Innate immune recognition of viral infection

Toll-like receptors (TLRs) are key molecules of the innate immune systems, which detect conserved structures found in a broad range of pathogens and triggers innate immune responses. A subset of TLRs recognize viral components and induce antiviral responses by producing type I interferons. Whereas TLR2 and TLR4 recognize viral components at the cell surface, TLR3, TLR7, TLR8 and TLR9 are exclusively expressed in endosomal compartments. After phagocytes internalize viruses or virus-infected apoptotic cells, viral nucleic acids are released in phagolysosomes and are recognized by these TLRs. Recent reports have shown that hosts also have a mechanism to detect replicating viruses in the cytoplasm in a TLR-independent manner. In this review, we focus on the viral recognition by innate immunity and the signaling pathways.     

Innate visual object recognition in vertebrates: some proposed pathways and mechanisms

Almost all vertebrates are capable of recognizing biologically relevant stimuli at or shortly after birth, and in some phylogenetically ancient species visual object recognition is exclusively innate. Extensive and detailed studies of the anuran visual system have resulted in the determination of the neural structures and pathways involved in innate prey and predator recognition in these species [Behav. Brain Sci. 10 (1987) 337; Comp. Biochem. Physiol. A 128 (2001) 417]. The structures involved include the optic tectum, pretectal nuclei and an area within the mesencephalic tegmentum. Here we investigate the structures and pathways involved in innate stimulus recognition in avian, rodent and primate species. We discuss innate stimulus preferences in maternal imprinting in chicks and argue that these preferences are due to innate visual recognition of conspecifics, entirely mediated by subtelencephalic structures. In rodent species, brainstem structures largely homologous to the components of the anuran subcortical visual system mediate innate visual object recognition. The primary components of the mammalian subcortical visual system are the superior colliculus, nucleus of the optic tract, anterior and posterior pretectal nuclei, nucleus of the posterior commissure, and an area within the mesopontine reticular formation that includes parts of the cuneiform, subcuneiform and pedunculopontine nuclei. We argue that in rodent species the innate sensory recognition systems function throughout ontogeny, acting in parallel with cortical sensory and recognition systems. In primates the structures involved in innate stimulus recognition are essentially the same as those in rodents, but overt innate recognition is only present in very early ontogeny, and after a transition period gives way to learned object recognition mediated by cortical structures. After the transition period, primate subcortical sensory systems still function to provide implicit innate stimulus recognition, and this recognition can still generate orienting, neuroendocrine and emotional responses to biologically relevant stimuli.     

Innate barriers to viral infection

Innate immunity represents the foremost barrier to viral infection. In order to infect a cell efficiently, viruses need to evade innate immune effectors such as interferons and inflammatory cytokines. Pattern recognition receptors can detect viral components or pathogen-associated molecular patterns. These receptors then elicit innate immune responses that result in the generation of type I interferons and proinflammatory cytokines. Organized by the Society for General Microbiology, one session of this conference focused on the current state-of-the-art knowledge on innate barriers to infection of different RNA and DNA viruses. Experts working on innate immunity in the context of viral infection provided insight into different aspects of innate immune recognition and also discussed areas for future research. Here, we provide an overview of the session on innate barriers to infection.     

Innate immune response to viral infection

In viral infections the host innate immune system is meant to act as a first line defense to prevent viral invasion or replication before more specific protection by the adaptive immune system is generated. In the innate immune response, pattern recognition receptors (PRRs) are engaged to detect specific viral components such as viral RNA or DNA or viral intermediate products and to induce type I interferons (IFNs) and other pro-inflammatory cytokines in the infected cells and other immune cells. Recently these innate immune receptors and their unique downstream pathways have been identified. Here, we summarize their roles in the innate immune response to virus infection, discrimination between self and viral nucleic acids and inhibition by virulent factors and provide some recent advances in the coordination between innate and adaptive immune activation.     

Innate recognition of non-self nucleic acids

The immune system has evolved a plethora of innate receptors that detect microbial DNA and RNA, including Toll-like receptors in the endosomal compartment and RIG-I-like receptors and Nod-like receptors in the cytosol. Here we discuss the recognition of and responses to non-self nucleic acids via these receptors as well as their involvement in autoimmune diseases.     

Innate predator recognition in giant pandas

Innate predator recognition confers a survival advantage to prey animals. We investigate whether giant pandas exhibit innate predator recognition. We analyzed behavioral responses of 56 naive adult captive giant pandas (Ailuropoda melanoleuca), to urine from predators and non-predators and water control. Giant pandas performed more chemosensory investigation and displayed flehmen behaviors more frequently in response to predator urine compared to both non-predator urine and water control. Subjects also displayed certain defensive behaviors, as indicated by vigilance, and in certain cases, fleeing behaviors. Our results suggest that there is an innate component to predator recognition in captive giant pandas, although such recognition was only slight to moderate. These results have implications that may be applicable to the conservation and reintroduction of this endangered species.     

Innate immune recognition of respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in infants and young children. Severe clinical manifestation of RSV infection is a bronchiolitis, which is common in infants under six months of age. Recently, RSV has been recognized as an important cause of respiratory infection in older populations with cardiovascular morbidity or immunocompromised patients. However, neither a vaccine nor an effective antiviral therapy is currently available. Moreover, the interaction between the host immune system and the RSV pathogen during an infection is not well understood. The innate immune system recognizes RSV through multiple mechanisms. The first innate immune RSV detectors are the pattern recognition receptors (PRRs), including toll-like receptors (TLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and nucleotide-biding oligomerization domain (NOD)-like receptors (NLRs). The following is a review of studies associated with various PRRs that are responsible for RSV virion recognition and subsequent induction of the antiviral immune response during RSV infection. [BMB Reports 2014; 47(4): 184-191]     

Innate recognition of malarial parasites by mammalian hosts

Innate immunity plays a central role in combating infections. However, the importance of innate immune sensors in detecting intracellular parasites, such as Plasmodium spp., has only recently emerged as a central topic in the field of host-pathogen interactions. Genetic dissection of innate immune pathways has uncovered a complex relationship between the host innate immune system and Plasmodium blood-stage parasites. In fact, recognition molecules of the innate immune system, such as toll-like receptors, might not only be implicated in host defense but also in the pathogenesis of the disease. Whether Plasmodium liver stage parasites are recognised and controlled by the host innate immune system remains to be discovered. In this review we discuss recent findings on how the host innate immune system may sense and fight the different forms of Plasmodium and how the latter may have evolved mechanisms to escape host detection and/or to manipulate the defensive reaction of the host.     

Innate recognition of microbial-derived signals in immunity and inflammation

Microbes generate a vast array of different types of conserved structural components called pathogen-associated molecular patterns(PAMPs),which canbe recognized by cells of the innate immune system.This recognition of "nonself" signatures occurs through host pattern recognition receptors(PRRs),suggesting that microbial-derived signals are good targets for innate immunity to discriminate between self- and nonself.Such PAMP-PRR interactions trigger multiple but distinct downstream signaling cascades,subsequently leading to production of proinflammatory cytokines and interferons that tailor immune responses to particular microbes.Aberrant PRR signals have been associated with various inflammatory diseases and fine regulation of PRR signaling is essential for avoiding excessive inflammatory immune responses and maintaining immune homeostasis.In this review we summarize the ligands and signal transduction pathways of PRRs and highlight recent progress of the mechanisms involved in microbe-specific innate immune recognition during immune responses and inflammation,which may provide new targets for therapeutic intervention to the inflammatory disorders.     

Innate immune mechanisms of colitis and colitis-associated colorectal cancer

The innate immune system provides first-line defences in response to invading microorganisms and endogenous danger signals by triggering robust inflammatory and antimicrobial responses. However, innate immune sensing of commensal microorganisms in the intestinal tract does not lead to chronic intestinal inflammation in healthy individuals, reflecting the intricacy of the regulatory mechanisms that tame the inflammatory response in the gut. Recent findings suggest that innate immune responses to commensal microorganisms, although once considered to be harmful, are necessary for intestinal homeostasis and immune tolerance. This Review discusses recent findings that identify a crucial role for innate immune effector molecules in protection against colitis and colitis-associated colorectal cancer and the therapeutic implications that ensue.     

Innate and enhanced predator recognition in hatchery-reared chinook salmon

We used a laboratory behaviour assay to investigate how innate predator recognition, handling stress, retention time, and number of conditioning events might affect chemically mediated anti-predator conditioning for hatchery-reared chinook salmon, Oncorhynchus tshawytscha. Juvenile chinook salmon with no prior exposure to predatory stimuli exhibited innate fright responses to northern pikeminnow, Ptychocheilis oregonensis, odour, regardless of whether the salmon came from a population that exists in sympatry or allopatry with northern pikeminnows. Juvenile chinook salmon exhibited enhanced predator recognition following a single conditioning event with conspecific extract and northern pikeminnow odour. Handling similar to what hatchery salmon might experience prior to release did not substantially reduce the conditioned response. When we conditioned juvenile chinook salmon in hatchery rearing vessels, fish from tanks treated once exhibited a conditioned response to northern pikeminnow odour in aquaria, but only for one behaviour (feeding response), and fish treated twice did not respond. The results suggest that enhanced recognition of predator stimuli occurs quickly, but may be to some extent context-specific, which may limit conditioned fright responses after release into the natural environment.     

Innate immune responses in peptidoglycan recognition protein L-deficient mice

Peptidoglycan recognition proteins (PGRPs) constitute a family of innate immune recognition molecules. In Drosophila, distinct PGRPs bind to peptidoglycans on gram-positive or gram-negative bacteria and provide essential signals upstream of the Toll and Imd pathways required for immunity against infection. Four PGRPs, PGRP-L, -S, -Ialpha, and -Ibeta, are expressed from three genes in mammals. In this paper, we provide direct evidence that the longest family member, PGRP-L, is a secreted serum protein with the capacity to multimerize. Using gene targeting to create PGRP-L-deficient mice, we demonstrate little contribution by PGRP-L to systemic challenge using gram-negative bacteria (Escherichia coli, slightly less susceptible), Gram-positive bacteria (Staphylococcus aureus), or yeast (Candida albicans). Peritoneal macrophages from PGRP-L-deficient mice produced decreased amounts of the inflammatory cytokines interleukin 6 and tumor necrosis factor alpha when stimulated with E. coli or lipopolysaccharide, but comparable amounts when stimulated with S. aureus, C. albicans, or their cell wall components. Additionally, these cells produced similar amounts of cytokines when challenged with gram-positive or -negative peptidoglycans. In contrast to its critical role in immunity in flies, PGRP-L is largely dispensable for mammalian immunity against bacteria and fungi.     

Toll样受体对病原寄生虫的天然免疫识别

Toll样受体是机体天然免疫系统最重要的模式识别受体之一,通过识别病原寄生虫的病原相关分子模式,活化依赖和非依赖于髓样分化因子88的信号转导通路,诱导干扰素、炎症因子、趋化因子等的表达以及树突状细胞的成熟,抵御病原寄生虫的感染。因此,以下综述了Toll样受体对原病寄生虫,尤其对动物寄生性原虫与蠕虫感染的模式识别与天然免疫应答机制,以进一步理解病原寄生虫与宿主相互作用的复杂性,为寄生虫病的有效防治提供理论参考。     

Innate immune recognition of flagellin limits systemic persistence of Brucella

Brucella are facultative intracellular bacteria that cause chronic infections by limiting innate immune recognition. It is currently unknown whether Brucella FliC flagellin, the monomeric subunit of flagellar filament, is sensed by the host during infection. Here, we used two mutants of Brucella melitensis, either lacking or overexpressing flagellin, to show that FliC hinders bacterial replication in vivo. The use of cells and mice genetically deficient for different components of inflammasomes suggested that FliC was a target of the cytosolic innate immune receptor NLRC4 in vivo but not in macrophages in vitro where the response to FliC was nevertheless dependent on the cytosolic adaptor ASC, therefore suggesting a new pathway of cytosolic flagellin sensing. However, our work also suggested that the lack of TLR5 activity of Brucella flagellin and the regulation of its synthesis and/or delivery into host cells are both part of the stealthy strategy of Brucella towards the innate immune system. Nevertheless, as a flagellin‐deficient mutant of B. melitensis wasfound to cause histologically demonstrable injuries in the spleen of infected mice, we suggested that recognition of FliC plays a role in the immunological stand‐off between Brucella and its host, which is characterized by a persistent infection with limited inflammatory pathology.     

Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2

Toll-like receptors (TLRs) are pathogen recognition molecules that activate the immune system as part of the innate immune response. Microbial recognition by TLRs plays a crucial role in the host immune system's decision to respond or not to a particular microbial infection. Lipopolysaccharide (LPS), a membrane glycolipid of Gram-negative bacteria, exhibits strong immunostimulating activity among TLR ligands and has been studied in great detail. Recent studies have shown that cell surface TLR4-MD-2 physically interacts with LPS and triggers the release of an LPS signal, revealing a host-pathogen interaction mediated by TLR.     

Analyzing protein-DNA recognition mechanisms

We present a computational algorithm that can be used to analyze the generic mechanisms involved in protein-DNA recognition. Our approach is based on energy calculations for the full set of base sequences that can be threaded onto the DNA within a protein-DNA complex. It is able to reproduce experimental consensus binding sequences for a variety of DNA binding proteins and also correlates well with the order of measured binding free energies. These results suggest that the crystal structure of a protein-DNA complex can be used to identify all potential binding sequences. By analyzing the energy contributions that lead to base sequence selectivity, it is possible to quantify the concept of direct versus indirect recognition and to identify a new concept describing whether the protein-DNA interaction and DNA deformation terms select optimal binding sites by acting in accord or in disaccord.