Immune Receptor Complex Research Articles

Open reading frame mining identifies a TLR4 binding domain in the primary sequence of ECRG4.

The embedding of small peptide ligands within large inactive pre-pro-precursor proteins encoded by orphan open reading frames (ORFs) makes them difficult to identify and study. To address this problem, we generated oligonucleotide (< 100-400 base pair) combinatorial libraries from either the epidermal growth factor (EGF) ORF that encodes the > 1200 amino acid EGF precursor protein or the orphan ECRG4 ORF, that encodes a 148 amino acid Esophageal Cancer Related Gene 4 (ECRG4), a putative cytokine precursor protein of up to eight ligands. After phage display and 3-4 rounds of biopanning for phage internalization into prostate cancer epithelial cells, sequencing identified the 53-amino acid EGF ligand encoded by the 5' region of the EGF ORF and three distinct domains within the primary sequence of ECRG4: its membrane targeting hydrophobic signal peptide, an unanticipated amino terminus domain at ECRG437-63 and a C-terminus ECRG4133-148 domain. Using HEK-blue cells transfected with the innate immunity receptor complex, we show that both ECRG437-63 and ECRG4133-148 enter cells by interaction with the TLR4 immune complex but neither stimulate NFkB. Taken together, the results help establish that phage display can be used to identify cryptic domains within ORFs of the human secretome and identify a novel TLR4-targeted internalization domain in the amino terminus of ECRG4 that may contribute to its effects on cell migration, immune cell activation and tumor suppression.

Mechanism of plant immune activation and signaling: Insight from the first solved plant resistosome structure.

This commentary introduces an exciting breakthrough: the first solved structure of a plant NLR immune receptor complex. The significance of this work, including the similarity between the activation of NLRs from plants and animals, and potentially novel mechanism of immune signaling in plants, were discussed and put into perspective.

(213) IgG-Immune Complex Directly Activates Joint Sensory Neurons through Neuronal FcγRI to Induce Arthritis Pain

Joint pain in rheumatoid arthritis (RA) represents a significant health burden. Although RA pain is conventionally thought to result from inflammation, it often persists even after control of inflammation with available therapies, suggesting the additional involvements of non-inflammatory mechanisms. Yet, such mechanisms remain largely unexplored. Our in situ hybridization assays suggested that the immune complex receptor FcγRI was expressed in a subpopulation of joint sensory neurons. Consistent with this finding, the proportion of joint sensory neurons exhibiting a Ca2+ increase in response to IgG-immune complex (IgG-IC), assayed both in vitro and in vivo, was lower in global FcγRI−/− mice, compared with wildtype mice. Injection of IgG-IC but not monomeric IgG into one ankle of naive mice evoked joint pain-related behaviors without concurrent joint swelling. This effect was diminished in global FcγRI−/− mice. Ablation of T and B cells, mast cells or macrophages had no effect on IgG-IC evoked nocifensive behaviors. Under arthritic conditions, FcγRI mRNA expression and function were upregulated in dorsal root ganglion (DRG) in a mouse model of antigen-induced arthritis (AIA). In vivo extracellular electrophysiological recordings on intact DRG showed that genetic deletion of FcγRI reduced the incidence of abnormal activity and mechanical hypersensitivity of joint sensory neurons in the context of AIA. Acute blockade of FcγRI with neutralizing antibody and genetic knockout of FcγRI significantly attenuated pain-related behaviors in the AIA model. Conversely, no significant differences between treatments or genotypes were observed in the inflamed joint in the expression level of cytokines or in immune cell infiltration. These findings indicate that FcγRI may contribute to arthritis pain through a non-inflammatory mechanism that parallels inflammation and joint damage and point towards a promising therapeutic target to consider for RA pain that is resistant to current anti-inflammatory treatments. Supported by NIAMS 1R01AR072230 to L.Q.

Early signalling mechanisms underlying receptor kinase-mediated immunity in plants.

Pattern-recognition receptors (PRRs), which are single transmembrane proteins belonging to the receptor-like kinase (RLK) and receptor-like protein (RLP) super families, sense microbe- and host-derived molecular patterns to activate immune responses in plants. PRRs associate with co-receptors, scaffold proteins and receptor-like cytoplasmic kinases (RLCKs) to form immune receptor complexes at the cell surface, allowing activation of cellular responses upon perception of extracellular ligands. Recent advances have uncovered new mechanisms by which these immune receptor complexes are regulated at the levels of composition, stability and activity. It has become clear that RLCKs are central components directly linking PRRs to multiple downstream signalling modules. Furthermore, new studies have provided important insights into the regulation of reactive oxygen species, mitogen-activated protein (MAP) kinase cascades and heterotrimeric G proteins, which has not only deepened our understanding of immunity, but also expanded our view of transmembrane signalling in general. This article is part of the theme issue 'Biotic signalling sheds light on smart pest management'.

Contriving multiepitope subunit vaccine by exploiting structural and nonstructural viral proteins to prevent Epstein-Barr virus-associated malignancy.

Cancer is one of the common lifestyle diseases and is considered to be the leading cause of death worldwide. Epstein-Barr virus (EBV)-infected individuals remain asymptomatic; but under certain stress conditions, EBV may lead to the development of cancers such as Burkitt's and Hodgkin's lymphoma and nasopharyngeal carcinoma. EBV-associated cancers result in a large number of deaths in Asian and African population, and no effective cure has still been developed. We, therefore, tried to devise a subunit vaccine with the help of immunoinformatic approaches that can be used for the prevention of EBV-associated malignancies. The epitopes were predicted through B-cell, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) from the different oncogenic proteins of EBV. A vaccine was designed by combining the B-cell and T-cell (HTL and CTL) epitopes through linkers, and for the enhancement of immunogenicity, an adjuvant was added at the N-terminal. Further, homology modeling was performed to generate the 3D structure of the designed vaccine. Moreover, molecular docking was performed between the designed vaccine and immune receptor (TLR-3) to determine the interaction between the final vaccine construct and the immune receptor complex. In addition, molecular dynamics was performed to analyze the stable interactions between the ligand final vaccine model and receptor TLR-3 molecule. Lastly, to check the expression of our vaccine construct, we performed in silico cloning. This study needed experimental validation to ensure its effectiveness and potency to control malignancy.

Distinct modes of derepression of an Arabidopsis immune receptor complex by two different bacterial effectors

Plant intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors often function in pairs to detect pathogen effectors and activate defense. The Arabidopsis RRS1-R-RPS4 NLR pair recognizes the bacterial effectors AvrRps4 and PopP2 via an integrated WRKY transcription factor domain in RRS1-R that mimics the effector's authentic targets. How the complex activates defense upon effector recognition is unknown. Deletion of the WRKY domain results in an RRS1 allele that triggers constitutive RPS4-dependent defense activation, suggesting that in the absence of effector, the WRKY domain contributes to maintaining the complex in an inactive state. We show the WRKY domain interacts with the adjacent domain 4, and that the inactive state of RRS1 is maintained by WRKY-domain 4 interactions before ligand detection. AvrRps4 interaction with the WRKY domain disrupts WRKY-domain 4 association, thus derepressing the complex. PopP2-triggered activation is less easily explained by such disruption and involves the longer C-terminal extension of RRS1-R. Furthermore, some mutations in RPS4 and RRS1 compromise PopP2 but not AvrRps4 recognition, suggesting that AvrRps4 and PopP2 derepress the complex differently. Consistent with this, a "reversibly closed" conformation of RRS1-R, engineered in a method exploiting the high affinity of colicin E9 and Im9 domains, reversibly loses AvrRps4, but not PopP2 responsiveness. Following RRS1 derepression, interactions between domain 4 and the RPS4 C-terminal domain likely contribute to activation. Simultaneous relief of autoinhibition and activation may contribute to defense activation in many immune receptors.

Abstract 1708: Effective and reversible control of anti-tumor activity in vivo with a drug-regulated CAR T cell platform (DARIC)

Abstract Redirecting T cells against tumors by introducing antigen-specific chimeric antigen receptors (CAR) has shown promising clinical results as a potential treatment strategy for certain cancers. However, traditional CARs are constitutively active, resulting in the persistent loss of all target cells (including off -tumor, on-target activity against normal tissues that express the target antigen) and enhanced potential of excessive T cell activation to drive cytokine release syndrome. While “off switches” based on suicide cassettes or other depleting cell approaches are in development, such systems by definition result in the elimination of the therapeutic cells. Here we have developed a novel drug-regulated CAR-based antigen targeting approach termed Dimerizing Agent Regulated Immune-receptor Complex (DARIC) that aims to: i) minimize the long-term toxicity of CAR T treatment; ii) allow the targeting of previously inaccessible antigens; and iii) be amenable to multiplex antigen targeting. The DARIC platform separates the antigen recognition and signaling functions of a CAR into two distinct polypeptides that are further engineered to contain the FKPB12 and FRB small-molecule regulated dimerization domains. In the absence of the dimerizing drug (e.g. rapamycin or the non-immunosuppressive rapalog AP21967) the DARIC system lacks signaling activity. However, the addition of dimerizing agent drives the interaction of the two DARIC subunits, fully restoring CAR function. Using CD19 as a model system, we show that treatment of CD19-DARIC+ T cells with rapamycin or AP21967 results in equivalent cytotoxicity, cytokine production and proliferation compared to a standard CD19-targeting CAR. Importantly, CD19-DARIC T cells were activated by picomolar levels of rapamycin and exhibited a higher antigen sensitivity than standard CD19-CAR T cells in vitro. In an aggressive CD19+Nalm-6 xenograft tumor mouse model, CD19-DARIC T cells did not exhibit anti-tumor activity in the absence of dimerizing agent. However, CD19-DARIC treated mice that received either low-dose rapamycin or AP21967 showed an equivalent level of tumor control compared to standard CD19-CAR treated animals. This activity was dependent on the presence of the dimerizing drug, as cessation of drug treatment resulted in the loss of CD19-DARIC T cell activity and the expansion of Nalm-6 tumors cells in the DARIC T cell treated mice, consistent with the ability to switch off CD19-DARIC T cells in vivo by withdrawing drug. Taken together, these results highlight the potential of the DARIC platform to facilitate the regulation of CAR T cell function both in vitro and in vivo. Citation Format: Wai-Hang Leung, Michael Certo, Holly Horton, Joel Gay, Tracy VandenBerg, Jordan Jarjour, Alexander Astrakhan. Effective and reversible control of anti-tumor activity in vivo with a drug-regulated CAR T cell platform (DARIC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1708. doi:10.1158/1538-7445.AM2017-1708

Protein-protein interactions in the RPS4/RRS1 immune receptor complex.

Plant NLR (Nucleotide-binding domain and Leucine-rich Repeat) immune receptor proteins are encoded by Resistance (R) genes and confer specific resistance to pathogen races that carry the corresponding recognized effectors. Some NLR proteins function in pairs, forming receptor complexes for the perception of specific effectors. We show here that the Arabidopsis RPS4 and RRS1 NLR proteins are both required to make an authentic immune complex. Over-expression of RPS4 in tobacco or in Arabidopsis results in constitutive defense activation; this phenotype is suppressed in the presence of RRS1. RRS1 protein co-immunoprecipitates (co-IPs) with itself in the presence or absence of RPS4, but in contrast, RPS4 does not associate with itself in the absence of RRS1. In the presence of RRS1, RPS4 associates with defense signaling regulator EDS1 solely in the nucleus, in contrast to the extra-nuclear location found in the absence of RRS1. The AvrRps4 effector does not disrupt RPS4-EDS1 association in the presence of RRS1. In the absence of RRS1, AvrRps4 interacts with EDS1, forming nucleocytoplasmic aggregates, the formation of which is disturbed by the co-expression of PAD4 but not by SAG101. These data indicate that the study of an immune receptor protein complex in the absence of all components can result in misleading inferences, and reveals an NLR complex that dynamically interacts with the immune regulators EDS1/PAD4 or EDS1/SAG101, and with effectors, during the process by which effector recognition is converted to defense activation.

A Cysteine-Rich Protein Kinase Associates with a Membrane Immune Complex and the Cysteine Residues Are Required for Cell Death.

Membrane-localized proteins perceive and respond to biotic and abiotic stresses. We performed quantitative proteomics on plasma membrane-enriched samples from Arabidopsis (Arabidopsis thaliana) treated with bacterial flagellin. We identified multiple receptor-like protein kinases changing in abundance, including cysteine (Cys)-rich receptor-like kinases (CRKs) that are up-regulated upon the perception of flagellin. CRKs possess extracellular Cys-rich domains and constitute a gene family consisting of 46 members in Arabidopsis. The single transfer DNA insertion lines CRK28 and CRK29, two CRKs induced in response to flagellin perception, did not exhibit robust alterations in immune responses. In contrast, silencing of multiple bacterial flagellin-induced CRKs resulted in enhanced susceptibility to pathogenic Pseudomonas syringae, indicating functional redundancy in this large gene family. Enhanced expression of CRK28 in Arabidopsis increased disease resistance to P. syringae Expression of CRK28 in Nicotiana benthamiana induced cell death, which required intact extracellular Cys residues and a conserved kinase active site. CRK28-mediated cell death required the common receptor-like protein kinase coreceptor BAK1. CRK28 associated with BAK1 as well as the activated FLAGELLIN-SENSING2 (FLS2) immune receptor complex. CRK28 self-associated as well as associated with the closely related CRK29. These data support a model where Arabidopsis CRKs are synthesized upon pathogen perception, associate with the FLS2 complex, and coordinately act to enhance plant immune responses.

Plant innate immunity in rice: a defense against pathogen infection

Abstract A large number of pathogenic microorganisms cause rice diseases that lead to enormous yield losses worldwide. Such losses are important because rice is a staple food for more than half of the world's population. Over the past two decades, the extensive study of the molecular interactions between rice and the fungal pathogen Magnaporthe oryzae and between rice and the bacterial pathogen Xanthomonas oryzae pv. oryzae has made rice a model for investigating plant–microbe interactions of monocotyledons. Impressive progress has been recently achieved in understanding the molecular basis of rice pathogen-associated molecular pattern-immunity and effector-triggered immunity. Here, we briefly summarize these recent advances, emphasizing the diverse functions of the structurally conserved fungal effectors, the regulatory mechanisms of the immune receptor complexes, and the novel strategies for breeding disease resistance. We also discuss future research challenges.

The μ Subunit of Arabidopsis Adaptor Protein-2 Is Involved in Effector-Triggered Immunity Mediated by Membrane-Localized Resistance Proteins.

Endocytosis has been suggested to be important in the cellular processes of plant immune responses. However, our understanding of its role during effector-triggered immunity (ETI) is still limited. We have previously shown that plant endocytosis, especially clathrin-coated vesicle formation at the plasma membrane, is mediated by the adaptor protein-2 (AP-2) complex and that loss of the μ subunit of AP-2 (AP2M) affects plant growth and floral organ development. Here, we report that AP2M is required for full-strength ETI mediated by the disease resistance (R) genes RPM1 and RPS2 in Arabidopsis. Reduced ETI was observed in an ap2m mutant plant, measured by growth of Pseudomonas syringae pv. tomato DC3000 strains carrying the corresponding effector genes avrRpm1 or avrRpt2 and by hypersensitive cell death response and defense gene expression triggered by these strains. In contrast, RPS4-mediated ETI and its associated immune responses were not affected by the ap2m mutation. While RPM1 and RPS2 are localized to the plasma membrane, RPS4 is localized to the cytoplasm and nucleus. Our results suggest that AP2M is involved in ETI mediated by plasma membrane-localized R proteins, possibly by mediating endocytosis of the immune receptor complex components from the plasma membrane.

Crystallization and Structure Determination of Superantigens and Immune Receptor Complexes.

Structure determination of superantigens and the complexes they form with immune receptors have over the years provided insight in their modes of action. This technique requires growing large and highly ordered crystals of the superantigen or receptor-superantigen complex, followed by exposure to X-ray radiation and data collection. Here, we describe methods for crystallizing superantigens and superantigen-receptor complexes using the vapor diffusion technique, how the crystals may be optimized, and lastly data collection and structure determination.

A truncated NLR protein, TIR-NBS2, is required for activated defense responses in the exo70B1 mutant.

During exocytosis, the evolutionarily conserved exocyst complex tethers Golgi-derived vesicles to the target plasma membrane, a critical function for secretory pathways. Here we show that exo70B1 loss-of-function mutants express activated defense responses upon infection and express enhanced resistance to fungal, oomycete and bacterial pathogens. In a screen for mutants that suppress exo70B1 resistance, we identified nine alleles of TIR-NBS2 (TN2), suggesting that loss-of-function of EXO70B1 leads to activation of this nucleotide binding domain and leucine-rich repeat-containing (NLR)-like disease resistance protein. This NLR-like protein is atypical because it lacks the LRR domain common in typical NLR receptors. In addition, we show that TN2 interacts with EXO70B1 in yeast and in planta. Our study thus provides a link between the exocyst complex and the function of a ‘TIR-NBS only’ immune receptor like protein. Our data are consistent with a speculative model wherein pathogen effectors could evolve to target EXO70B1 to manipulate plant secretion machinery. TN2 could monitor EXO70B1 integrity as part of an immune receptor complex.

Esophageal cancer-related gene-4 (ECRG4) interactions with the innate immunity receptor complex

The human c2orf40 gene encodes a tumor suppressor gene called esophageal cancer-related gene-4 (ECRG4) with pro- and anti-inflammatory activities that depend on cell surface processing. Here, we investigated its physical and functional association with the innate immunity receptor complex. Interactions between ECRG4 and the innate immunity receptor complex were assessed by flow cytometry, immunohistochemistry, confocal microscopy, and co-immunoprecipitation. Phage display was used for ligand targeting to cells that overexpress the TLR4-MD2-CD14. Immunoprecipitation and immunohistochemical studies demonstrate a physical interaction between ECRG4 and TLR4-MD2-CD14 on human granulocytes. Flow cytometry shows ECRG4 on the cell surface of a subset of CD14(+) and CD16(+) leukocytes. In a cohort of trauma patients, the C-terminal 16 amino acid domain of ECRG4 (ECRG4(133-148)) appears to be processed and shed, presumably at a thrombin-like consensus sequence. Phage targeting this putative ligand shows that this peptide sequence internalizes into cells through the TLR4/CD14/MD2 complex, but modulates inflammation through non-canonical, NFκB signal transduction. ECRG4 is present on the surface of human monocytes and granulocytes. Its interaction with the human innate immunity receptor complex supports a role for cell surface activation of ECRG4 during inflammation and implicates this receptor in its mechanism of action.

Negative control of BAK1 by protein phosphatase 2A during plant innate immunity.

Recognition of pathogen-associated molecular patterns (PAMPs) by surface-localized pattern-recognition receptors (PRRs) activates plant innate immunity, mainly through activation of numerous protein kinases. Appropriate induction of immune responses must be tightly regulated, as many of the kinases involved have an intrinsic high activity and are also regulated by other external and endogenous stimuli. Previous evidences suggest that PAMP-triggered immunity (PTI) is under constant negative regulation by protein phosphatases but the underlying molecular mechanisms remain unknown. Here, we show that protein Ser/Thr phosphatase type 2A (PP2A) controls the activation of PRR complexes by modulating the phosphostatus of the co-receptor and positive regulator BAK1. A potential PP2A holoenzyme composed of the subunits A1, C4, and B'η/ζ inhibits immune responses triggered by several PAMPs and anti-bacterial immunity. PP2A constitutively associates with BAK1 in planta. Impairment in this PP2A-based regulation leads to increased steady-state BAK1 phosphorylation, which can poise enhanced immune responses. This work identifies PP2A as an important negative regulator of plant innate immunity that controls BAK1 activation in surface-localized immune receptor complexes.

HSP90s are required for NLR immune receptor accumulation in Arabidopsis.

Heat shock proteins (HSPs) serve as molecular chaperones for diverse client proteins in many biological processes. In plant immunity, cytosolic HSP90s participate in the assembly, stability control and/or activation of immune receptor complexes. In this paper we report that in addition to the well-established positive roles that HSP90 isoforms play in plant immunity, they are also involved in the negative regulation of immune receptor accumulation. Point mutations in two HSP90 genes, HSP90.2 and HSP90.3, were identified from a forward genetic screen designed to isolate mutants with enhanced disease resistance. We found that specific mutations in HSP90.2 and HSP90.3 lead to heightened accumulation of immune receptors, including SNC1, RPS2 and RPS4. HSP90s may assist SGT1 in the formation of SCF E3 ubiquitin ligase complexes that target immune receptors for degradation. Such regulation is critical for maintaining appropriate levels of immune receptor proteins to avoid autoimmunity.

The FLS2-Associated Kinase BIK1 Directly Phosphorylates the NADPH Oxidase RbohD to Control Plant Immunity

The Arabidopsis immune receptor FLS2 senses the bacterial flagellin epitope flg22 to activate transient elevation of cytosolic calcium ions, production of reactive oxygen species (ROS), and other signaling events to coordinate antimicrobial defenses, such as stomatal closure that limits bacterial invasion. However, how FLS2 regulates these signaling events remains largely unknown. Here we show that the receptor-like cytoplasmic kinase BIK1, a component of the FLS2 immune receptor complex, not only positively regulates flg22-triggered calcium influx but also directly phosphorylates the NADPH oxidase RbohD at specific sites in a calcium-independent manner to enhance ROS generation. Furthermore, BIK1 and RbohD form a pathway that controls stomatal movement in response to flg22, thereby restricting bacterial entry into leaf tissues. These findings highlight a direct role of the FLS2 complex in the regulation of RbohD-mediated ROS production and stomatal defense.

Receptor‐Like Kinases in Plant Innate Immunity

Plants employ a highly effective surveillance system to detect potential pathogens, which is critical for the success of land plants in an environment surrounded by numerous microbes. Recent efforts have led to the identification of a number of immune receptors and components of immune receptor complexes. It is now clear that receptor-like kinases (RLKs) and receptor-like proteins (RLPs) are key pattern-recognition receptors (PRRs) for microbe- and plant-derived molecular patterns that are associated with pathogen invasion. RLKs and RLPs involved in immune signaling belong to large gene families in plants and have undergone lineage specific expansion. Molecular evolution and population studies on phytopathogenic molecular signatures and their receptors have provided crucial insight into the co-evolution between plants and pathogens. [Figure: see text] Jian-Min Zhou (Corresponding author).

Differential expression of functional Fc-receptors and additional immune complex receptors on mouse kidney cells

The precise mechanisms by which circulating immune complexes accumulate in the kidney to form deposits in glomerulonephritis are not well understood. In particular, the role of resident cells within glomeruli of the kidney has been widely debated. Immune complexes have been shown to bind one glomerular cell type (mesangial cells) leading to functional responses such as pro-inflammatory cytokine production. To further assess the presence of functional immunoreceptors on resident glomerular cells, cultured mouse renal epithelial, endothelial, and mesangial cells were treated with heat-aggregated mouse IgG or preformed murine immune complexes. Mesangial and renal endothelial cells were found to bind IgG complexes, whereas glomerular epithelial cell binding was minimal. A blocking antibody for Fc-gamma receptors reduced binding to mesangial cells but not renal endothelial cells, suggesting differential immunoreceptor utilization. RT-PCR and immunostaining based screening of cultured renal endothelial cells showed limited low-level expression of known Fc-receptors and Ig binding proteins. The interaction between mesangial cells and renal endothelial cells and immune complexes resulted in distinct, cell-specific patterns of chemokine and cytokine production. This novel pathway involving renal endothelial cells likely contributes to the predilection of circulating immune complex accumulation within the kidney and to the inflammatory responses that drive kidney injury.

Fungal effector Ecp6 outcompetes host immune receptor for chitin binding through intrachain LysM dimerization

While host immune receptors detect pathogen-associated molecular patterns to activate immunity, pathogens attempt to deregulate host immunity through secreted effectors. Fungi employ LysM effectors to prevent recognition of cell wall-derived chitin by host immune receptors, although the mechanism to compete for chitin binding remained unclear. Structural analysis of the LysM effector Ecp6 of the fungal tomato pathogen Cladosporium fulvum reveals a novel mechanism for chitin binding, mediated by intrachain LysM dimerization, leading to a chitin-binding groove that is deeply buried in the effector protein. This composite binding site involves two of the three LysMs of Ecp6 and mediates chitin binding with ultra-high (pM) affinity. Intriguingly, the remaining singular LysM domain of Ecp6 binds chitin with low micromolar affinity but can nevertheless still perturb chitin-triggered immunity. Conceivably, the perturbation by this LysM domain is not established through chitin sequestration but possibly through interference with the host immune receptor complex. DOI:http://dx.doi.org/10.7554/eLife.00790.001.