抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Assembly of the cell surface IL-10 receptor complex is the first step in initiating IL-10 signaling pathways that regulate intestinal inflammation, viral persistence and even tumor surveillance The discovery of IL-10 homologs in the genomes of herpes viruses suggests IL-10 signaling pathways can be manipulated at the level of the receptor complex This chapter will describe our current molecular understanding of IL-10 receptor assembly based on crystal structures and biochemical analyses of cellular and viral IL-10 receptor complexes

The molecular basis of IL-10 function: from receptor structure to the onset of signaling.

IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Karin R. Engelhardt and Bodo Grimbacher Control of intestinal inflammation by interleukin-10. Abhisake Kole and Kevin J. Maloy Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Maria Grazia Roncarolo, Silvia Gregori, Rosa Bacchetta and Manuela Battaglia. Interleukin-10-producing B cells and the regulation of immunity. Ellen Hilgenberg, Ping Shen, Van Duc Dang, Stefanie Ries, Imme Sakwa and Simon Fillatreau. Pathogen Manipulation of cIL-10 Signaling Pathways: Opportunities for Vaccine Development? Meghan K. Eberhardt and Peter A. Barry IL-10: achieving balance during persistent viral infection. Cherie T. Ng and Michael B.A. Oldstone The role of microRNAs in the control and mechanism of action of IL-10. Susan R. Quinn, Luke A. O'Neill The regulation of IL-10 expression. Leona Gabrysova, Ashleigh Howes, Margarida Saraiva and Anne O'Garra The Molecular Basis of IL-10 Function: From Receptor Structure to the Onset of Signaling. Mark R. Walter Role of IL-22 in microbial host defense Celine Eidenschenk, Sascha Rutz, Oliver Liesenfeld, Wenjun Ouyang

/pdf/interleukin-10-in-health-and-disease-333nnu9k53.pdf

Interleukin-10 in health and disease

The natural history of human cytomegalovirus (HCMV) is inextricably associated with mucosal surfaces. The vast preponderance of primary infections occur following mucosal exposure to infectious virions, and the high seroprevalence of HCMV throughout the world is due to long-term excretion of HCMV in bodily fluids from multiple mucosal sites. Accumulating evidence presents a model where the earliest virus-host interactions following infection dictate the long-term pattern of infection, alter innate immune responses that skew adaptive responses to enable persistence within an immune host, and are essential for reinfection of a host with prior immunity. HCMV has evolved a complex repertoire of viral functions fine-tuned to manipulate the immune environment both locally at the sites of infection and systemically within an infected host. Collectively, viral immune modulation represents a significant impediment for an HCMV vaccine. As HCMV can disseminate beyond mucosal surfaces to reinfect immune hosts, it may not matter whether prior immunity results from prior infection or immunization. A better understanding of the earliest virus-hosts interactions at mucosal surfaces may identify elements of the viral proteome that are especially susceptible to vaccine-mediated disruption and prevent challenge virus from disseminating to distal sites, particularly the maternal-fetal interface.

/pdf/using-the-nonhuman-primate-model-of-hcmv-to-guide-vaccine-27c7xb5tbk.pdf

Using the Nonhuman Primate Model of HCMV to Guide Vaccine Development

Herpesviruses have acquired numerous genes from their hosts. Although these homologs are not essential for viral replication, they often have important immunomodulatory functions that ensure viral persistence in the host. Some of these viral molecules are called virokines as they mimic cellular cytokines of their host such as interleukin-10 (cIL-10). In recent years, many viral homologs of IL-10 (vIL-10s) have been discovered in the genome of members of the order Herpesvirales. For some, gene and protein structure as well as biological activity and potential use in the clinical context have been explored. Besides virokines, herpesviruses have also captured genes encoding membrane-bound host immunomodulatory proteins such as major histocompatibility complex (MHC) molecules. These viral MHC mimics also retain many of the functions of the cellular genes, in particular directly or indirectly modulating the activity of natural killer cells. The mechanisms underlying capture of cellular genes by large DNA viruses are still enigmatic. In this review, we provide an update of the advances in the field of herpesviral gene piracy and discuss possible scenarios that could explain how the gene transfer from host to viral genome was achieved.

Herpesviral capture of immunomodulatory host genes.

Author(s): Logsdon, Naomi J; Eberhardt, Meghan K; Allen, Christopher E; Barry, Peter A; Walter, Mark R | Abstract: BackgroundHuman cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ∼26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties.Methods and findingsStructural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10.ConclusionThis study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection.

/pdf/design-and-analysis-of-rhesus-cytomegalovirus-il-10-mutants-4or6idk4cq.pdf

Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

PS2-111. Targeting the IL-10 signalling pathway as a vaccine strategy for HCMV

Interleukin-20 (IL-20) is an IL-10-family cytokine that regulates innate and adaptive immunity in skin and other tissues. In addition to protecting the host from various external pathogens, dysregulated IL-20 signaling has been shown to contribute to the pathogenesis of human psoriasis. IL-20 signals through two cell-surface receptor heterodimers, IL-20R1–IL-20R2 and IL-22R1–IL-20R2. In this report, crystals of the IL-20–IL-20R1–IL-20R2 ternary complex have been grown from polyethylene glycol solutions. The crystals belonged to space group P41212 or P43212, with unit-cell parameters a = 111, c = 135 A, and diffracted X-­rays to 3 A resolution. The crystallographic asymmetric unit contains one IL-­20–IL-20R1–IL-20R2 complex, corresponding to a solvent content of approximately 54%.

/pdf/purification-crystallization-and-preliminary-x-ray-4284cmpqdr.pdf

Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex.

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Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

PS2-111. Targeting the IL-10 signalling pathway as a vaccine strategy for HCMV

Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex.