Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response

The antiviral innate immune response follows the detection of viral components by host pattern recognition receptors (PRRs). Two families of PRRs have emerged as key sensors of viral infection: Toll-like receptors (TLRs) and retinoic acid inducible gene-I like RNA helicases (RLHs). TLRs patrol the extracellular and endosomal compartments; signalling results in a type-1 interferon response and/or the production of pro-inflammatory cytokines. In contrast, RLHs survey the cytoplasm for the presence of viral double-stranded RNA. In the face of such host defence, viruses have developed strategies to evade TLR/RLH signalling. Such host-virus interactions provide the opportunity for manipulation of PRR signalling as a novel therapeutic approach.     

Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling

Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING, and viral replicase proteins co-localize with STING in HCoV-NL63-infected cells. Ectopic expression of catalytically active PLP2-TM blocks STING dimer formation and negatively regulates assembly of STING-MAVS-TBK1/IKKε complexes required for activation of IRF-3. STING dimerization was also substantially reduced in cells infected with SARS-CoV. Furthermore, the level of ubiquitinated forms of STING, RIG-I, TBK1 and IRF-3 are reduced in cells expressing wild type or catalytic mutants of PLP2-TM, likely contributing to disruption of signaling required for IFN induction. These results describe a new mechanism used by CoVs in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction.     

Baculovirus capsid display potentiates OVA cytotoxic and innate immune responses

Baculoviruses (BV) are DNA viruses that are pathogenic for insects. Although BV infect a range of mammalian cell types, they do not replicate in these cells. Indeed, the potential effects of these insect viruses on the immune responses of mammals are only just beginning to be studied. We show in this paper that a recombinant Autographa californica multiple nuclear polyhedrosis virus carrying a fragment of ovalbumin (OVA) on the VP39 capsid protein (BV-OVA) has the capacity to act as an adjuvant and vector of antigens in mice, thereby promoting specific CD4 and cytotoxic T cell responses against OVA. BV also induced in vivo maturation of dendritic cells and the production of inflammatory cytokines, thus promoting innate and adaptive immune responses. The OVA-specific response induced by BV-OVA was strong enough to reject a challenge with OVA-expressing melanoma cells (MO5 cells) and effectively prolonged survival of MO5 bearing mice. All these findings, together with the absence of pre-existing immunity to BV in humans and the lack of viral gene expression in mammalian cells, make BV a candidate for vaccination.     

Skin innate immune response to flaviviral infection

Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika andWest Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.     

The innate immune response in human tuberculosis

Mycobacterium tuberculosis (Mtb) infection can be cleared by the innate immune system before the initiation of an adaptive immune response. This innate protection requires a variety of robust cell autonomous responses from many different host immune cell types. However, Mtb has evolved strategies to circumvent some of these defences. In this mini‐review, we discuss these host–pathogen interactions with a focus on studies performed in human cells and/or supported by human genetics studies (such as genome‐wide association studies).     

Postnatal programming of the innate immune response

A host's defensive response to a pathogen is a phylogenetically ancient reaction that consists of a CNS-mediated series of autonomic, hormonal and behavioral responses that combine to combat infection. The absence of such defense results in greater morbidity and mortality and thus, these responses are essential for survival. The postnatal period represents a malleable phase in which the long-term behavior and physiology of the developing organism, including its immune responses, can be influenced. Postnatal challenge of the immune system by introduction of live replicating infections, or administration of bacterial and viral mimetics, can result in a multidomain alteration to the defenses of the adult host. Findings from our laboratory and others' indicate that the postnatal administration of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (PolyI:C), which mimic bacterial and viral infections respectively, can influence the neuroimmune response (generation of fever and production of cytokines) to a second challenge to the immune system in adulthood. This long-lasting alteration in the innate immune response is associated with myriad other effects on the animal's physiology and appears to be primarily mediated by a sensitized hypothalamic-pituitary-adrenal axis. Thus, a transient immunological perturbation to a developing animal may program the organism for subsequent health complications as an adult. In this review we discuss some of the potential mechanisms for these phenomena.     

长链非编码RNA——抗病毒天然免疫应答的新兴调控因子

长链非编码RNA(long non-coding RNAs, lncRNAs)是长度超过200nt的非编码RNA分子的总称。作为一类重要的基因调控因子,lncRNAs在表观遗传学、转录及转录后等多个水平调控靶基因的表达。近年来的研究表明,许多lncRNAs可被病毒或干扰素(interferon, IFN)诱导表达,并作为调控因子在IFN介导的抗病毒天然免疫应答中调节抗病毒相关基因的表达。本文重点阐述了lncRNAs在IFN介导的抗病毒天然免疫应答中的调控作用,尤其是对干扰素刺激基因(interferon-stimulated genes, ISGs)转录的调控作用,并归纳了lncRNAs、IFN和ISGs形成的调控网络,以期为从事lncRNAs调控IFN介导的抗病毒天然免疫应答机制研究的相关科研人员提供参考。     

模式识别受体介导的天然免疫反应调节获得性免疫的机理

模式识别受体（PRR）的发现推动了免疫学领域的迅速发展.在近15年时间里,揭示了PRR启动的天然免疫反应机制及信号转导途径,并对天然免疫反应调节获得性免疫产生的机制进行了广泛研究.本文综述该领域一些新的重要发现,集中讨论病原体激活抗原递呈细胞的天然免疫反应调节淋巴细胞介导的抗原特异性获得性免疫机理,以及不同天然免疫途径在宿主抵抗感染和修复组织损伤中的作用,并讨论该领域尚未解决的重要问题.     

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.     

The innate immune response to Trypanosoma cruzi infection

Trypanosoma cruzi infection is a major public health problem in Latin America. The host innate immune system plays a pivotal role in the recognition of T. cruzi infection and the subsequent development of adaptive immunity. In this review, we focus on the TLR-dependent and -independent innate immune responses to T. cruzi.     

Drosophila innate immune response pathways moonlight in neurodegeneration

In this Extra View, we highlight recent Drosophila research that has uncovered a new role for the innate immune response. The research indicates that, in addition to combating infection, the innate immune response promotes neurodegeneration. Our publication (Petersen et al., 2012) reveals a correlative relationship between the innate immune response and neurodegeneration in a model of the human disease Ataxia-telangiectasia (A-T). We also found that glial cells are responsible for the innate immune response in the A-T model, and work by others implicates glial cells in neurodegeneration. Additionally, publications by Chinchore et al. (2012) and Tan et al. (2008) reveal a causative role for the innate immune response in models of human retinal degenerative disorders and Alzheimer disease, respectively. Collectively, these findings suggest that activation of the innate immune response is a shared cause of neurodegeneration in different human diseases.     

The receptor that tames the innate immune response

Tissue injury, hypoxia and significant metabolic stress activate innate immune responses driven by tumor necrosis factor (TNF)-α and other proinflammatory cytokines that typically increase damage surrounding a lesion. In a compensatory protective response, erythropoietin (EPO) is synthesized in surrounding tissues, which subsequently triggers antiinflammatory and antiapoptotic processes that delimit injury and promote repair. What we refer to as the sequelae of injury or disease are often the consequences of this intentionally discoordinated, primitive system that uses a "scorched earth" strategy to rid the invader at the expense of a serious lesion. The EPO-mediated tissue-protective system depends on receptor expression that is upregulated by inflammation and hypoxia in a distinctive temporal and spatial pattern. The tissue-protective receptor (TPR) is generally not expressed by normal tissues but becomes functional immediately after injury. In contrast to robust and early receptor expression within the immediate injury site, EPO production is delayed, transient and relatively weak. The functional EPO receptor that attenuates tissue injury is distinct from the hematopoietic receptor responsible for erythropoiesis. On the basis of current evidence, the TPR is composed of the β common receptor subunit (CD131) in combination with the same EPO receptor subunit that is involved in erythropoiesis. Additional receptors, including that for the vascular endothelial growth factor, also appear to be a component of the TPR in some tissues, for example, the endothelium. The discoordination of the EPO response system and its relative weakness provide a window of opportunity to intervene with the exogenous ligand. Recently, molecules were designed that preferentially activate only the TPR and thus avoid the potential adverse consequences of activating the hematopoietic receptor. On administration, these agents successfully substitute for a relative deficiency of EPO production in damaged tissues in multiple animal models of disease and may pave the way to effective treatment of a wide variety of insults that cause tissue injury, leading to profoundly expanded lesions and attendant, irreversible sequelae.