Research ArticleInfectious Disease

Cytomegalovirus infection enhances the immune response to influenza

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ra43
DOI: 10.1126/scitranslmed.aaa2293
  • Fig. 1. Different immunological profiles in aging versus CMV seropositivity.

    The contribution of age and CMV to immunological and gene expression profiles was estimated by a combination of nuclear norm and the elastic net methods (see Materials and Methods). The magnitudes of the regression coefficients used to separate the classes yCMV− and oCMV− (CMV-independent age effect) or yCMV− and yCMV+ (age-independent CMV effect) are shown in light and dark gray bars, respectively. Only two parameters, the frequency of CD8+ CD28 and CD8+ TEM cells, overlapped between these classification tasks. Fourteen of 16 (87.5%) of the parameters used to separate the yCMV− from yCMV+ classes were up-regulated in CMV; in contrast, most parameters used to separate the yCMV− from oCMV− classes (16 of 23, 69.5%) were down-regulated in aging.

  • Fig. 2. Young but not old CMV+ individuals have a better response to influenza vaccination.

    The GMT for all three strains in the vaccine was calculated for each individual in the study and a standardized score [delta (Δ) post-pre GMT] for response was computed as described in Methods (y axis). (A to C) A higher response is observed in yCMV+ compared to yCMV− in the first (A) and second (B) year, as well as in an independent validation study conducted during the 2010 to 2011 influenza season (C). No significant differences (n.s.) were observed between oCMV− and oCMV+. Green bars, CMV–; yellow bars, CMV+. The age ranges for young and older individuals were 20 to 30 and 60 to >89 years, respectively (A); 22 to 32 (young) and 62 to >89 (older) years (B); and 19 to 44 years (C).

  • Fig. 3. Reduced viral titer and enhanced IAV-specific CD8+ T cell responses in early and established but not long-standing MCMV latency.

    (A to F) Groups of C57BL/6 mice were mock-infected or infected with 4 × 104 plaque-forming units (PFU) of MCMV Smith strain intraperitoneally and challenged with 106 EID50 (mean egg infective dose) of IAV x31 intranasally 5 weeks (early latency) (A and D), 12 weeks (established latency) (B and E), or 9 months (long-standing latency) later (C and F). Seven days after IAV infection, influenza viral titer was determined (upper panel) and IAV-specific T cells were enumerated from the bronchoalveolar lavage (BAL) of IAV+ MCMV– (MCMV–) or IAV+ MCMV+ (MCMV+) mice by tetramer staining for NP-, PA-, and PB1-specific responses. Data are representative of three independent experiments with four to six mice per group in each experiment. Significance was determined by t test for viral titer and using the Fisher’s combined probability test for comparison of specific T cell responses.

  • Fig. 4. The effect of MCMV on cross-protection against influenza is IFN-γ–mediated.

    Groups of C57BL/6 mice or IFN-γ–deficient mice (on the C57BL/6 background) were mock-infected or infected with 4 × 104 PFU of MCMV Smith strain intraperitoneally and challenged 5 to 6 weeks later with 106 EID50 of IAV x31 intranasally. (A) IAV lung viral titers from control [wild-type (WT)] or IFN-γ–deficient co-infected (IAV+ MCMV+) mice were determined at day 7 after IAV infection in early MCMV latency (>5 weeks). (B) IAV-specific CD8+ T cells were enumerated from the BAL of WT and IFN-γ–deficient MCMV and IAV co-infected mice by tetramer staining for NP-, PA-, and PB1-specific responses 7 days after IAV infection. Significance was determined by t test. Data are representative of two independent experiments with three to five mice per group. Significance was determined by t test for viral titer and using the Fisher’s combined probability test for comparison of specific T cell responses.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/281/281ra43/DC1

    Materials and Methods

    Fig. S1. Study design.

    Fig. S2. Gating strategy for phosphoflow assays.

    Fig. S3. No significant effect of EBV in immune measures and response to influenza vaccine.

    Fig. S4. Manhattan plot showing genetic variants that associate with CMV-related phenotypic alteration.

    Fig. S5. SNAP plot of notable SNPs found to be associated with the CD4+ CD28 cell frequency on chromosome 6.

    Fig. S6. SNAP plot of notable SNPs found to be associated with the CD4+ CD28 cell frequency on chromosome 9.

    Table S1. Subjects’ baseline characteristics.

    Table S2. Immune parameters computationally selected in all six classification problems.

    References (7174)

  • Supplementary Material for:

    Cytomegalovirus infection enhances the immune response to influenza

    David Furman,* Vladimir Jojic, Shalini Sharma, Shai S. Shen-Orr, Cesar J. L. Angel, Suna Onengut-Gumuscu, Brian A. Kidd, Holden T. Maecker, Patrick Concannon, Cornelia L. Dekker, Paul G. Thomas, Mark M. Davis*

    *Corresponding author. E-mail: mdavis{at}cmgm.stanford.edu (M.M.D.); furmand{at}stanford.edu (D.F.)

    Published 1 April 2015, Sci. Transl. Med. 7, 281ra43 (2015)
    DOI: 10.1126/scitranslmed.aaa2293

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Study design.
    • Fig. S2. Gating strategy for phosphoflow assays.
    • Fig. S3. No significant effect of EBV in immune measures and response to influenza vaccine.
    • Fig. S4. Manhattan plot showing genetic variants that associate with CMV-related phenotypic alteration.
    • Fig. S5. SNAP plot of notable SNPs found to be associated with the CD4+ CD28cell frequency on chromosome 6.
    • Fig. S6. SNAP plot of notable SNPs found to be associated with the CD4+ CD28cell frequency on chromosome 9.
    • Table S1. Subjects’ baseline characteristics.
    • Table S2. Immune parameters computationally selected in all six classification problems.
    • References (7174)

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