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author:("Cao, wiping")
1.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans 
Nature immunology  2008;10(1):116-125.
A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene ‘signatures’ that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4—an orchestrator of the integrated stress response—that correlated with and predicted YF-17D CD8+ T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
PMCID: PMC4049462  PMID: 19029902
2.  CD4+CD25+FoxP3+ regulatory T cells and cytokines interact with estradiol in cases of missed abortion 
The aim of this study was to examine the interaction of estradiol (E2) with CD4+CD25+FoxP3+ regulatory T (Treg) cells and cytokines in cases of missed abortion (MA). The peripheral blood lymphocytes from patients with MA and controls (normal pregnancy and non-pregnant females) were isolated from the blood by Ficoll density gradient centrifugation. CD4+CD25+ Treg cells were isolated from peripheral blood mononuclear cells (PBMCs). The frequencies of CD4+CD25+FoxP3+ Treg cells and mRNA expression of transcription factor forkhead box protein 3 (FoxP3) in the peripheral blood of MA (n=33), normal pregnancy (n=33) and non-pregnant females (n=27) were determined by intracellular three-color flow cytometry and quantitative polymerase chain reaction (qPCR), respectively. The serum levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) were measured by enzyme-linked immunosorbent assay (ELISA) and a chemiluminescent immunoassay was used to examine the serum E2 levels. It was observed that the percentage of Foxp3+ T cells in the peripheral blood of patients with MA were lower compared with those in the normal pregnancy and healthy non-pregnant controls. The results demonstrated that MA patients exhibited decreased levels of a peripheral Th2-related cytokine (IL-4) and E2. Furthermore, the low levels of CD4+CD25+Foxp3+ T cells and IL-4 correlated positively with serum concentrations of E2. The data indicated that maternal immunological changes may reverse maternal tolerance in MA, and this phenomenon may be due to the interaction of E2 with CD4+CD25+Foxp3+ T cells and cytokines in MA.
PMCID: PMC3881057  PMID: 24396417
early missed abortion; CD4+CD25+FoxP3+ regulatory T cells; cytokine; interferon-γ; interleukin-4; estradiol
3.  Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway 
Nature immunology  2008;9(10):1157-1164.
Robust production of type I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its ‘downstream’ mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-α/β production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-α/β production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-α/β responses by pDCs.
PMCID: PMC3732485  PMID: 18758466
4.  TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice 
Journal of Virology  2012;86(20):10988-10998.
Recognition of pathogen-associated molecular patterns by pattern recognition receptors of the innate immune system is crucial for the initiation of innate and adaptive responses and for immunological memory. We investigated the role of TLR7 in the induction of adaptive immunity and long-term memory following influenza virus infection and vaccination in C57BL/6 mice. During infection with influenza A/PR8/34 virus, the absence of either TLR7 or MyD88 leads to reduced virus-specific antibodies in the serum and antibody-secreting cells in their secondary lymphoid organs, particularly in bone marrow. In spite of this, the absence of TLR7/MyD88 signaling did not impair the production of protective antibodies. Following immunization with the 2009 pandemic inactivated split vaccine, TLR7−/− mice had significantly lower levels of germinal center formation, antibody-secreting cells, and circulating influenza virus-specific antibodies than control animals. Consequently, TLR7−/− mice failed to develop protective immunological memory upon challenge. Furthermore, the immunogenicity of the split vaccine was likely due to TLR7 recognition of virion RNA, as its removal from the split vaccine significantly reduced the levels of influenza virus-specific antibodies and compromised the vaccine protective efficacy in mice. Taken together, our data demonstrate that TLR7 plays an important role in vaccine-induced humoral immune responses to influenza virus through the interaction with viral RNA present in the split vaccine.
PMCID: PMC3457183  PMID: 22837197
5.  Complete Genome Sequence of a Novel Type of Human Parechovirus Strain Reveals Natural Recombination Events 
Journal of Virology  2012;86(16):8892-8893.
Human parechoviruses (HPeVs) are a species in the Parechovirus genus of the Picornaviridae family. We report a complete genome sequence of a novel HPeV strain, CH-ZJ1, that was found in an infant with gastroenteritis in Zhenjiang City, China. The complete genome consists of 7,298 nucleotides (nt), excluding the 3′ poly(A) tail; the open reading frame is mapped between nucleotide positions 654 and 7211 and encodes a 2,185-amino acid (aa) polyprotein. The phylogenetic tree obtained for the complete genome of this HPeV strain and the other HpeV strains available in GenBank indicated that CH-ZJ1 is intervenient between HpeV type 4 (HpeV4) and HpeV5. Phylogenetic analysis based on the 3D and VP1 genes reveals two incongruent trees. Recombination detection indicated that CH-ZJ1 might be a recombinant which was produced by more than one genomic recombination event that occurred among HPeV1, HPeV4, and HPeV3 strains.
PMCID: PMC3421728  PMID: 22843855
6.  Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population 
Aging and Disease  2011;3(1):68-90.
Influenza is an important contributor to morbidity and mortality worldwide. Accumulation of genetic mutations termed antigenic drift, allows influenza viruses to inflict yearly epidemics that may result in 250,000 to 500,000 deaths annually. Over 90% of influenza-related deaths occur in the older adult population. This is at least in part a result of increasing dysregulation of the immune system with age, termed immunosenescence. This dysregulation results in reduced capacity to cope with infections and decreased responsiveness to vaccination. The older adult population is in dire need of improved vaccines capable of eliciting protective responses in the face of a waning immune system. This review focuses on the status of immunity, responses to influenza vaccination, and strategies that are currently being explored to elicit enhanced immune responses in this high risk population.
PMCID: PMC3320806  PMID: 22500272
Aging; Influenza; Vaccination; Immune Response; Immunosenescence
7.  The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling 
Nature immunology  2010;11(7):608-617.
The mechanisms that initiate T helper type 2 (TH2) responses are poorly understood. Here we demonstrate that cysteine protease–induced TH2 responses occur via ‘cooperation’ between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated TH2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the TH1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4+ basophils to the lymph node. Thus, the TH2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.
PMCID: PMC3145206  PMID: 20495560

Results 1-7 (7)