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Innate Immunity in Animals
Acute inflammation is the central feature of innate immunity. The first step in the inflammatory process is the early detection of either invading organisms or damaged tissues. Most invaders are recognized by pattern-recognition receptors that bind and recognize conserved molecules expressed on microbial surfaces. These pathogen-associated molecular patterns (PAMPs) are one type of initiating trigger. The second type of trigger are molecules released from broken or damaged cells. These are called damage-associated molecular patterns (DAMPs). There are many different pattern-recognition receptors, but the most important are the toll-like receptors (TLRs). TLRs are a family of at least 10 different receptors found on the surface or in the cytoplasm of cells such as macrophages, intestinal epithelial cells, and mast cells. The TLRs bind to PAMPs commonly expressed by extracellular bacteria such as lipopolysaccharides, flagellin, and lipoproteins. The cytoplasmic TLRs, in contrast, bind the nucleic acids of intracellular viruses. Once they bind these ligands, the TLRs trigger the production of inflammatory cytokines such as interleukin 1 (IL-1) or tumor necrosis factor alpha (TNF-alpha).
IL-1 and the other cytokines produced in response to TLR stimulation then trigger acute inflammation. They initiate the adherence of circulating leukocytes to blood vessel walls close to sites of invasion. These leukocytes, especially neutrophils, then leave the blood vessels and migrate to invasion sites, attracted by microbial products, small proteins called chemokines, and molecules from damaged cells. Once they arrive at the invasion site, the neutrophils bind invading bacteria, ingest them by phagocytosis, and kill them. This is largely mediated by a metabolic pathway called the respiratory burst that generates potent oxidants such as hydrogen peroxide and hypochloride ions. Neutrophils, however, have minimal energy reserves and can only undertake few phagocytic events before they are depleted.
Even when the inflammatory response is successful in killing invading microbes , the body must still remove cell debris and dying cells and repair the damage. This is the task of macrophages. Tissue macrophages originate from blood monocytes. They, like neutrophils, are attracted to sites of microbial invasion and tissue damage by chemokines, DAMPs, and PAMPs, where they finish off any surviving invaders. They also ingest and destroy any remaining neutrophils, thus ensuring that the neutrophil oxidants are removed without toxic spills occurring in the tissues. Finally, another population of macrophages begins the process of tissue repair. Macrophages that complete the destructive process are optimized for microbial destruction and are called M1 cells. Macrophages optimized for tissue repair and removal of damaged tissues are called M2 cells.
Many of the molecules produced as a result of inflammation and tissue damage, such as IL-1 and TNF, can leak into the bloodstream, where they circulate. They can enter the brain and trigger sickness behavior for example, they cause a fever, suppress appetite, and produce sleepiness and depression. They also mobilize energy reserves from fat and muscle. This sickness behavior is believed to enhance the defense of the body by redirecting energy toward fighting off invaders.
Circulating cytokines from inflammatory sites also act on liver cells, causing the cells to secrete a mixture of “acute-phase proteins,” so-called because their blood levels climb steeply when acute inflammation develops. Different mammals produce different acute-phase proteins, including serum amyloid A, C-reactive protein, and many different iron-binding proteins.
Influenza virus infection is one of the leading causes of mortality and morbidity worldwide. Seasonal influenza infections causes three to five million cases of severe illness every year, and approximately 250,000–500,000 deaths worldwide . Furthermore, due to major genetic changes in influenza virus, the so-called antigenic shift, when whole segments of different virus strains are interchanged in the same host, the virus can become highly pathogenic and cause global pandemics with great number of deaths .
Influenza A is the best studied member of the Orthomyxoviridae family, comprised of negative-sense single-stranded RNA (ssRNA) enveloped virus. It contains a genome composed of eight segments of ssRNA enclosed by nucleoprotein forming the so-called ribonucleoprotein (RNP) complexes that carry also their own polymerases PA, PB1 and PB2 . The subtypes of the virus are defined by the differences in viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) and virtually all the various virus subtypes can be found in migratory birds—the natural reservoir of influenza A virus . Different subtypes can infect and cause disease in a diverse number of species including birds, pigs and humans . In humans, influenza virus infection is in most cases confined to the respiratory tract , and most commonly caused by influenza A H1N1, influenza A H3N2, influenza B Victoria and influenza B Yamagata . The virus reaches the human respiratory epithelium and attaches to the N-acetylneuraminic acid (also called sialic acid) of epithelial cells. HA is the protein needed for virus binding to the host cell and differences in structure and conformation of this viral glycoprotein determines the receptor specificity of influenza A virus . After infecting epithelial cells the virus can spread and infect immune or non-immune cells in the respiratory tract.
The lung is in constant contact with the environment and in consequence with different potential pathogens. Therefore, there are several barriers that can limit the growth and establishment of a microorganism in the respiratory surface, including the mucus and the immune system . The inflammatory response is an important defense mechanism against influenza A virus infection (IAV) preventing the replication and spread of the virus. However, an uncontrolled and exacerbated response to the virus may be associated with intense lung injury and death [10–12]. Indeed, there are several studies which have suggested a tight association between inflammation and the most severe cases of IAV infection [13–15]. Therefore, the inflammatory response triggered by IAV infections can be described as a double edge sword—it is necessary to protect against viral infection but may also cause severe pulmonary injury (Fig. 1). It is our hypothesis that there are mediators of the inflammatory response that are preferentially associated with severe disease but not necessary for protection against the virus. Based on this tenet we might be able to develop novel therapeutic targets to treat the severe manifestations of the disease. This review will focus on features of the inflammatory innate responses against influenza A virus that are preferentially involved in causing severe pulmonary disease.
Inflammation as a double edge sword during Influenza A infection. The low response leads to an insufficient control of the virus and can also predisposes to secondary bacterial infections. On the other hand, an excessive uncontrolled inflammatory response leads to increased immunopathology, morbidity and mortality
Inflammation and immune response
Tissue inflammation involves an influx of immune cells — including neutrophils, monocytes and macrophages — to various tissues, such as the skin, gut or lung 1 . This process is often regulated by a complex hierarchy of immune cells, cell surface receptors, signal transduction and the resultant gene transcription and translation of immunomodulating factors. Activation of receptors on immune cells drives signalling cascades that dictate, maintain and amplify local or systemic immune responses. Accordingly, chronic or dysregulated signalling can perpetuate inflammation and generate excessive levels of superoxide radicals, proteases, and cytokines and chemokines that can then cause tissue damage 14 . Importantly, the production of these pro-inflammatory mediators is subject to multiple regulatory mechanisms at the transcriptional and post-transcriptional levels. Early induction of the majority of inflammatory transcripts depends on transcription factor networks including NF-κB (canonical and non-canonical), signal transducers and activators of transcription (STATs), nuclear factor of activated T cells (NFATs) and interferon-regulatory factors (IRFs). However, the net production of the corresponding proteins depends, in part, on mitogen-activated protein kinases (MAPK) and molecular programmes that regulate transcript stability and translation 14 . The canonical NF-κB pathway mediates the activation of transcription factors NF-κB1 p50, transcription factor p65 (encoded by RELA) and proto-oncogene REL, whereas the non-canonical NF-κB pathway selectively activates p100-sequestered NF-κB members, predominantly NF-κB2 p52 subunit and RelB 15 . MAPK signalling (such as that mediated by ERK1/2 and p38) regulates RNA stability and translation of cytokines, which enable immune cells to respond promptly 16 . The STAT family of transcription factors integrates the signalling cascade of several cytokine receptors and ligands 13 . Activated STATs bind to GAS (IFNγ-activated sequence) DNA elements, and initiate transcription of target genes. Diverse outcomes of STAT signalling are not only determined by the expression of specific receptors but also by the interaction of STATs (such as STAT5) with cofactors, and by the cell-specific activity of members of the suppressor of cytokine signalling (SOCS) family, which negatively regulate STAT function 13 . Therefore, complex positive and negative regulatory networks orchestrate immune responses.
The physiological or pathogenic immune response involves multiple receptors on different immune cells and their cognate ligands. Host immunity is divided into innate and adaptive immune responses 17 . The former reacts rapidly and non-specifically to pathogens, whereas the latter responds in a slower but specific manner, with the generation of long-lived immunological memory 17 . Strict regulation of immune response is partly regulated by CD4 + T helper (TH) cells because they regulate the function of other immune or even non-immune cells 18 . Naive CD4 + T cells can differentiate into multiple distinct T cell subsets, such as TH1, TH2, TH17 and Treg cells, depending on the cytokine milieu 18 . Treg cells are essential in preventing autoimmune diseases and avoiding prolonged immunopathological processes and allergies acting via classic suppressive mechanisms on other immune cells as well as reparative functions 19 . B cells, in addition to their function in antibody production, also express a high level of MHC class II and can present antigens to TH cells to mount an immune response 20 . Self-reactive B cells and T cells can turn the immune system against its own body to cause various autoimmune disorders 5 .
The innate immune response is carried out by neutrophils and plasmacytoid dendritic cells (pDCs), basophils, natural killer cells, innate lymphoid cells and granulocytes 21 . These cells express various cytokines and selected receptors and ligands to mount an immune response 21 . Cytokines and other inflammatory mediators function as messengers that bind to specific receptors to regulate immune response 1 . The TNF superfamily contains 19 members that bind 29 receptors that are expressed predominantly by immune cells and function as cytokines regulating diverse cellular functions, including immune response and inflammation 22 . The IL-1R family comprises ten members 23 , and includes several ligand-binding receptors (IL-1R1, IL-1R2, IL-1R4, IL-1R5, IL-1R6), two types of accessory chain (IL-1R3, IL-1R7), molecules that act as inhibitors of IL-1 and IL-18 cytokines (IL-1R2, IL-1R8, IL-18BP) and two orphan receptors (IL-1R9, IL-1R10) with no known ligand 23 . The majority of the receptors from the IL-1R family promote activation, proliferation, differentiation and production of pro-inflammatory cytokines from various cell types 23 . IL-6 is a pleiotropic cytokine implicated in several diseases, including arthritis, sepsis, anaemia of chronic diseases, angiogenesis acute-phase response, bone and cartilage metabolism disorders and cancer 24 . IL-6 binds IL-6R, which has two subunits, IL-6Rα and IL-6Rβ (also known as gp130). Cells only express gp130 and are not responsive to IL-6 alone, but they can respond to a complex formed by IL-6 bound to a naturally occurring soluble form of the IL-6R, a process known as trans-signalling and that controls the pro-inflammatory responses of IL-6 (ref. 24 ). The discovery of the IL-6–IL-6R axis provided a foundation to understand the biology of a group of related cytokines, including the IL-12 family of cytokines (IL-12, IL-23, IL-27, IL-35), which use shared receptors and cytokine subunits 25 . IL-12 is produced by innate cells, such as macrophages and dendritic cells, and binds to a heterodimeric receptor formed by IL-12Rβ1 and IL-12Rβ2, which promotes development of IFNγ-producing TH1 cells from naive T cells 26 . IL-23 is also produced by innate cells and signals through the IL-23R and the shared subunit IL-12Rβ1 (ref. 27 ). IL-23 is a heterodimeric cytokine formed by the p19 and p40 subunits that binds the IL-12Rβ1 and IL-23R receptor complex expressed by several cells (natural killer cells, macrophages, dendritic cells, memory T cells and keratinocytes). Comparing the phenotypes of mice deficient in IL-23 or IL-12 receptor and ligand subunits established that IL-23 is a main culprit in autoimmune disease models 27,28 . IL-23 facilitates the production of IL-17 in TH17 cells and acts on cellular targets — including keratinocytes, neutrophils, endothelial cells and fibroblasts — to stimulate production of various chemokines and cytokines, which, in turn, promote tissue inflammation 28 . Correspondingly, the blockade of IL-17 or IL-23 is effective in managing the symptoms of certain diseases, such as psoriasis 28 .
IgG Fc receptors (FcRs) bind to antibodies to clear infected cells or invading pathogens 29 . This complex mediates inflammatory signalling via the immunoreceptor tyrosine-based activation motif (ITAM) in phagocytic or cytotoxic cells to destroy microbes, or in infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity 29 . In similar fashion, autoantibodies and autoimmune complexes (autoantibody bound to self-antigen) may serve as pathogenic factors in autoimmune or inflammatory injury, as they are responsible for the initiation of the inflammatory cascade and its resulting tissue damage 29 .
Toll-like receptors (TLRs) are sensors of microbial antigens that recognize pathogen-associated molecular patterns (PAMPs), which are conserved structures found on microbial cell walls that activate the host innate immune response 30 . TLRs can also recognize damage-associated molecular patterns (DAMPs) that are generated in the host following tissue injury or cellular activation 30 . There are ten TLRs identified in humans (TLR1–TLR10). Most TLRs are expressed on the cell surface and recognize antigens present on bacterial outer membranes. TLR3, TLR7, TLR8 and TLR9, however, are expressed intracellularly in endosomes and recognize nucleic acid ligands from various sources, including viruses or DAMPs 30 . Excessive TLR activation by DAMPs or PAMPs disrupts the immune homeostasis by sustained pro-inflammatory cytokine production, and consequently contributes to the development of several inflammatory diseases 30 .
RESOLUTION OF INFLAMMATION
To prevent progression from acute inflammation to persistent, chronic inflammation, the inflammatory response must be suppressed to prevent additional tissue damage. Inflammation resolution is a well-managed process involving the spatially- and temporally-controlled production of mediators, during which chemokine gradients are diluted over time. Circulating white blood cells eventually no longer sense these gradients and are not recruited to sites of injury. Dysregulation of this process can lead to uncontrolled chronic inflammation . Inflammation resolution processes that rectify tissue homeostasis include reduction or cessation of tissue infiltration by neutrophils and apoptosis of spent neutrophils, counter-regulation of chemokines and cytokines, macrophage transformation from classically to alternatively activated cells, and initiation of healing [79, 80].
Chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury , and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers . Understanding the common mechanisms that orchestrate dysfunction in the various organ systems will allow for development and production of improved targeted therapies.
Sepsis induces a multitude of defects in immunity that cause protracted inflammation, immune suppression, susceptibility to infections and insurmountable death. Although there are new cell-based methodologies available to identify patients with post-sepsis immune dysregulation, it is still unclear which interventions and at what time points targeting cell-specific deficits will be most beneficial for sepsis survival. Considering the overlapping, inter-related and interdigitating complexity of immune cell derangements, as well as the protracted and convoluted road to mortality, we believe that single-agent immune modulatory intervention as attempted in past sepsis trials will fail. Conversely, the notion of more thorough and rigorous patient stratification and selection, coupled with strategic and thoughtful long-term monitoring of immune function, combined with goal-directed immune modulatory therapy will, over time, provide optimal clinical benefit to those surviving initial sepsis.