Microbial influences on immune function and more
2011; Wiley; Volume: 245; Issue: 1 Linguagem: Inglês
10.1111/j.1600-065x.2011.01085.x
ISSN1600-065X
Autores Tópico(s)Immune responses and vaccinations
ResumoThis article introduces a series of reviews covering Microbial Influences on Immune Function appearing in Volume 245 of Immunological Reviews. The primary function of the immune system is clearly the elimination of microbial threats to the host. At the same time, multicellular eukaryotic organisms even the most primitive like hydra (genus Cnidaria) (1), comprise living consortia with myriads of microbes. Both pathogens and mutualistic microbes are involved in symbiotic relationships with their eukaryotic hosts. Whereas pathogens causing acute illnesses have developed measures to subdue or evade host defense mechanisms to allow their short-term replication, chronic pathogens, and commensal microorganisms both require strategies that would allow their long-term survival. The mutualistic relationships with commensals were obvious to great biologists of the past, with Louis Pasteur suggesting that germ-free animals should be made as a means to study the symbiotic functions of microorganisms and Ilya Metchnikoff advocating the use of probiotic yogurt. Much has changed since then, and we are now living in a new era, in which systematic computational brute force approaches promise to bring us understanding of the most fascinating interactions happening between the host and its microbiota. At the same time, many aspects of host–commensal interactions require deep understanding of the animal and human physiology. The topic of microbial influences on immunity is incredibly complex. In this volume, we review microbial–immune system interactions that go beyond straight elimination of the microbial insult, although it is impossible to cover all aspects of these interactions at once. Thus, we focus on some issues that are important for human health and also require further development (Fig. 1). Local and systemic influences of microbes on their host’s physiology. The in situ hybridization of an intestinal section (A) with a common 16S rRNA gene probe (image by Maria Prokhorovich) reveals the massive presence of bacteria in the lumen, fewer in the mucous layer and very few bacteria attached to the epithelial cell layer. The gut microbiota produces molecular signals that affect the gut-associated immune system and the balance between activating and inhibitory signals and cells (2, 8, 11, 12, 19). The microbiota is critical for resistance to pathogens (13), whereas the host produces effector molecules [anti-microbials and immunoglobulin A (IgA) antibodies] (14–16) to control both pathogens and commensals. The integrity of the epithelial barrier is under the influence of the microbiota (18, 19), whereas the development of the associated lymphoid compartments is developmentally predetermined in anticipation of bacterial colonization (22). Systemic signals from the microbes (B) include both bacteria and viruses as the signal sources. Infection with herpesviruses (cold sore on the upper lip) potentiates resistance to other pathogens (23) (positive influences are shown as red arrows, negative influences as black arrows). The intestinal microbiota also influences viral infections: intestinal bacteria help to clear an infection of the respiratory tract (24), however, bacterial lipopolysaccharide facilitates replication of orally transmitted viruses (26, 27). Autoimmune and inflammatory disorders do not escape the influence of commensal microbes. Viral infections can provoke autoimmune reactions in the brain by ‘molecular mimicry’ (30). Commensal bacteria can either promote inflammatory cells in the spleen and augment inflammation in other tissues, such as joints, or, on the other hand, reduce autoimmunity in the pancreas (12). Microbial metabolites can reduce inflammation locally in the gut and in distal organs (joints) (19). The angry face of the model exemplifies microbial influences on the perception of pain and behavior (31). Th17, T-helper 17; Treg, T-regulatory cells. The first group of reviews addresses the role of microbiota and specific microbial lineages in maintenance of the host’s health. The enormous complexity of the mammalian and human microbiota and the multiple effects that microbes have on the immune system bring up a question that is crucial for translational therapeutic or preventative applications: could these multiple functions be ascribed to a single or limited number of microbial lineages? Furthermore, could such functions be elicited by particular molecules in a unique (non-redundant) fashion? Several reviews in this volume address these questions, even if the primary focus of a review is different. Surana and Kasper (2) focus on the effects on the immune system that are elicited by bacterial polysaccharides with an emphasis on polysaccharide A (PSA) of Bacterioides fragilis. They summarize over 30 years of studies that identified a unique human commensal and its capsular component, PSA, capable of stimulating immune response as well as of suppressing immune reactivity. These studies revealed fundamental common features of the interactions between the host and microbes that are clinging to their mucosal niche: activation of anti-inflammatory cytokines [primarily interleukin-10 (IL-10)] and suppressive T-regulatory cells (Tregs). Using a gnotobiotic approach, several recent studies have shown that bacterial consortia of limited diversity could elicit Treg expansion and/or induction of pro-inflammatory T-helper 17 (Th17) cells (3–5). Segmented filamentous bacteria (SFB) are uniquely strong inducers of the Th17 cells in mice (3, 6). Humans do not seem to harbor SFB, thus Th17-inducing function belongs to other bacteria. Interestingly, B. fragilis lacking PSA is also a Th17 inducer in gnotobiotic (monocolonized) mice (7). Thus, some molecular insights into what makes commensals capable of inducing either pro-inflammatory or anti-inflammatory types of responses are starting to emerge. Denise Kelly and colleagues (8) review the progress in using microbial lineages and especially microbial effector molecules for treatment of inflammatory disorders such as inflammatory bowel disease (IBD). The studies of effector molecules open the possibility of designing novel lineages of bacteria with probiotic properties with the ability to stably colonize the gut, which commonly used probiotics do not have. New interactions of microbial effectors and structural components with pattern recognition receptors (PRRs) (9) are being constantly discovered, as in a recent description of the recognition of the type III secretion needle by NLRC4 inflammasome (10). Both Kelly and colleagues (8) and Surana and Kasper (2) make projections on how this knowledge will advance drug discovery and therapies for inflammatory disorders. An important point is also made that the genetics of the host may have a say in how the effectors influence the immune system. Recently, Macpherson’s group (5) has shown that a small bacterial consortium, altered-Schaedler’s flora, was capable of inducing Th17 response in B6 mice but not in other strains of mice. It would be incredibly interesting to discover which gene(s) is in control of such a basic interaction, and it would be important for the future personalized use of microbial effectors for the treatment of the human maladies. In other reviews, Chinen and Rudensky (11) nicely summarize recent findings of commensal/host interactions. They point out that animals with genetic deficiencies in their immune system provide strong evidence of the host’s control over friendly microbiota, which may become not so friendly in the immunocompromised host. They discuss the role of commensal microbes (including the role of specific lineages) in intestinal inflammation and their influence on adaptive immunity. They also describe the latest findings concerning the balancing role of Tregs in intestinal homeostasis, including the role of locally activated induced Tregs. The review by Diane Mathis and Christophe Benoist (12) (see below) also touches upon the role of specific lineages of commensals in one of the major autoimmune disorders – type-1 diabetes (T1D). Finally, a review from Wolf-Dietrich Hardt’s group (13) describes a model of a pathogen–host interaction that is based on the depletion of commensal microbiota. ‘Colonization resistance’ provided by resident microbiota is one of the key benefits that mammalian hosts receive from their prokaryotic friends. Microbiota is required for resistance to infection by Salmonella typhimurium, for clearance of the infection and for control over the severity of the enteropathy. Gnotobiotic mice with low complexity microbiota appear to be a great tool to address the questions related to the resistance to enteric pathogens. The review also emphasizes the importance of the host’s genetic make up for host–microbiota–pathogen interactions. The second group of reviews is dedicated to the effector mechanisms that help to shape the microbial repertoire and keep it under control. The microbes, of course, reciprocate to control these mechanisms of control to sustain the mutualistic relationship. Lehrer and Lu (14) in a manner full of wit describe the discoveries of small charged peptides (defensins) and their fascinating anti-bacterial and antiviral properties. Kinnebrew and Pamer (15) focus on the role of a different anti-bacterial effector, RegIIIγ, which is structurally a C-type lectin. They review the findings of bacterial sensing by both intestinal epithelial cells (IEC) and cells of hematopoietic origin in the gut. They emphasize the role that cytokines play in coordination of anti-microbial activity. Specifically, the role of the IL23-IL22-STAT3 (signal transducer and activator of transcription 3) axis is found to be of importance for protection against many intestinal infections. The contributions of different cells to this pathway are discussed. They also point out that intestinal homeostasis includes the dynamic stability of microbiota. Although it is not yet clear ‘how the intestinal immune system maintains both tolerance and a healthy inflammatory tone’, the usage of antibiotics can ablate the homeostatic signals coming from commensals. The authors suggest that microbial agonists of PRRs can be used to restore the anti-microbial effector secretion impaired by antibiotics. Andrew Macpherson and colleagues (16) review their progress as well as general knowledge on the very important effector mechanism that controls and shapes commensal microbiota and protects from pathogens – secreted immunoglobulin A (IgA) antibodies. IgA biology is different from other Ig isotypes, as it seems that its most important role is to control commensal microorganisms. IgA can be induced in a T-cell-independent manner but can also require T cells for production. Importantly, the T cells that promote IgA production are likely Treg cells (17). The authors also detail their critical discovery of the memory loss by B cells producing IgA of certain specificities under changing conditions where new microbes are being introduced to the gut. There are still many mysteries surrounding the physiology of IgA, but Macpherson and colleagues suggest that IgA’s main function is to keep at bay the most dominant microbes that are also capable of trespassing the protective mucous layer and interacting with IECs. The third group of reviews deals with the communications between microbes and the epithelial barrier. Goto and Kiyono (18) note that the intestinal barrier system serves as a home for commensal bacteria but also as a ‘disease initiation site’. They describe the roles in barrier function of the mucus layer and epithelial layer, providing details for the role of the individual cell types within this monolayer. They summarize data on the role of surface modifications, such as fucosylation of IECs, in the symbiotic relationship between microbes and the host. Fucosyl residues can be used as a food source or as an adhesion anchor for microbes. It seems especially important due to the genetic link between one of the fucosyl-transferases and the onset of IBD in humans. Furthermore, they discuss the influences of microbial pathogen-associated molecular patterns and metabolites on the function of the epithelial barrier, a ‘critical defense barrier’. An Australian group led by Charles Mackay (19) focuses more specifically on the microbial metabolites that contribute to the maintenance of epithelial integrity and discuss the role of dysbiosis in the loss thereof. They point at the effects of modern environmental factors (dietary changes, antibiotic use, and the developed communal hygiene) on the rise of inflammatory and allergic diseases. Since dietary and metabolic changes have been shown to modify microbiota (20, 21), it became clear that both of these factors can serve as major modifiers of homeostasis in the intestine and also elsewhere, promoting or augmenting diseases such as T1D, rheumatoid arthritis, and asthma. The review then focuses on the short chain fatty acids (SCFA) that are the products of fermentation by anaerobic bacteria. SCFA serve as a source of energy for IECs, but they can also directly affect immune functions through triggering specialized G-protein-coupled receptors. A deficiency in a SCFA receptor, GPR43, exacerbates several inflammatory conditions but does not affect sterile inflammation induced by activation of the inflammasome by uric acid crystals. SCFAs modify intestinal integrity and permeability, although it is not clear whether all of their effects are triggered through GPR43. It is also not yet clear whether the ability of SCFAs to modify gene expression is due to inhibiting the histone deacetylase activity. They further discuss the possibilities of using modified-probiotic microbes to deliver protective metabolites to the inflamed gut and also point to the fact that any clinical trials of the new strategies must be rigorous to insure proper colonization of the recipients. Gérard Eberl (22) gives a detailed account of the development and evolution of the RORγt+ cells. These cells are of extreme importance as tissue organizers and participate in the control of both pathogenic and commensal microbes. The review recollects the history of the discovery of these interesting cells and then describes the functions of the subsets of lymphoid cells expressing RORγt in development (LTi cells) and in immune responses [innate lymphoid cells (ILCs), αβ, and γδ T cells, and invariant natural killer T cells]. Type 17 immunity promoted by ILCs before birth and colonization by microbiota creates a pro-inflammatory milieu in the intestinal tissues. In the adult, production of IL-22 by ILCs expressing RORγt is required for protection from enteropathogens and invasive commensals. Eberl discusses the properties of RORγt+ cells that develop dependently or independently of the type 17 milieu. Finally, he summarizes what is known about RORγt in evolution. Many invertebrates have a signature of type 17 immunity, but a RORγt analog has not been found. RORγt seems to be a master regulator acquired later in evolution, whereas major innate mechanisms that it controls were already in place. It is suggested that mammals evolved to use the RORγt+ LTi cells in sterile conditions before birth as a preemptive measure (inducing peripheral lymphoid tissues) to control the expected new tenants and pathogenic perpetrators. The fourth group of reviews addresses several issues involving interactions of viruses and the immune system. First, the review by Eric Barton and his colleagues (23) addresses the relationship between the immune system, microbial pathogens, and latent herpesviruses that infect most of the living humans. The long co-evolution of pathogenic herpesviruses with the human species has reduced their pathogenicity, and they are asymptomatic in the majority of infected individuals. Barton and colleagues review the data that argue that the immune system is aware of the viral presence and can control viral reactivation, and they also show that the viruses can change the outcome of infections with other pathogens. They point out that clinical latency of herpesviruses [such as a β-herpesvirus, human cytomegalovirus (HCMV)] is accompanied by high levels of circulating anti-HCMV T cells, which do not show functional exhaustion for a long time. These cells are activated in infections by other pathogens (‘heterologous immunity’). As the authors point out, this phenomenon is not universal and clearly depends on the nature of the second pathogen. They discuss this and other mechanisms involved in virus-dependent enhancement of protection. The property of enhancement of immunity has a flip side – enhancement of autoimmunity and inflammation, which is also discussed in the review along with the current evidence that latency is linked to tumorigenesis and protection against allergies. The review also cautions that universal vaccination against herpesviruses can disrupt the ‘virus–host equilibria that have adapted over hundreds of millions of years’ of co-evolution. Iris Pang and Akiko Iwasaki (24) describe the innate and adaptive mechanisms involved in antiviral immunity. The most exciting part of the review deals with the influence of commensal microbiota on antiviral responses. Germ-free mice lacking microbiota appeared to be susceptible to several different viruses. However, Iwasaki’s group (25) was the first one to alert virologists and immunologists to the fact that intestinal microbial signaling through PRRs was responsible for distal enhancement of anti-influenza virus response in the respiratory tract. Importantly, the influences of microbiota on antiviral immunity may not always be beneficial. In recent publications from Golovkina’s and Pfeiffer’s groups (26, 27), it was found that orally transmitted viruses can use the microbiota for their own good. Mouse mammary tumor virus (MMTV) replicates poorly in mice lacking the TLR4 receptor and eventually is entirely lost (28). However, it also does not infect germ-free animals, suggesting that the microbiota is critical for its replication. It turns out that MMTV harbors lipopolysaccharide (LPS) from bacterial commensals and stimulates a tolerogenic pathway that eliminates the immune response against MMTV. In the second example of viruses taking advantage of microbiota, human reovirus, and poliovirus were shown to greatly enhance their infectivity when LPS was available (29). In this case, LPS recognition by TLRs was not required, and the mode of its action remains unclear. However, these two studies together with findings discussed by Pang and Iwasaki in this issue have changed our mental separation of viruses and bacteria in the induction and amelioration of the viral diseases. On the practical side, the potential use of probiotics and antibiotics for treatment of viral infections should be carefully studied. Emily Chastain and Stephen Miller (30) review the role of molecular mimicry in triggering autoimmune conditions. Viruses are used as an example to make the case for this important pathological mechanism. Molecular mimicry requires an identity or functional similarity between antigenic peptides provided by an infectious agent and self-peptides produced by the host. It also requires that ‘adaptive autoimmunity’ be activated via the interaction of T cells with antigen-presenting cells presenting the mimic peptide-major histocompatibility complex (MHC) complex along with costimulatory molecules and cytokines. In other words, autoimmunity induced by this mechanism will fall under the category of ‘polygenic MHC-dependent diseases requiring environmental trigger through PRRs’ (16). The review focuses on the mouse model of multiple sclerosis that was developed in Miller’s lab and made unique contributions to the understanding of autoimmunity in the central nervous system. One other review deals with autoimmunity, using T1D as a model for the studies of microbial influences on the loss and maintenance of tolerance to self. Diane Mathis and Christophe Benoist (12) discuss environmental, stochastic, and epigenetic influences on T1D development, which has a strong genetic component. They also discuss the ability of isolated lineages and larger microbial consortia to affect autoimmunity and, importantly, the stages in pathogenesis on which the microbes impinge. The review suggests future important lines of research for this exciting field. The very final review is by the group led by Mauro Teixeira (31). It makes an important point that the role of the microbiota is wider than provision of tonic signals to the immune system or colonization resistance: it can also affect behavioral responses. The authors show that colonization of germ-free animals leads to many effects that can be reliably traced during the transition in the elaborate experimental setting. The indigenous microbiota affects how the host perceives and treats the environmental stimuli such as pain, which in turn modifies animal or human behavior: animals protect the affected area, humans seek medical attention. The microbiota also affects the levels of neurotransmitters leading to behavioral changes. These fascinating findings remind us that the role of the microbiota in the maintenance of health of the super-organism (us and our little mutualistic friends) is not just in local elicitation of certain cytokines but much broader. Moreover, through the modification of the behavior of one individual, microbes are influencing the behavior of other individuals around. Incredible, isn’t it?
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