Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Nov;82(11):1966-75.
doi: 10.1002/jmv.21899.

Differential cellular immune responses to wild-type and attenuated edmonston tag measles virus strains are primarily defined by the viral phosphoprotein gene

Iana H Haralambieva  1 , Inna G Ovsyannikova, Neelam Dhiman, Robert A Vierkant, Robert M Jacobson, Gregory A Poland
Affiliations

Differential cellular immune responses to wild-type and attenuated edmonston tag measles virus strains are primarily defined by the viral phosphoprotein gene

Iana H Haralambieva et al. J Med Virol. 2010 Nov.

Abstract

The measles virus phosphoprotein (P) gene encodes the P, V, and C proteins, which have multiple functions including type I interferon (IFN) inhibition. With a focus on viral immune modulation, we conducted a study on healthy vaccinees (n=179) to compare cytokine secretion patterns/cell frequencies and gene expression after in vitro encounter with a highly attenuated strain of measles virus (MVEdmtag), wild-type MV (MVwt) or recombinant MVEdmtag expressing the wild-type P gene (MVwtP). Cytokines were quantified by ELISA and Elispot. Gene expression profiling was performed using real-time PCR. We found differential MV-specific cytokine responses to all detected cytokines characterized by significantly higher cytokine levels (P<0.001) and higher frequencies (P<0.0001) of cytokine-producing cells after stimulation with the highly attenuated MVEdmtag strain in comparison with MVwt or MVwtP. Furthermore, gene expression profiling revealed significant cytokine suppression at the transcriptional level for viruses encoding the functional wt P gene, compared to attenuated MVEdmtag (P<0.05). Using lentivirus-mediated stable expression of P gene-encoded proteins in human cell lines, we demonstrated that the expression of the functional wt V protein significantly down-modulated the induction of IFNs type I, II, and III in lymphocytes and monocytes. Taken together our results indicate that Th1, Th2, and innate/inflammatory cytokine responses in vaccinees are suppressed both at the protein and transcriptional level by viruses expressing the functional wt P gene products. The functional P gene-encoded viral proteins (particularly V proteins) emerge as crucial immune evasion factors for modulating and shaping the measles virus-specific cytokine responses in humans.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Schematic representation of the viruses used in the study and P/V/C protein differences. Strain-specific amino acid (aa) substitutions (Y110H in P/V proteins and C272R in V protein), known to affect IFN signaling are shown with arrows.
Fig. 2
Fig. 2
Total IFN-γ and IL-10 Elispot cell frequencies in vaccinees after encounter with different MV strains. Frequencies of IL-10-producing cells (A), and IFN-γ-producing cells (B) in vaccinees upon stimulation with MVEdmtag, MVwt, or MVwtP viruses. Results are presented as median cytokine-positive spots per 2 × 105 cells ± interquartile range. *P <0.0001 for wtP encoding viruses in comparison to MVEdmtag (paired t-test).
Fig. 3
Fig. 3
Cytokine gene down-modulation in vaccinees upon stimulation with MVs, encoding the functional wild-type P gene. Normalized expression levels (2−ΔCt ) for cytokine genes in the two groups (stimulated with different viruses) are represented on each scatter plot. Values are plotted on the log scale. The line of identity and the lines representing fourfold change as a threshold for difference are shown. Dots represent individual genes. Dots within the diagonal lines represent genes not changed between groups. Dots, which fall to the right of the lower line indicate gene down-regulation (more than fourfold) of: (A) Group 2 (MVwt-stimulated group, y-axis) versus Group 1 (MVEdmtag-stimulated group, x-axis); (B) Group 3 (MVwtP-stimulated group, y-axis) versus Group 1 (MVEdmtag-stimulated group, x-axis); (C) Group 2 (MVwt-stimulated group, y-axis) versus Group 3 (MVwtP-stimulated group, x-axis). All down-regulated genes are significantly different between groups (P <0.05).
Fig. 4
Fig. 4
The functional wild-type V protein significantly attenuates the induction of IFNs in human lymphocytes and monocytes. A–C: The P, V, and C proteins of wild-type (wt, lighter gray bars) MV and attenuated Edmtag MV (edm, darker gray bars) were stably expressed in BJAB cell line (normal BJAB is represented by black bars) and used in comparative IFN induction experiments (see the Materials and Methods Section). **P <0.0001; ***P <0.01; ****P <0.05 (paired t-test). D–F: The P, V, and C proteins of wild-type (wt, lighter gray bars) MV and attenuated Edmtag MV (edm, darker gray bars) were similarly expressed in the human monocytic cell line THP-1 (normal THP-1 is represented by black bars) and used in comparative IFN induction experiments (see the Materials and Methods Section). *P <0.001; **P <0.0001 (paired t-test). Background levels of cytokine secretion in cultures (for all stable cell lines) not stimulated with measles virus were subtracted from the levels of MVEdmtag-induced responses to produce the “corrected” secretion values shown. Values represent mean (from triplicate) ± SD. The data shown are representative of three experiments (each cell type) with similar results.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall RE. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA. 2004;101:17264–17269. - PMC - PubMed
    1. Berghall H, Siren J, Sarkar D, Julkunen I, Fisher PB, Vainionpaa R, Matikainen S. The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines. Microbes Infect. 2006;8:2138–2144. - PubMed
    1. Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol. 2002;76:8729–8736. - PMC - PubMed
    1. Bouche FB, Ertl OT, Muller CP. Neutralizing B cell response in measles. Viral Immunol. 2002;15:451–471. - PubMed
    1. Caignard G, Guerbois M, Labernardiere JL, Jacob Y, Jones LM, Wild F, Tangy F, Vidalain PO Infectious Mapping Project I-MAP. Measles virus V protein blocks Jak1-mediated phosphorylation of STAT1 to escape IFN-alpha/beta signaling. Virology. 2007;368:351–362. - PubMed

Publication types

MeSH terms