Interferon and Interferon-Induced Chemokine Expression Is Associated with Control of Acute Viremia in West Nile Virus-Infected Blood Donors

Tobler, Leslie H.; Cameron, Mark J.; Lanteri, Marion C.; Prince, Harry E.; Danesh, Ali; Persad, Desmond; Lanciotti, Robert S.; Norris, Philip J.; Kelvin, David J.; Busch, Michael P.

doi:10.1086/591466

Cited by 44 publications

(56 citation statements)

References 15 publications

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“…Cytometric bead array analysis of plasma cytokines and chemokines. Plasma was available for 19 of the 32 panels described above and was analyzed by human Th1/Th2 cytokine, inflammation, and chemokine Cytometric Bead Array (CBA) kits (BD Biosciences) according to the manufacturer's protocols (60). Residual plasma volume was insufficient for testing on the remaining 13 subjects.…”

Section: Methodsmentioning

confidence: 99%

Tregs control the development of symptomatic West Nile virus infection in humans and mice

Lanteri¹,

O’Brien²,

Purtha³

et al. 2009

J. Clin. Invest.

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173

213

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West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4 + Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded significantly in the 3 months after index (RNA + ) donations in all subjects. Symptomatic donors exhibited lower Treg frequencies from 2 weeks through 1 year after index donation yet did not show differences in systemic T cell or generalized inflammatory responses. In parallel prospective experimental studies, symptomatic WNV-infected mice also developed lower Treg frequencies compared with asymptomatic mice at 2 weeks after infection. Moreover, Treg-deficient mice developed lethal WNV infection at a higher rate than controls. Together, these results suggest that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans.

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Section: Methodsmentioning

confidence: 99%

Tregs control the development of symptomatic West Nile virus infection in humans and mice

Lanteri¹,

O’Brien²,

Purtha³

et al. 2009

J. Clin. Invest.

Self Cite

173

213

View full text Add to dashboard Cite

show abstract

“…In addition, a strain of WNV that fails to block the type I IFN signal transduction pathway is phenotypically attenuated in mice (23,50). Clinically, during acute DENV infection, innate immune responses play a key role in determining disease outcome (35), and resolution of WNV infection requires effective IFN-mediated innate host responses (23,43,53). Therefore, understanding how the IFN-mediated innate immune response functions is one of the critical frontiers in the molecular biology of WNV and DENV pathogenesis (1, 44).…”

mentioning

confidence: 99%

Identification of Five Interferon-Induced Cellular Proteins That Inhibit West Nile Virus and Dengue Virus Infections

Jiang

Weidner

Qing

et al. 2010

J Virol

301

344

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Interferons (IFNs) are key mediators of the host innate antiviral immune response. To identify IFNstimulated genes (ISGs) that instigate an antiviral state against two medically important flaviviruses, West Nile virus (WNV) and dengue virus (DENV), we tested 36 ISGs that are commonly induced by IFN-␣ for antiviral activity against the two viruses. We discovered that five ISGs efficiently suppressed WNV and/or DENV infection when they were individually expressed in HEK293 cells. Mechanistic analyses revealed that two structurally related cell plasma membrane proteins, IFITM2 and IFITM3, disrupted early steps (entry and/or uncoating) of the viral infection. In contrast, three IFN-induced cellular enzymes, viperin, ISG20, and double-stranded-RNA-activated protein kinase, inhibited steps in viral proteins and/or RNA biosynthesis. Our results thus imply that the antiviral activity of IFN-␣ is collectively mediated by a panel of ISGs that disrupt multiple steps of the DENV and WNV life cycles.West Nile virus (WNV) and dengue virus (DENV) are mosquito-borne flaviviruses that cause invasive neurological diseases and lethal hemorrhagic fever in humans, respectively (6, 32). Since its first incursion into New York City in 1999, WNV has rapidly spread throughout the continental United States and has recently reached South America (29, 34). In most cases, WNV infection of people resolves as an asymptomatic or a mild febrile illness. However, approximately 1% of infections result in severe neurological disorders, such as encephalitis and meningitis (27). Unlike WNV, for which people are only accidental hosts, DENV has fully adapted to humans (32). It has apparently lost the need for an enzootic cycle and causes a range of diseases in people, from acute febrile illness to life-threatening dengue hemorrhagic fever/dengue shock syndrome (6). Four distinct serotypes of DENV have spread throughout the tropical and subtropical parts of the world, with an estimated 50 to 100 million human cases annually and about 2.5 billion people worldwide being at risk of infection (32). Effective antiviral therapies and vaccines to treat or prevent WNV and DENV infections in humans are not yet available.Type I interferons (IFNs), represented by IFN-␣ and IFN-␤, have been demonstrated to play an essential role in defending against WNV and DENV infections. For example, mice with deficiencies in the induction of type I IFNs and the receptor or JAK-STAT signal transduction pathway of the cytokines are vulnerable to WNV and DENV infections (7,38,42,(49)(50)(51). In addition, a strain of WNV that fails to block the type I IFN signal transduction pathway is phenotypically attenuated in mice (23,50). Clinically, during acute DENV infection, innate immune responses play a key role in determining disease outcome (35), and resolution of WNV infection requires effective IFN-mediated innate host responses (23,43,53). Therefore, understanding how the IFN-mediated innate immune response functions is one of the critical frontiers in the molecular biology of WN...

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“…A number of techniques have recently been developed or improved to address these limitations, including mRNA expression profiling (29), mass spectroscopy (9), and multiplex assays based on flow cytometry, bead-based assays, or electrochemiluminescent assay. The ability to measure a broad array of cytokines using small sample volumes has allowed new insight into disease pathogenesis, for example, defining the ontogeny of cytokine induction in acute viral infections (18,30,31).…”

mentioning

confidence: 99%

Multisite Comparison of High-Sensitivity Multiplex Cytokine Assays

Breen

Reynolds

Cox

et al. 2011

Clin Vaccine Immunol

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150

130

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The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1␤ was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.

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Interferon and Interferon-Induced Chemokine Expression Is Associated with Control of Acute Viremia in West Nile Virus-Infected Blood Donors

Cited by 44 publications

References 15 publications

Tregs control the development of symptomatic West Nile virus infection in humans and mice

Tregs control the development of symptomatic West Nile virus infection in humans and mice

Identification of Five Interferon-Induced Cellular Proteins That Inhibit West Nile Virus and Dengue Virus Infections

Multisite Comparison of High-Sensitivity Multiplex Cytokine Assays

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