intense inflammatory response. This inflammatory process is characterized by an influx of neutrophils and macrophages and the secretion of proinflammatory cytokines such as interleukin-1, interleukin-8, and tumor necrosis factor-α (Fig. 2). Proteases, oxidants, and α- defensins are released from inflammatory cells and con- tribute further to tissue destruction. DNA from lysed neu- trophils, epithelial cells, and bacteria increases the viscosity of airway secretions, leading to further impairment of mucociliary function. Exhaled air from patients with CF contains less nitric oxide (NO) than that from normal con- trols, indicating increased metabolism of NO or decreased production due to downregulation of inducible NO syn- thase (27, 28). NO has various functions, ranging from reg- ulation of inflammatory and immune cells and smooth muscle tone to antimicrobial activity, and may be protec- tive or deleterious in CF lung disease. Despite the alter- ations of the innateimmunesystem, the adaptive immunesystem seems to be intact. Most patients develop antibod- ies to antigens of P. aeruginosa (29). Later stages of the dis- ease are characterized by chronic endobronchial infection with P. aeruginosa and other organisms despite persistent mobilization of innate and acquired immunity.
We describe a new link between the immunesystem and the reproductive endocrine system that is regulated by the TNF recep- tor superfamily member CD40, an immune costimulatory molecule whose expression on dendritic cells is critical for the initiation of cell-mediated immune responses (19, 20). Forced ligation of CD40 with agonistic anti-CD40 antibodies caused a systemic inflamma- tory response that efficiently induced embryo resorption in mice early in gestation. However, pregnancy failure occurred not through immune cell activation at the maternal-fetal interface, but rather through decreased progesterone synthesis by the corpus luteum. Luteal insufficiency was induced largely by activated NK cells, required the actions of the proinflammatory cytokine TNF-α, and was associated with impaired prolactin receptor signaling. Further- more, luteal insufficiency correlated with the induction of suppres- sor of cytokine signaling 1 (Socs1) and Socs3, two members of the Socs family of proteins that provide critical feedback inhibition of JAK/STAT signaling at the immediate postreceptor level (21–23). The gestational effects of CD40 ligation delineate an in vivo path- way whereby activation of the innateimmunesystem with associ- ated inflammatory cytokine production leads to pregnancy failure through inhibition of the reproductive endocrine system.
HIV-1 infection is inherently a progressive disorder that is especially productive of a chronic participation of in- jury to CD4+ T-lymphocytes within additional contex- tual conditioning of the AIDS phenomenon. This inher- ently progressive infection is suggestive in itself of a profound involvement of the innateimmunesystem in particular. Interferon lamba 3 activates the innate im- mune system through the JAK-STAT pathway in macro- phages. It inhibits HIV-1 replication in these cells and induces many antiviral cellular factors and interferon regulatory mediators . Plasmacytoid dendritic cells serve as an essential link between innate and adaptive immune systems; the fate of these cells in HIV-1 infec- tion is unclear . The realization of monocyte/macro- phage participation in the accumulation of the HIV-1 virions indicates the essential character of an infection that arises primarily from innateimmune defects. Macro- phages and their monocyte precursors show marked het- erogeneity and may be either proinflammatory or alter- natively activated .
Increasing environmental and anthropogenic pressures facing corals worldwide (Burke et al., 2011) highlight the urgent need for tools to evaluate and monitor coral health to manage and pre-empt activities that might cause further declines. Given the importance of immunesystem function for health, parameters associated with the innateimmunesystem could make ideal stress biomarkers for coral health. A number of studies have identified activity of the prophenoloxidase (proPO) system, an important component of the innateimmunesystem of invertebrates (Cerenius et al., 2010a), and expression of green fluorescent protein-like (GFP-like) proteins as potential coral stress biomarkers based on detectable responses to variations in environmental parameters (D'Angelo et al., 2008; Smith-Keune and Dove, 2008; Palmer et al., 2010; Roth et al., 2010; Palmer et al., 2011b; Roth and Deheyn, 2013). Both parameters respond to warm seawater temperature anomalies, which are known to significantly affect the health of the coral holobiont, causing shifts in coral-associated microbial communities (Littman et al., 2010), increases in the virulence of coral pathogens (Ben-Haim et al., 2003b; Vidal-Dupiol et al., 2011b), and disruptions to the coral-Symbiodinium endosymbiosis leading to bleaching (Douglas, 2003). Heavy monsoonal rainfall, which results in reduced salinity and increased terrestrial run-off leading to increased levels of turbidity and agricultural pollutants, is also a major stressor for corals. Warm seawater temperatures and changes in salinity and agricultural pollutants have all been shown to compromise the functioning of the innateimmune systems of a range of marine invertebrates (Tseng and Chen, 2004; Ellis et al., 2011; Lin et al., 2012). In addition, both low salinity (Kerswell and Jones, 2003; Jones and Berkelmans, 2014) and cold sea surface temperatures (Saxby et al., 2003; Hoegh-Guldberg et al., 2005) have been implicated in coral bleaching. Extremes in seasonal environmental conditions can therefore significantly affect coral health, fitness and disease susceptibility. Although targeted, short-term studies are beginning to explore how environmental stressors affect the proPO-activating system and GFP-like protein expression, an understanding of what constitutes healthy baseline levels is needed to explore the potential of these two parameters as stress biomarkers.
In aquatic organisms, it is widely accepted that the NPs first target the outer skin and the intestine, 10 which corre- lates with the primary sites where the innateimmunesystem can be activated. On the external epithelial membranes of fish, NPs can interfere with the lateral line system, inducing oxidative stress or apoptotic cell death in neuromasts, ulti- mately leading to a reduction of functional neuromasts and attenuated orientation within a current. 11–13 Although lateral line neuromasts are used for screening purposes to identify immunomodulatory compounds, NPs have not yet been assessed for this activity. In intestines of juvenile fish, an im- mune response after NP exposure was detected by increased mRNA levels of pro-inflammatory related genes after copper (Cu) NPs exposure. 14 Moreover, the effect was more pro- nounced for the NP than for the soluble copper exposure. In zebrafish embryos, despite being a widely used organism to screen for NP toxicity or investigate immune responses, target sites of NPs have not yet been explored for such responses. Whole embryo assessment revealed that gold NPs (1.5 nm) al- ter genes involved in inflammatory pathways after waterborne exposure of dechorionated embryos 15 and injected silica NPs (62 nm) lead to neutrophil-mediated cardiac inflammation. 16 Innateimmune responses in early life stages of fish triggered by NPs is thus conceivable, however, the assessment and lo- calization of inflammation as a molecular key event after wa- terborne exposure of NPs remains largely unexplored.
Understanding the mechanisms by which herpes simplex virus (HSV) evades host immune defenses is critical to defining new approaches for therapy and prevention. We performed transcriptional analyses and immunocytochemistry on sequential biopsy specimens of lesional tissue from the acute through the posthealing phases of recurrent mucocutaneous HSV-2 infection. Histological analysis of these biopsy specimens during the acute stage revealed a massive infiltration of T cells, as well as monocytes/macrophages, a large amount of myeloid, and a small number of plasmacytoid dendritic cells, in the dermis of these lesional biopsy specimens. Type I interferon (IFN- ␤ and IFN- ␣ ) was poorly expressed and gamma IFN (IFN- ␥ ) potently induced during time periods in which we detected abundant amounts of HSV-2 antigens and HSV-2 RNA. IFN-stimulated genes were also markedly upregulated, with expression patterns that more closely matched those in primary human fibroblasts treated by IFN- ␥ than those in fibroblasts treated by IFN- ␤ . Transcriptional arrays of the same lesional biopsy sites during healing and at 2 and 4 weeks posthealing revealed no HSV nucleic acids or antigen; however, there was persistent expression of IFN- ␥ , with very low levels of IFN- ␤ and IFN- ␣ . The findings of extremely low levels of IFN- ␣ and IFN- ␤ , despite the presence of a large number of cells capable of synthesizing these substances, suggest a potent alteration in host defense during HSV-2 infection in vivo. HSV-2’s blockade of the innateimmune system’s production of type I IFN may be a major factor in allowing the virus to break through host mucosal defenses.
The endosomal TLR9 is the only TLR that is able to sense DNA by specifically binding to unmethylated cytosine-guanosine containing (CpG) motifs within DNA and trigger IFN production, a feature commonly found in bacterial and viral genomes but rare within the human genome (Hemmi et al., 2000). Despite this, TLR9 independent activation of the innateimmunesystem by DNA has been observed. Studies in TLR9 deficient mice still exhibited IFN-β production in response to DNA, suggesting a novel TLR9 independent DNA sensing mechanism (Okabe et al., 2005). Before any potential TLR independent DNA sensors were discovered it was clear that signalling via TANK-binding kinase 1 (TBK1) and IRF3 was pivotal to the DNA response that resulted in induction of type I IFNs (Stetson and Medzhitov, 2006, Ishii et al., 2008). A major breakthrough for understanding intracellular DNA sensing occurred with the discovery of the endoplasmic reticulum (ER) bound stimulator of IFN genes (STING) (Ishikawa and Barber, 2008). STING was identified as a crucial upstream adaptor of TBK1 and IRF3 in the DNA response pathway (Zhong et al., 2008, Tanaka and Chen, 2012). However, how DNA activates STING signalling has been studied intensely and yielded a surprising number of upstream sensors (see Figure 7 for a summary of these pathways).
immunocyte. This distinction becomes blurred because of cross-talk between activated KCs and immunocytes that begins immediately upon lesion forma- tion and culminates in the mature psori- atic plaque. This uncertainty prompts further questions: Does psoriasis repre- sent a primary defect in the terminal dif- ferentiation response to injury by KCs that fail to produce a normal stratum corneum and, therefore, do not create a protective physiological barrier? Alterna- tively, is the aberrant KC differentiation program in psoriasis a consequence of an influx of pathogenic immunocytes par- ticipating in a rogue auto-immune reac- tion? These possibilities are relevant to our understanding of the hyperrespon- siveness of pre-psoriatic skin reported by Travers et al. in this issue of the JCI (3). In this Commentary, I synthesize available data into a multistep model, taking a novel view of psoriasis from the perspec- tive of the innateimmunesystem. This approach may lead to new avenues for investigators confronting this perplexing skin problem that involves dynamic and reversible epidermal remodeling.
Inflammation is a rapid yet coordinated response that can lead to the destruction of microbes and host tissue. Triggers capable of inducing an inflammatory response include tissue damage and infection by pathogenic and nonpathogenic microbes. Each of these triggers represents a qualitatively distinct stress to the host immunesystem, yet our understanding of whether they are interpreted as such remains poor. Accumulating evidence suggests that recognition of these distinct stimuli converges on many of the same receptors of the innateimmunesystem. Here I provide an overview of these innate receptors and suggest that the innateimmunesystem can interpret the context of an inflammatory trigger and direct inflammation accordingly.
Enterovirus A71 (EV-A71) is a growing threat to public health, particularly in the Asia-Pacific region. EV-A71 infection is most prevalent in infants and children and causes a wide spectrum of clinical complications, including hand-foot- and-mouth disease (HFMD), pulmonary and neurological disorders. The pathogenesis of EV-A71 infection is poorly understood at present. It is likely that viral factors and host immunity, and their interplay, affect the pathogenesis and outcome of EV-A71 infection. The mammalian innateimmunesystem forms the first layer of defense against viral infections and triggers activation of adaptive immunity leading to full protection. In this review, we discuss recent advances in our understanding of the interaction between EV-A71 and the innateimmunesystem. We discuss the role of pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and inflammasomes, in the detection of EV-A71 infection and induction of antiviral immunity. As a counteraction, EV-A71 viral proteins target multiple innateimmune pathways to facilitate viral replication in host cells. These novel insights at the virus-host interphase may support the future development of vaccines and therapeutics against EV-A71 infection.
Immune dysfunction can provoke (multiple) organ failure in severely injured patients. This dysfunction manifests in two forms, which follow a biphasic pattern. During the first phase, in addition to the injury by trauma, organ damage is caused by the immunesystem during a systemic inflammatory response. During the second phase the patient is more susceptible for sepsis due to host defence failure (immune paralysis). The pathophysiological model outlined in this review encompasses etiological factors and the contribution of the innateimmunesystem in the end organ damage. The etiological factors can be divided into intrinsic (genetic predisposition and physiological status) and extrinsic components (type of injury or "traumaload" and surgery or "intervention load"). Of all the factors, the intervention load is the only one which, can be altered by the attending emergency physician. Adjustment of the therapeutic approach and choice of the most appropriate treatment strategy can minimize the damage caused by the immune response and prevent the development of immunological paralysis. This review provides a pathophysiological basis for the damage control concept, in which a staged approach of surgery and post-traumatic immunomonitoring have become important aspects of the treatment protocol. The innateimmunesystem is the main objective of immunomonitoring as it has the most prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-cells of the innateimmunesystem in the processes that lead to organ failure. These cells are controlled by cytokines, chemokines, complement factors and specific tissue signals. The contribution of tissue barrier integrity and its interaction with the innateimmunesystem is further evaluated.
Also the role of LPS originating from both cyanobacte- ria and eubacteria has to be critically reflected. The con- troversies about pro- or anti-inflammatory activities of cyanobacterial LPS may be explained by the effects of bloom-associated bacterial LPS, potentially sensitizing GIT epithelia for the effects of other toxins. A similar effect was observed with the pore-forming lipopeptides anabae- nolysins A and B, where a transient increase in cell mem- brane permeability facilitated nodularin uptake, lowering the effective concentration for nodularin toxicity . Cyanobacterial LPS activity on the mucosal innateimmunesystem does not sufficiently explain the GIT symptoms observed upon acute oral exposure to cyanobacterial blooms. However, the total bloom LPS released during a bloom, including pro-inflammatory LPS from bloom-asso- ciated bacteria, may facilitate the penetration of gastroin- testinal epithelia and thereby promote the uptake of other cyanobacterial toxins by macrophages or into the blood via the paracellular route as suggested for CYN [141, 156].
Second, while it is clear that detection of classical PAMPs is central to immune surveillance, we also believe that the innateimmunesystem can sense viral infections through other mechanisms. It seems likely that novel principles of pathogen recognition remain to be discovered, by which viral activities rather than molecular structures are sensed. This would allow the host to distinguish pathogenic from non-‐pathogenic infections. Lytic infection, a property of all herpesviruses, is an activity directly associated with pathogenicity, and a recent report has shown that 2’ 5’ oligoadenylate synthetase is induced in virus-‐ infected cells, released following cell lysis and subsequently taken up by non-‐infected cells to exert antiviral activity 132 . It will be interesting to establish if host sensing of pathogen-‐induced processes is a whole new
In A. gambiae, it has been shown that malaria infection induces a large number of immune effector genes, which form an important line of defence against Plasmodium parasites. In our microarray screen, sHz treatment in- duced several PRRs, which have been associated with con- trol of Plasmodium infection in the mosquito (Figure 2B and Table 1). Among them are some potent immune factors, as TEP1 (thioester-containing protein 1), APL1 (Anopheles Plasmodium-responsive leucine-rich repeat 1) and FBN9 (fibrinogen immunolectin 9) (Table 1). Evi- dence from observations in vertebrates and co-localization at parasite surface led Garver et al.  to speculate that a lectin complement-like pathway mechanism, in which TEP1 and FBN9 cooperate to destroy pathogens, may exist in mosquitoes as well. Our data showed that these two genes presented similar expressions (Table 1). APL1C and LRIM1 (leucine-rich repeat immune protein 1), an- other two PRR members of the complement-like pathway in A. gambiae [24,25], showed similar expressions in our microarray analysis (Table 1). In addition to the inter- action with TEP1, the LRIM1/APL1C complex interacts with the mature forms of other proteins such as TEP3 and TEP4 , both also up-regulated after sHz treatment (Table 1). The basal expression of TEP1 and LRIM1 is representative of the pre-invasion phase , which is in accordance with our results for the induction of these genes in the fat body before parasite invasion. Of note, these genes are believed to be hemocyte-specific, which
Reflecting the cytokine profile, primary neonatal infection al- tered the T cell response to reinfection. Mice previously infected as neonates had a peak influx of both CD4 and CD8 T cells at day 7 after infection. Mice previously infected as adults had a peak of CD4 T cells at day 4, and mice infected as neonates had a peak of CD4 T cells at day 7 (Fig. 2H). There were significantly more CD8 T cells recruited to the lungs of neonatally infected mice on day 7 after reinfection (P ⬍ 0.001; Fig. 2I). As seen before (5), there were also more IL-4-producing CD4 cells and IFN- ␥ -producing CD8 T cells in neonatally primed mice than adults, peaking at day 7 (data not depicted). In spite of the increased inflammation, mice ini- tially infected as neonates had a greater viral load than mice ini- tially infected as adults (Fig. 2J). As previously observed, age at initial RSV infection affected the weight loss profile during sec- ondary reinfection. In mice initially infected as neonates, reinfec- tion caused weight loss starting on day 2 and peaking on day 5, while primary adult infection was protective against weight loss during reinfection (Fig. 2K). These data suggest that innate cell recruitment strongly correlated with disease, as measured by the amplitude of cytokine production, cellularity, and weight loss.
Zebrafish has become a prominent vertebrate model to study human infectious disease, especially for TB (130, 131). First, because the natural fish pathogen, Mycobacterium marinum, a close relative to Mtb, can induce granuloma formation in adults and larvae of zebrafish. The granulomas in adult fish are very similar to those observed during human latent TB progression and zebrafish larvae provide unique access to the earliest stages of the formation of these granulomas (132, 133). Second, the relatively small size of embryos allows infection assays to be performed at a large scale. In addition, the transparent larvae are ideal for imaging the early steps of the infection process in real time. The short generation time of 3-4 months is useful for generating transgenic lines and other genetics approaches. Last but not the least, zebrafish have a 3-4 weeks separation stage between development of innate and adaptive immunity after fertilization (134, 135), which gives the possibility to study the host innateimmune response to infection in the absence of adaptive immune responses. Zebrafish have lymphatics but lack lymph nodes, so the adaptive immune cells mainly develop and function in the spleen, the kidney and the thymus (131, 136-138). Furthermore, fish do not have bone marrow and instead the anterior part of the kidney functions as a major site of hematopoiesis. Anatomically, this is therefore different from mammals, but zebrafish shares most of the primary constituents of innate and adaptive immunity with mammals (136, 139, 140). Zebrafish larvae can only activate innate immunity to provide resistance against Mtb infection. The two most important immune cell types for the innate defenses, macrophages and neutrophils, are already functional from 1 day post fertilization (dpf) (141-143).
Although we found considerable interspecific variation in both innate and humoral immune components, differences were most pronounced for complement-mediated lysis and primary and secondary humoral immune responses. This result suggests that not all immune components are under the same pressure to be internally regulated. Indeed, the levels of natural antibodies varied little, even among species with such different body masses as the sanderling and the bar-tailed godwit. This is consistent with the idea that natural antibody production is largely independent of internal and external stimuli (Ochsenbein and Zinkernagel, 2000). However, although natural antibodies are present in relatively low densities, they play an important role in the initial recognition of foreign particles and they support subsequent defense by the complement cascade and the acquired humoral response (Ochsenbein and Zinkernagel, 2000; Turner, 2000). Therefore, organisms may benefit by maintaining a minimum level of immunoglobulins, as these molecules likely convey benefits in terms of earlier detection of parasites. With respect to the innateimmunesystem, we found no difference between the five shorebird species in natural antibody levels, whereas ruddy turnstones showed a higher complement system activity than the four other species. For the humoral responses of the acquired immunesystem, pre-injection, primary and secondary antibody titers against diphtheria toxoid and secondary antibody titers against tetanus were higher in ruddy turnstones, whereas there were no differences in antibody responses between any of the other shorebird species.
The human endometrium is an important site of innateimmune defence, giving protection against uterine infection. Such protection is critical to successful implantation and pregnancy. Infection is a major cause of preterm birth and can also cause infertility and ectopic pregnancy. Natural anti- microbial peptides are key mediators of the innateimmunesystem. These peptides, between them, have anti-bacterial, anti-fungal and anti-viral activity and are expressed at epithelial surfaces throughout the female genital tract. Two families of natural anti-microbials, the defensins and the whey acidic protein (WAP) motif proteins, appear to be prominent in endometrium. The human endometrial epithelium expresses beta-defensins 1–4 and the WAP motif protein, secretory leukocyte protease inhibitor. Each beta-defensin has a different expression profile in relation to the stage of the menstrual cycle, providing potential protection throughout the cycle. Secretory leukocyte protease inhibitor is expressed during the secretory phase of the cycle and has a range of possible roles including anti-protease and anti-microbial activity as well as having effects on epithelial cell growth. The leukocyte populations in the endometrium are also a source of anti- microbial production. Neutrophils are a particularly rich source of alpha-defensins, lactoferrin, lysozyme and the WAP motif protein, elafin. The presence of neutrophils during menstruation will enhance anti-microbial protection at a time when the epithelial barrier is disrupted. Several other anti-microbials including the natural killer cell product, granulysin, are likely to have a role in endometrium. The sequential production of natural anti-microbial peptides by the endometrium throughout the menstrual cycle and at other sites in the female genital tract will offer protection from many pathogens, including those that are sexually transmitted.