope‐protein based vaccine candidate 122. However, no novel therapeutics are yet available for WNV treatment or prevention. With ongoing research efforts, our understanding of the role of cytokines and inflammation in age‐related susceptibility to WNV infection is growing. An increased proinflammatory milieu prevails in ageing, and immunotherapeutics now provide specific pharmacological blockade of IL‐1β activity in inflammatory diseases. Agents such as anakinra have an excellent safety record and multiple routes of administration, and resveratrol shows a strong inhibitory effect on proinflammatory marker secretion 123, 124. However, IL‐1β plays an important role in controlling WNV in the neurological WNV infection, so tissue‐specific balance is essential to guide development of targeted therapeutic approaches.

The need for greater understanding and treatments is compelling. A large portion of the world has a habitat suitable for Aedes mosquitoes and our population is ageing. Thus the range of the main WNV vector mosquito leads to potential exposure of > 2 billion people 13. Heightened attention to preventive measures and precautions is essential, particularly for older people, as well as intensified effort for discovery of targeted immune therapeutics.


Immunosenescence: the importance of considering age in health and disease. Clinical and Experimental Immunology 2017, 187: 1–3.

The convergence of senescence and nutrient sensing during lymphocyte ageing. Clinical and Experimental Immunology 2017, 187: 4–5.

Immune senescence: significance of the stromal microenvironment. Clinical and Experimental Immunology 2017, 187: 6–15.

Innate immune responses in the ageing lung. Clinical and Experimental Immunology 2017, 187: 16–25.

Intracellular signalling pathways: targets to reverse immunosenescence. Clinical and Experimental Immunology 2017, 187: 35–43.

Ageing and inflammation in patients with HIV infection. Clinical and Experimental Immunology 2017, 187: 44–52.

Considerations for successful cancer immunotherapy in aged hosts. Clinical and Experimental Immunology 2017, 187: 53–63.

Ageing and obesity similarly impair antibody responses. Clinical and Experimental Immunology 2017, 187: 64–70.

The life cycle of a T cell after vaccination – where does immune ageing strike? Clinical and Experimental Immunology 2017, 187: 71–81.

Herpes zoster and the search for an effective vaccine. Clinical and Experimental Immunology 2017, 187: 82–92.

Adult vaccination against tetanus and diphtheria: the European perspective. Clinical and Experimental Immunology 2017, 187: 93–99.

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The author has no disclosure to declare.

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This work is supported in part by awards from the NIH (N01‐HHSN272201100019C and U19 AI 089992). The author thanks many colleagues for helpful discussions, Anna Malawista for valuable assistance, and regrets the omission of many excellent papers due to limitations of space.

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  1. Gubler DJ. The continuing spread of West Nile virus in the western hemisphere. Clin Infect Dis2007; 45:1039–46. [PubMed] [Google Scholar]
  2. Centers for Disease Control and Prevention CDC. West Nile virus, Final Cumulative Maps and Data for 1999–2014; 2015. Available at: May 31, 2016
  3. Lindsey NP, Lehman JA, Staples JE, Fischer M. West Nile virus and other arboviral diseases—United States, 2014. Morb Mortal Wkly Rep2015; 64:929. [PubMed] [Google Scholar]
  4. Petersen LR, Carson PJ, Biggerstaff BJ, Custer B, Borchardt SM, Busch MP. Estimated cumulative incidence of West Nile virus infection in US adults, 19990000Epidemiol Infect2013; 141:591–5. [PubMed] [Google Scholar]
  5. Colpitts TM, Conway MJ, Montgomery RR, Fikrig E. West Nile virus: biology, transmission and human infection. Clin Microbiol Rev2012; 25:635–48. [PMC free article] [PubMed] [Google Scholar]
  6. Chancey C, Grinev A, Volkova E, Rios M. The global ecology and epidemiology of West Nile virus. BioMed Res Int2015; 2015:376230. [PMC free article] [PubMed] [Google Scholar]
  7. Gray TJ, Webb CE. A review of the epidemiological and clinical aspects of West Nile virus. Int J Gen Med2014; 7:193–203. [PMC free article] [PubMed] [Google Scholar]
  8. Pisani G, Cristiano K, Pupella S, Liumbruno GM. West Nile Virus in Europe and safety of blood transfusion. Transfus Med Hemother2016; 43:158–67. [PMC free article] [PubMed] [Google Scholar]
  9. Gobbi F, Capelli G, Angheben A et alHuman and entomological surveillance of West Nile fever, dengue and chikungunya in Veneto Region, Italy, 20100000BMC Infect Dis 2014; 14:60. [PMC free article] [PubMed] [Google Scholar]
  10. Dreier J, Vollmer T, Hinse D, Heuser EJ, Pisani G, Knabbe C. Implementation of NAT screening for West Nile virus and experience with seasonal testing in Germany. Transfus Med Hemother2016; 43:28–36. [PMC free article] [PubMed] [Google Scholar]
  11. Chiari M, Calzolari M, Prosperi A et alSurveillance of mosquitoes and selected arthropodborne viruses in the context of Milan EXPO 2015Int J Environ Res Public Health 2016; 13:E689. [PMC free article] [PubMed] [Google Scholar]
  12. Kraemer MU, Sinka ME, Duda KA et alThe global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus . Elife 2015; 4:e08347. [PMC free article] [PubMed] [Google Scholar]
  13. Messina JP, Kraemer MU, Brady OJ et alMapping global environmental suitability for Zika virus. Elife 2016; 5:e15272. [PMC free article] [PubMed] [Google Scholar]
  14. Thompson M, Berke O. Evaluation of the control of West Nile virus in Ontario: did risk patterns change from 2005 to 2012?Zoonoses Public Health 2016; doi:10.1111/zph.12285. [PubMed] [Google Scholar]
  15. Montgomery RR, Murray KO. Risk factors for West Nile virus Infection and disease in populations and individuals. Expert Rev Anti Infect Ther2015; 13:317–25. [PMC free article] [PubMed] [Google Scholar]
  16. Hayes EB, Komar N, Nasci RS, Montgomery SP, O'Leary DR, Campbell GL. Epidemiology and transmission dynamics of West Nile virus disease. Emerg Infect Dis2005; 11:1167–73. [PMC free article] [PubMed] [Google Scholar]
  17. Hasbun R, Garcia MN, Kellaway J et alWest Nile virus retinopathy and associations with long term neurological and neurocognitive sequelae. PLOS ONE 2016; 11:e0148898. [PMC free article] [PubMed] [Google Scholar]
  18. Centers for Disease Control (CDC) . West Nile virus Final Cumulative Maps and Data for 19990000; 2015. Available at: May 31, 2016
  19. Williamson PC, Custer B, Biggerstaff BJ et alIncidence of West Nile virus infection in the DallasFort Worth metropolitan area during the 2012 epidemicEpidemiol Infect 2016; 1–9. [PubMed] [Google Scholar]
  20. United Nations Department of Economic and Social Affairs, Population Department. World Population Ageing 2013. New York: UN Population Division, 2013: ST/ESA/SER.A/348.
  21. Murray K, Baraniuk S, Resnick M et alRisk factors for encephalitis and death from West Nile virus infection. Epidemiol Infect 2006; 134:1325–32. [PMC free article] [PubMed] [Google Scholar]
  22. Sejvar JJ, Lindsey NP, Campbell GL. Primary causes of death in reported cases of fatal West Nile Fever, United States, 2002–2006. Vector Borne Zoonotic Dis2011; 11:161–4. [PubMed] [Google Scholar]
  23. Baymakova M, Trifonova I, Panayotova E et alFatal case of West Nile neuroinvasive disease in Bulgaria. Emerg Infect Dis 2016; 22. [PMC free article] [PubMed] [Google Scholar]
  24. Lanteri MC, Kaidarova Z, Peterson T et alAssociation between HLA class I and class II alleles and the outcome of West Nile virus infection: an exploratory study. PLOS ONE 2011; 6:e22948. [PMC free article] [PubMed] [Google Scholar]
  25. Yakub I, Lillibridge KM, Moran A et alSingle nucleotide polymorphisms in genes for 2′5′oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infectionJ Infect Dis 2005; 192:1741–8. [PubMed] [Google Scholar]
  26. Lim JK, Lisco A, McDermott DH et alGenetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLOS Pathog 2009; 5:e1000321. [PMC free article] [PubMed] [Google Scholar]
  27. Bigham AW, Buckingham KJ, Husain S et alHost genetic risk factors for West Nile virus infection and disease progression. PLOS ONE 2011; 6:e24745. [PMC free article] [PubMed] [Google Scholar]
  28. Loeb M, Eskandarian S, Rupp M. Genetic variants and susceptibility to neurological complications following West Nile virus infection. J Infect Dis2011; 204:1031. [PMC free article] [PubMed] [Google Scholar]
  29. Loeb M. Genetic susceptibility to West Nile virus and dengue. Public Health Genomics2013; 16:4–8. [PubMed] [Google Scholar]
  30. Lim JK, McDermott DH, Lisco A et alCCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J Infect Dis 2010; 201:178–85. [PMC free article] [PubMed] [Google Scholar]
  31. Long D, Deng X, Singh P, Loeb M, Lauring AS, Seielstad M. Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease. Genes Immun2016; 17:298–304. [PMC free article] [PubMed] [Google Scholar]
  32. Hoffman KW, Sachs D, Bardina SV et alDifferences in early cytokine production are associated with greater symptom development following WNV infection. Journal of Infectious Diseases 2016; 214:634–43. [PMC free article] [PubMed] [Google Scholar]
  33. You F, Wang P, Yang L et alELF4 is critical for induction of type I interferon and the host antiviral response. Nat Immunol 2013; 14:1237–46. [PMC free article] [PubMed] [Google Scholar]
  34. Qian F, Goel G, Meng H et alSystems immunology reveals markers of susceptibility to West Nile virus infection. Clin Vaccine Immunol 2015; 22:6–16. [PMC free article] [PubMed] [Google Scholar]
  35. James EA, Gates TJ, LaFond RE et alNeuroinvasive West Nile infection elicits elevated and atypically polarized T cell responses that promote a pathogenic outcome. PLOS Pathog 2016; 12:e1005375. [PMC free article] [PubMed] [Google Scholar]
  36. Arjona A, Foellmer H, Town T et alAbrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 2007; 117:3059–66. [PMC free article] [PubMed] [Google Scholar]
  37. Das R, Loughran K, Murchison C et alAssociation between high expression macrophage migration inhibitory factor (MIF) Alleles and West Nile virus encephalitis. Cytokine 2016; 78:51–4. [PMC free article] [PubMed] [Google Scholar]
  38. Carr EJ, Dooley J, GarciaPerez JE et alThe cellular composition of the human immune system is shaped by age and cohabitationNat Immunol 2016; 17:461–8. [PMC free article] [PubMed] [Google Scholar]
  39. Shaw AC, Goldstein DR, Montgomery RR. Agedependent dysregulation of innate immunityNat Rev Immunol2013; 13:875–87. [PMC free article] [PubMed] [Google Scholar]
  40. Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J Biochem2007; 141:137–45. [PubMed] [Google Scholar]
  41. Town T, Bai F, Wang T et alTlr7 mitigates lethal West Nile encephalitis by affecting interleukin 23dependent immune cell infiltration and homingImmunity 2009; 30:242–53. [PMC free article] [PubMed] [Google Scholar]
  42. Montgomery RR, Shaw AC. Paradoxical changes in innate immunity in aging: recent progress and new directions. J Leukoc Biol2015; 98:937–43. [PMC free article] [PubMed] [Google Scholar]
  43. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol2012; 331–41. [PubMed] [Google Scholar]
  44. Kong KF, Delroux K, Wang X et alDysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderlyJ Virol 2008; 82:7613–23. [PMC free article] [PubMed] [Google Scholar]
  45. Qian F, Wang X, Zhang l et alImpaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J Infect Dis 2011; 203:1415–24. [PMC free article] [PubMed] [Google Scholar]
  46. Xie G, Luo H, Pang L et alDysregulation of tolllike receptor 7 compromises innate and adaptive T cell responses and host resistance to an attenuated West Nile virus infection in old miceJ Virol 2015; 90:1333–44. [PMC free article] [PubMed] [Google Scholar]
  47. Wang P, Arjona A, Zhang Y et alCaspase12 controls West Nile virus infection via the viral RNA receptor RIGINatImmunol 2010; 11:912–9. [PMC free article] [PubMed] [Google Scholar]
  48. Lazear HM, Diamond MS. New insights into innate immune restriction of West Nile virus infection. Curr Opin Virol2015; 11:1–6. [PMC free article] [PubMed] [Google Scholar]
  49. Pillai PS, Molony RD, Martinod K et alMx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 2016; 352:463–6. [PMC free article] [PubMed] [Google Scholar]
  50. Liu HM, Jiang F, Loo YM et alRegulation of retinoic acid inducible geneI (RIGI) activation by the histone deacetylase 6EBioMedicine 2016; 9:195–206. [PMC free article] [PubMed] [Google Scholar]
  51. Walsh ME, Bhattacharya A, Sataranatarajan K et alThe histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging. Aging Cell 2015; 14:957–70. [PMC free article] [PubMed] [Google Scholar]
  52. Franceschi C, Capri M, Monti D et alInflammaging and antiinflammaging: a systemic perspective on aging and longevity emerged from studies in humansMech Ageing Dev 2007; 128:92–105. [PubMed] [Google Scholar]
  53. Schoggins JW, MacDuff DA, Imanaka N et alPanviral specificity of IFNinduced genes reveals new roles for cGAS in innate immunityNature 2014; 505:691–5. [PMC free article] [PubMed] [Google Scholar]
  54. Butcher SK, Chahal H, Nayak L et alSenescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol 2001; 70:881–6. [PubMed] [Google Scholar]
  55. Fulop T, Larbi A, Douziech N et alSignal transduction and functional changes in neutrophils with aging. Aging Cell 2004; 3:217–26. [PubMed] [Google Scholar]
  56. Hazeldine J, Harris P, Chapple IL et alImpaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell 2014; 13:690–8. [PMC free article] [PubMed] [Google Scholar]
  57. Qian F, Guo X, Wang X et alReduced bioenergetics and Tolllike receptor 1 function in human polymorphonuclear leukocytes in agingAging 2014; 6:131–9. [PMC free article] [PubMed] [Google Scholar]
  58. Bai F, Kong KF, Dai J et alA paradoxical role for neutrophils in the pathogenesis of West Nile virusJ Infect Dis 2010; 202:1804–12. [PMC free article] [PubMed] [Google Scholar]
  59. Pingen M, Bryden SR, Pondeville E et alHost inflammatory response to mosquito bites enhances the severity of arbovirus infection. Immunity 2016; 44:1455–69. [PMC free article] [PubMed] [Google Scholar]
  60. Samuel MA, Diamond MS. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol2005; 79:13350–61. [PMC free article] [PubMed] [Google Scholar]
  61. Grubaugh ND, Massey A, Shives KD, Stenglein MD, Ebel GD, Beckham JD. West Nile virus population structure, injury, and interferonstimulated gene expression in the brain from a fatal case of encephalitisOpen Forum Infect Dis2016; 3:ofv182. [PMC free article] [PubMed] [Google Scholar]
  62. Cho H, Shrestha B, Sen GC, Diamond MS. A role for Ifit2 in restricting West Nile virus infection in the brain. J Virol2013; 87:8363–71. [PMC free article] [PubMed] [Google Scholar]
  63. Gorman MJ, Poddar S, Farzan M, Diamond MS. The interferonstimulated gene IFITM3 restricts West Nile virus infection and pathogenesisJ Virol2016; 90:8212–25. [PMC free article] [PubMed] [Google Scholar]
  64. Daffis S, Suthar MS, Szretter KJ, Gale M Jr, Diamond MS. Induction of IFNbeta and the innate antiviral response in myeloid cells occurs through an IPS1dependent signal that does not require IRF3 and IRF7PLOS Pathog2009; 5:e1000607. [PMC free article] [PubMed] [Google Scholar]
  65. Suthar MS, Brassil MM, Blahnik G et alA systems biology approach reveals that tissue tropism to West Nile virus is regulated by antiviral genes and innate immune cellular processes. PLOS Pathog 2013; 9:e1003168. [PMC free article] [PubMed] [Google Scholar]
  66. LopezVerges S, Milush JM, Schwartz BS et alExpansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infectionProc Natl Acad Sci USA 2011; 108:14725–32. [PMC free article] [PubMed] [Google Scholar]
  67. Jost S, Altfeld M. Control of human viral infections by natural killer cells. Annu Rev Immunol2013; 31:163–94. [PubMed] [Google Scholar]
  68. Nielsen CM, White MJ, Bottomley C et alImpaired NK cell responses to pertussis and H1N1 influenza vaccine antigens in human cytomegalovirusinfected individualsJ Immunol 2015; 194:4657–67. [PMC free article] [PubMed] [Google Scholar]
  69. Zhang M, Daniel S, Huang Y et alAntiWest Nile virus activity of in vitro expanded human primary natural killer cellsBMC Immunol 2010; 11:3. [PMC free article] [PubMed] [Google Scholar]
  70. StraussAlbee DM, Fukuyama J, Liang EC et alHuman NK cell repertoire diversity reflects immune experience and correlates with viral susceptibilitySci Transl Med 2015; 7:297ra115. [PMC free article] [PubMed] [Google Scholar]
  71. Le GarffTavernier M, Beziat V, Decocq J et alHuman NK cells display major phenotypic and functional changes over the life spanAging Cell 2010; 9:527–35. [PubMed] [Google Scholar]
  72. Hazeldine J, Lord JM. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev2013; 12:1069–78. [PMC free article] [PubMed] [Google Scholar]
  73. Solana R, Campos C, Pera A, Tarazona R. Shaping of NK cell subsets by aging. Curr Opin Immunol2014; 29:56–61. [PubMed] [Google Scholar]
  74. Wang T, Gao Y, Scully E et alGamma delta T cells facilitate adaptive immunity against West Nile virus infection in mice. J Immunol 2006; 177:1825–32. [PubMed] [Google Scholar]
  75. Argentati K, Re F, Donnini A et alNumerical and functional alterations of circulating gammadelta T lymphocytes in aged people and centenarians. J Leukoc Biol 2002; 72:65–71. [PubMed] [Google Scholar]
  76. ColonnaRomano G, Aquino A, Bulati M et alImpairment of gamma/delta T lymphocytes in elderly: implications for immunosenescenceExp Gerontol 2004; 39:1439–46. [PubMed] [Google Scholar]
  77. CicinSain L, Brien JD, Uhrlaub JL, Drabig A, Marandu TF, NikolichZugich J. Cytomegalovirus infection impairs immune responses and accentuates Tcell pool changes observed in mice with agingPLOS Pathog2012; 8:e1002849. [PMC free article] [PubMed] [Google Scholar]
  78. Marandu TF, Oduro JD, Borkner L et alImmune protection against virus challenge in aging mice is not affected by latent herpesviral infections. J Virol 2015; 89:11715–7. [PMC free article] [PubMed] [Google Scholar]
  79. Frasca D, Blomberg BB. B cell function and influenza vaccine responses in healthy aging and disease. Curr Opin Immunol2014; 29:112–8. [PMC free article] [PubMed] [Google Scholar]
  80. Qian F, Thakar J, Yuan X et alImmune markers associated with host susceptibility to infection with West Nile virus. Viral Immunol 2014; 27:39–47. [PMC free article] [PubMed] [Google Scholar]
  81. Sitati EM, Diamond MS. CD4+ Tcell responses are required for clearance of West Nile virus from the central nervous systemJ Virol2006; 80:12060–9. [PMC free article] [PubMed] [Google Scholar]
  82. Shrestha B, Diamond MS. Role of CD8+ T cells in control of West Nile virus infection. J Virol2004; 78:8312–21. [PMC free article] [PubMed] [Google Scholar]
  83. Lanteri MC, Diamond MS, Law JP et alIncreased frequency of Tim3 expressing T cells is associated with symptomatic West Nile virus infectionPLOS ONE 2014; 9:e92134. [PMC free article] [PubMed] [Google Scholar]
  84. Lanteri MC, O'Brien KM, Purtha WE et alTregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest 2009; 119:3266–77. [PMC free article] [PubMed] [Google Scholar]
  85. Parsons R, Lelic A, Hayes L et alThe memory T cell response to West Nile virus in symptomatic humans following natural infection is not influenced by age and is dominated by a restricted set of CD8+ T cell epitopes. J Immunol 2008; 181:1563–72. [PubMed] [Google Scholar]
  86. Lelic A, Verschoor CP, Ventresca M et alThe polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age. PLOS Pathog 2012; 8:e1003076. [PMC free article] [PubMed] [Google Scholar]
  87. Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, NikolichZugich J. Key role of T cell defects in agerelated vulnerability to West Nile virusJ Exp Med2009; 206:2735–45. [PMC free article] [PubMed] [Google Scholar]
  88. Richner JM, Gmyrek GB, Govero J et alAgedependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of West Nile virus infectionPLOS Pathog 2015; 11:e1005027. [PMC free article] [PubMed] [Google Scholar]
  89. Uhrlaub JL, Brien JD, Widman DG, Mason PW, NikolichZugich J. Repeated in vivostimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitisJ Immunol 2011; 186:3882–91. [PMC free article] [PubMed] [Google Scholar]
  90. Goldberg EL, RomeroAleshire MJ, Renkema KR et alLifespanextending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanismsAging Cell 2015; 14:130–8. [PMC free article] [PubMed] [Google Scholar]
  91. Cho H, Diamond MS. Immune responses to West Nile virus infection in the central nervous system. Viruses2012; 4:3812–30. [PMC free article] [PubMed] [Google Scholar]
  92. Gorle N, Van Cauwenberghe C, Libert C, Vandenbroucke RE. The effect of aging on brain barriers and the consequences for Alzheimer's disease development. Mamm Genome2016; 27:407–20. [PubMed] [Google Scholar]
  93. Wang T, Town T, Alexoupoulou L, Anderson JF, Fikrig E, Flavell RA. Tolllike receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitisNat Med2004; 10:1366–73. [PubMed] [Google Scholar]
  94. Wang P, Dai J, Bai F et alMatrix metalloproteinase 9 facilitates West Nile Virus entry into the brain. J Virol 2008; 82:8978–85. [PMC free article] [PubMed] [Google Scholar]
  95. Dai J, Wang P, Bai F, Town T, Fikrig E. ICAM1 participates in the entry of West Nile virus into the central nervous systemJ Virol2008; 82:4164. [PMC free article] [PubMed] [Google Scholar]
  96. Wang S, Welte T, McGargill M et alDrak2 contributes to West Nile virus entry into the brain and lethal encephalitis. J Immunol 2008; 181:2084–91. [PMC free article] [PubMed] [Google Scholar]
  97. Wang P, Bai F, Zenewicz LA et alIL22 signaling contributes to West Nile virus encephalitis pathogenesisPLOS ONE 2012; 7:e44153. [PMC free article] [PubMed] [Google Scholar]
  98. Lazear HM, Nice TJ, Diamond MS, Interferon l. Immune functions at barrier surfaces and beyond. Immunity2015; 43:15–28. [PMC free article] [PubMed] [Google Scholar]
  99. Lazear HM, Daniels BP, Pinto AK et alInterferonlambda restricts West Nile virus neuroinvasion by tightening the blood–brain barrierSci Transl Med 2015; 7:284ra59. [PMC free article] [PubMed] [Google Scholar]
  100. King NJ, Getts DR, Getts MT, Rana S, Shrestha B, Kesson AM. Immunopathology of flavivirus infections. Immunol Cell Biol2007; 85:33–42. [PubMed] [Google Scholar]
  101. Klein RS, Lin E, Zhang B et alNeuronal CXCL10 directs CD8+ Tcell recruitment and control of West Nile virus encephalitisJ Virol 2005; 79:11457–66. [PMC free article] [PubMed] [Google Scholar]
  102. Zhang B, Chan YK, Lu B, Diamond MS, Klein RS. CXCR3 mediates regionspecific antiviral T cell trafficking within the central nervous system during West Nile virus encephalitisJ Immunol2008; 180:2641–9. [PubMed] [Google Scholar]
  103. Shrestha B, Zhang B, Purtha WE, Klein RS, Diamond MS. Tumor necrosis factor alpha protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system. J Virol2008; 82:8956–64. [PMC free article] [PubMed] [Google Scholar]
  104. Lim JK, Obara CJ, Rivollier A, Pletnev AG, Kelsall BL, Murphy PM. Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in West Nile virus encephalitis. J Immunol2011; 186:471–8. [PMC free article] [PubMed] [Google Scholar]
  105. Ramos HJ, Lanteri MC, Blahnik G et alIL1beta signaling promotes CNSintrinsic immune control of West Nile virus infectionPLOS Pathog 2012; 8:e1003039. [PMC free article] [PubMed] [Google Scholar]
  106. Durrant DM, Robinette ML, Klein RS. IL1R1 is required for dendritic cellmediated T cell reactivation within the CNS during West Nile virus encephalitisJ Exp Med2013; 210:503–16. [PMC free article] [PubMed] [Google Scholar]
  107. Castiglia V, Piersigilli A, Ebner F et alType I interferon signaling prevents IL1betadriven lethal systemic hyperinflammation during invasive bacterial infection of soft tissueCell Host Microbe 2016; 19:375–87. [PubMed] [Google Scholar]
  108. Langlais D, Barreiro LB, Gros P. The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J Exp Med2016; 213:585–603. [PMC free article] [PubMed] [Google Scholar]
  109. Chugh PE, Damania BA, Dittmer DP. Tolllike receptor3 is dispensable for the innate microRNA response to West Nile virus (WNV)PLOS ONE2014; 9:e104770. [PMC free article] [PubMed] [Google Scholar]
  110. Kumar M, Nerurkar VR. Integrated analysis of microRNAs and their disease related targets in the brain of mice infected with West Nile virus. Virology2014; 452–453:143–51. [PMC free article] [PubMed] [Google Scholar]
  111. Olivieri F, Procopio AD, Montgomery RR. Effect of aging on microRNAs and regulation of pathogen recognition receptors. Curr Opin Immunol2014; 29C:29–37. [PMC free article] [PubMed] [Google Scholar]
  112. Garg D, Cohen SM. miRNAs and aging: a genetic perspective. Ageing Res Rev2014; 17:3–8. [PubMed] [Google Scholar]
  113. Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol2008; 8:327–36. [PMC free article] [PubMed] [Google Scholar]
  114. Rothlin CV, CarreraSilva EA, Bosurgi L, Ghosh S. TAM receptor signaling in immune homeostasisAnnu Rev Immunol2015; 33:355–91. [PMC free article] [PubMed] [Google Scholar]
  115. Malawista A, Wang X, Trentalange M, Allore HG, Montgomery RR. Coordinated expression of tyro3, axl, and mer receptors in macrophage ontogeny. Macrophage2016; 3:e1261. [PMC free article] [PubMed] [Google Scholar]
  116. Miner JJ, Daniels BP, Shrestha B et alThe TAM receptor Mertk protects against neuroinvasive viral infection by maintaining bloodbrain barrier integrityNat Med 2015; 21:1464–72. [PMC free article] [PubMed] [Google Scholar]
  117. Meertens L, Carnec X, Lecoin MP et alThe TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe 2012; 12:544–57. [PMC free article] [PubMed] [Google Scholar]
  118. Morizono K, Xie Y, Olafsen T et alThe soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. Cell Host Microbe 2011; 9:286–98. [PMC free article] [PubMed] [Google Scholar]
  119. Carnec X, Meertens L, Dejarnac O et alThe phosphatidylserine and phosphatidylethanolamine receptor CD300a binds dengue virus and enhances infection. J Virol 2016; 90:92–102. [PMC free article] [PubMed] [Google Scholar]
  120. Blazquez AB, MartinAcebes MA, Saiz JC. Inhibition of West Nile virus multiplication in cell culture by antiParkinsonian drugsFront Microbiol2016; 7:296. [PMC free article] [PubMed] [Google Scholar]
  121. Green RR, Wilkins C, Pattabhi S, Dong R, Loo Y, Gale M Jr. Transcriptional analysis of antiviral small molecule therapeutics as agonists of the RLR pathway. Genom Data2016; 7:290–2. [PMC free article] [PubMed] [Google Scholar]
  122. Van Hoeven N, Joshi SW, Nana GI et alA novel synthetic TLR4 agonist adjuvant increases the protective response to a clinicalstage West Nile virus vaccine antigen in multiple formulationsPLOS ONE 2016; 11:e0149610. [PMC free article] [PubMed] [Google Scholar]
  123. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin1 in a broad spectrum of diseasesNat Rev Drug Discov2012; 11:633–52. [PMC free article] [PubMed] [Google Scholar]
  124. Limagne E, Lancon A, Delmas D, CherkaouiMalki M, Latruffe N. Resveratrol interferes with IL1betainduced proinflammatory paracrine interaction between primary chondrocytes and macrophagesNutrients2016; 8:E280. [PMC free article] [PubMed] [Google Scholar]

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