Mechanisms for control of skin immune function by the microbiome.

The skin represents the largest area for direct contact between microbes and host immunocytes and is a site for constant communication between the host and this diverse and essential microbial community. Coagulase-negative staphylococci are an abundant bacterial genus on the human skin and are regulated through various mechanisms that include the epidermal barrier environment and innate and adaptive immune systems within the epidermis and dermis. In turn, some species and strains of these bacteria produce beneficial products that augment host immunity by exerting specifically targeted antimicrobial, anti-inflammatory, or anti-neoplastic activity while also promoting broad innate and adaptive immune responses. The use of selected skin commensals as a therapeutic has shown promise in recent human clinical trials. This emerging concept of bacteriotherapy is defining mechanisms of action and validating the dependence on the microbiome for maintenance of immune homeostasis.

Probiotic Potential of Lactobacillus Species in Allergic Rhinitis.

Since conventional allergy medication for asthma or allergic rhinitis (AR) can cause side effects which limit the patients' quality of life, it is of interest to find other forms of therapy. In particular, probiotic bacteria, such as Lactobacillus species, have shown anti-allergic effects in various mouse and human studies. For instance, administration of some Lactobacillus species resulted in nasal and ocular symptom relief and improvement of quality of life in children and adults suffering from rhinitis. Different changes in cytokine profiles, such as elevated Th1 and decreased Th2 cytokines, reduced allergy-related immunoglobulins and cell immigration have been found in both human and murine studies. Positive effects on patients like less activity limitations or fewer rhinitis episodes and longer periods free from asthma or rhinitis were also described following oral administration of Lactobacillus bacteria. However, it is still unclear how this type of lactic acid bacteria leads to changes in the immune system and thus inhibits the development of allergies or relieves their symptoms. This review gives an overview of current studies and draws conclusions concerning the usage of probiotic Lactobacillus strains in AR.

Microbiota-antibody interactions that regulate gut homeostasis.

Immunoglobulin A (IgA) is the most abundant antibody at mucosal surfaces and has been the subject of many investigations involving microbiota research in the last decade. Although the classic functions of IgA include neutralization of harmful toxins, more recent investigations have highlighted an important role for IgA in regulating the composition and function of the commensal microbiota. Multiple reviews have comprehensively covered the literature that describes recent, novel mechanisms of action of IgA and development of the IgA response within the intestine. Here we focus on how the interaction between IgA and the microbiota promotes homeostasis with the host to prevent disease.

How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review.

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.

A Novel Immunobiotics Bacteroides dorei Ameliorates Influenza Virus Infection in Mice.

Objective: Probiotics can modulate immune responses to resist influenza infection. This study aims to evaluate the anti-viral efficacy of B. dorei. Methods: C57BL/6J mice were infected with influenza virus together with treatment of PBS vehicle, B. dorei, or oseltamivir respectively. Anti-influenza potency of B. dorei and the underlying mechanism were determined by measuring survival rate, lung viral load and pathology, gene expression and production of cytokines and chemokines, and analysis of gut microbiota. Results: Administration of B. dorei increased (by 30%) the survival of influenza-infected mice, and improved their weight loss, lung pathology, lung index, and colon length compared to the vehicle control group. B. dorei treatment reduced (by 61%) the viral load of lung tissue and increased expression of type 1 interferon more rapidly at day 3 postinfection. At day 7 postinfection, B. dorei-treated mice showed lower local (lung) and systemic (serum) levels of interferon and several proinflammatory cytokines or chemokines (IL-1ß, IL-6, TNF-α, IL-10, MCP-1 and IP-10) with a efficacy comparable to oseltamivi treatment. B. dorei treatment also altered gut microbiota as indicated by increased levels of Bacteroides, Prevotella, and Lactobacillus and decreased levels of Escherichia, Shigella, and Parabacteroides. Conclusion: B. dorei has anti-influenza effect. Its working mechanisms involve promoting earlier interferon expression and down-regulating both local and systemic inflammatory response. B. dorei changes the composition of gut microbiota, which may also contribute to its beneficial effects.

Concurrent Infection With the Filarial Helminth Litomosoides sigmodontis Attenuates or Worsens Influenza A Virus Pathogenesis in a Stage-Dependent Manner.

Filarial helminths infect approximately 120 million people worldwide initiating a type 2 immune response in the host. Influenza A viruses stimulate a virulent type 1 pro-inflammatory immune response that in some individuals can cause uncontrolled immunopathology and fatality. Although coinfection with filariasis and influenza is a common occurrence, the impact of filarial infection on respiratory viral infection is unknown. The aim of this study was to determine the impact of pre-existing filarial infection on concurrent infection with influenza A virus. A murine model of co-infection was established using the filarial helminth Litomosoides sigmodontis and the H1N1 (A/WSN/33) influenza A virus (IAV). Co-infection was performed at 3 different stages of L. sigmodontis infection (larval, juvenile adult, and patency), and the impact of co-infection was determined by IAV induced weight loss and clinical signs, quantification of viral titres, and helminth counts. Significant alterations of IAV pathogenesis, dependent upon stage of infection, was observed on co-infection with L. sigmodontis. Larval stage L. sigmodontis infection alleviated clinical signs of IAV co-infection, whilst more established juvenile adult infection also significantly delayed weight loss. Viral titres remained unaltered at either infection stage. In contrast, patent L. sigmdodontis infection led to a reversal of age-related resistance to IAV infection, significantly increasing weight loss and clinical signs of infection as well as increasing IAV titre. These data demonstrate that the progression of influenza infection can be ameliorated or worsened by pre-existing filarial infection, with the outcome dependent upon the stage of filarial infection.

Training the Fetal Immune System Through Maternal Inflammation-A Layered Hygiene Hypothesis.

Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune response. In its current iteration, the "hygiene hypothesis" suggests that reduced microbial exposures during early life restricts the production and differentiation of immune cells suited for immune regulation. Although it is now well-appreciated that the increase in hypersensitivity disorders represents a "perfect storm" of many contributing factors, we argue here that two important considerations have rarely been explored. First, the window of microbial exposure that impacts immune development is not limited to early childhood, but likely extends into the womb. Second, restricted microbial interactions by an expectant mother will bias the fetal immune system toward hypersensitivity. Here, we extend this discussion to hypothesize that the cell types sensing microbial exposures include fetal hematopoietic stem cells, which drive long-lasting changes to immunity.

Human gut bacteria contain acquired interbacterial defence systems.

The human gastrointestinal tract consists of a dense and diverse microbial community, the composition of which is intimately linked to health. Extrinsic factors such as diet and host immunity are insufficient to explain the constituents of this community, and direct interactions between co-resident microorganisms have been implicated as important drivers of microbiome composition. The genomes of bacteria derived from the gut microbiome contain several pathways that mediate contact-dependent interbacterial antagonism1-3. Many members of the Gram-negative order Bacteroidales encode the type VI secretion system (T6SS), which facilitates the delivery of toxic effector proteins into adjacent cells4,5. Here we report the occurrence of acquired interbacterial defence (AID) gene clusters in Bacteroidales species that reside within the human gut microbiome. These clusters encode arrays of immunity genes that protect against T6SS-mediated intra- and inter-species bacterial antagonism. Moreover, the clusters reside on mobile elements, and we show that their transfer is sufficient to confer resistance to toxins in vitro and in gnotobiotic mice. Finally, we identify and validate the protective capability of a recombinase-associated AID subtype (rAID-1) that is present broadly in Bacteroidales genomes. These rAID-1 gene clusters have a structure suggestive of active gene acquisition and include predicted immunity factors of toxins derived from diverse organisms. Our data suggest that neutralization of contact-dependent interbacterial antagonism by AID systems helps to shape human gut microbiome ecology.

Microbiota and Its Role on Viral Evasion: Is It With Us or Against Us?

Viruses are obligate intracellular pathogens that require the protein synthesis machinery of the host cells to replicate. These microorganisms have evolved mechanisms to avoid detection from the host immune innate and adaptive response, which are known as viral evasion mechanisms. Viruses enter the host through skin and mucosal surfaces that happen to be colonized by communities of thousands of microorganisms collectively known as the commensal microbiota, where bacteria have a role in the modulation of the immune system and maintaining homeostasis. These bacteria are necessary for the development of the immune system and to prevent the adhesion and colonization of bacterial pathogens and parasites. However, the interactions between the commensal microbiota and viruses are not clear. The microbiota could confer protection against viral infection by priming the immune response to avoid infection, with some bacterial species being required to increase the antiviral response. On the other hand, it could also help to promote viral evasion of certain viruses by direct and indirect mechanisms, with the presence of the microbiota increasing infection and viruses using LPS and surface polysaccharides from bacteria to trigger immunosuppressive pathways. In this work, we reviewed the interaction between the microbiota and viruses to prevent their entry into host cells or to help them to evade the host antiviral immunity. This review is focused on the influence of the commensal microbiota in the viruses' success or failure of the host cells infection.

Interaction With Nontypeable Haemophilus influenzae Alters Progression of Streptococcus pneumoniae From Colonization to Disease in a Site-Specific Manner.

BACKGROUND: Pneumococci and nontypeable Haemophilus influenzae (NTHi) often cocolonize children. The impact of species interactions on disease risk across the upper respiratory mucosa is not known. METHODS: We analyzed data from 4104 acute conjunctivitis (AC) cases, 11 767 otitis media (OM) cases, and 1587 nasopharyngeal specimens collected from Israeli children before pneumococcal conjugate vaccine introduction. We compared pneumococcal serotype distributions with NTHi present and absent, and compared single-species and mixed-species rates of serotype-specific progression from colonization to AC and OM. RESULTS: Pneumococcal serotypes causing single-species OM (NTHi absent) were less diverse than colonizing serotypes and also less diverse than those causing mixed-species OM; colonizing and OM-causing pneumococcal serotype distributions were more similar to each other with NTHi present than with NTHi absent. In contrast, serotype diversity did not differ appreciably between colonizing and AC-causing pneumococci, regardless of NTHi co-occurrence. The similarity of colonizing and AC-causing pneumococcal serotype distributions was consistent in the presence and absence of NTHi. Differences in rates that pneumococcal serotypes progressed from colonization to disease were reduced in both AC and OM when NTHi was present. CONCLUSIONS: Interactions with NTHi may alter progression of pneumococcal serotypes to diseases of the upper respiratory mucosa in a site-specific manner.

A long-distance relationship: the commensal gut microbiota and systemic viruses.

Recent advances defining the role of the commensal gut microbiota in the development, education, induction, function, and maintenance of the mammalian immune system inform our understanding of how immune responses govern the outcome of systemic virus infection. While characterization of the impact of the local oral, respiratory, dermal and genitourinary microbiota on host immune responses and systemic virus infection is in its infancy, the gut microbiota interacts with host immunity systemically and at distal non-gastrointestinal tract sites to modulate the pathogenesis of systemic viruses. Gut microbes, microbe-associated molecular patterns, and microbe-derived metabolites engage receptors expressed on the cell surface, in the endosome, or in the cytoplasm to orchestrate optimal innate and adaptive immune responses important for controlling systemic virus infection.

Curious entanglements: interactions between mosquitoes, their microbiota, and arboviruses.

Mosquitoes naturally harbor a diverse community of microorganisms that play a crucial role in their biology. Mosquito-microbiota interactions are abundant and complex. They can dramatically alter the mosquito immune response, and impede or enhance a mosquito's ability to transmit medically important arboviral pathogens. Yet critically, given the massive public health impact of arboviral disease, few such interactions have been well characterized. In this review, we describe the current state of knowledge of the role of microorganisms in mosquito biology, how microbial-induced changes to mosquito immunity moderate infection with arboviruses, cases of mosquito-microbial-virus interactions with a defined mechanism, and the molecular interactions that underlie the endosymbiotic bacterium Wolbachia's ability to block virus infection in mosquitoes.

Structure and immunomodulatory activity of a recombinant mucus-binding protein of Lactobacillus acidophilus.

AIM: The role of mucus-binding protein (MUB) on the adhesion activity and immunomodulatory effect of Lactobacillus acidophilus. MATERIALS & METHODS: The current research mainly focuses on the adhesion and immune function of MUB from L. acidophilus. The structural characteristics and adhesion properties of MUB were analyzed in the intestinal cell models. RESULTS: MUB can promote the aggregation and formation of a membrane-like morphology in L. acidophilus, which could increase the survival rate of L. acidophilus in gastrointestinal tract (GIT). Furthermore, MUB could trigger immune regulation and intestinal protection through the Toll-like receptor 4 (TLR4) signaling pathway and inhibit the activation of mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSION: MUB of L. acidophilus is an important component involved in bacterial-mucus interactions and immunomodulatory effect in gastrointestinal tract.

Mycobacterium tuberculosis: An Adaptable Pathogen Associated With Multiple Human Diseases.

Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is an extremely successful pathogen that adapts to survive within the host. During the latency phase of infection, M. tuberculosis employs a range of effector proteins to be cloud the host immune system and shapes its lifestyle to reside in granulomas, sophisticated, and organized structures of immune cells that are established by the host in response to persistent infection. While normally being restrained in immunocompetent hosts, M. tuberculosis within granulomas can cause the recrudescence of TB when host immunity is compromised. Aside from causing TB, accumulating evidence suggests that M. tuberculosis is also associated with multiple other human diseases, such as pulmonary complications, autoimmune diseases, and metabolic syndromes. Furthermore, it has been recently appreciated that M. tuberculosis infection can also reciprocally interact with the human microbiome, which has a strong link to immune balance and health. In this review, we highlight the adaptive survival of M. tuberculosis within the host and provide an overview for regulatory mechanisms underlying interactions between M. tuberculosis infection and multiple important human diseases. A better understanding of how M. tuberculosis regulates the host immune system to cause TB and reciprocally regulates other human diseases is critical for developing rational treatments to better control TB and help alleviate its associated comorbidities.

The Impact of Dietary Transition Metals on Host-Bacterial Interactions.

Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed "nutritional immunity." In response, bacteria have evolved elegant strategies to access metals and counteract this host defense. In mammals, metal abundance can drastically shift due to changes in dietary intake or absorption from the intestinal tract, disrupting the balance between host and pathogen in the fight for metals and altering susceptibility to disease. This review describes the current understanding of how dietary metals modulate host-microbe interactions and the subsequent impact on the outcome of disease.

Close Encounters of Three Kinds: Bacteriophages, Commensal Bacteria, and Host Immunity.

Recent years have witnessed an explosion of interest in the human microbiota. Although commensal bacteria have dominated research efforts to date, mounting evidence suggests that endogenous viral populations (the 'virome') play key roles in basic human physiology. The most numerous constituents of the human virome are not eukaryotic viruses but rather bacteriophages, viruses that infect bacteria. Here, we review phages' interactions with their immediate (prokaryotic) and extended (eukaryotic) hosts and with each other, with a particular emphasis on the temperate phages and prophages which dominate the human virome. We also discuss key outstanding questions in this emerging field and emphasize the urgent need for functional studies in animal models to complement previous in vitro work and current computational approaches.

Pre-colonization with the commensal fungus Candida albicans reduces murine susceptibility to Clostridium difficile infection.

Clostridium difficile is a major nosocomial pathogen responsible for close to half a million infections and 27,000 deaths annually in the U.S. Preceding antibiotic treatment is a major risk factor for C. difficile infection (CDI) leading to recognition that commensal microbes play a key role in resistance to CDI. Current antibiotic treatment of CDI is only partially successful due to a high rate of relapse. As a result, there is interest in understanding the effects of microbes on CDI susceptibility to support treatment of patients with probiotic microbes or entire microbial communities (e.g., fecal microbiota transplantation). The results reported here demonstrate that colonization with the human commensal fungus Candida albicans protects against lethal CDI in a murine model. Colonization with C. albicans did not increase the colonization resistance of the host. Rather, our findings showed that one effect of C. albicans colonization was to enhance a protective immune response. Mice pre-colonized with C. albicans expressed higher levels of IL-17A in infected tissue following C. difficile challenge compared to mice that were not colonized with C. albicans. Administration of cytokine IL-17A was demonstrated to be protective against lethal murine CDI in mice not colonized with C. albicans. C. albicans colonization was associated with changes in the abundance of some bacterial components of the gut microbiota. Therefore, C. albicans colonization altered the gut ecosystem, enhancing survival after C. difficile challenge. These findings demonstrate a new, beneficial role for C. albicans gut colonization.

Together Forever: Bacterial-Viral Interactions in Infection and Immunity.

Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies demonstrate the microbiota plays an important role in mediating host-viral interactions and determining the outcomes of these encounters. This review outlines recently described examples of how bacteria and viruses impact each other particularly during infectious processes. Mechanistically, these effects can be broadly categorized as reflecting direct bacterial-viral interactions and/or involving microbial impacts upon innate and/or adaptive immunity.

A polymicrobial view of disease potential in Crohn's-associated adherent-invasive E. coli.

The human gut is home to trillions of bacteria and provides the scaffold for one of the most complex microbial ecosystems in nature. Inflammatory bowel diseases, such as Crohn's disease, involve a compositional shift in the microbial constituents of this ecosystem with a marked expansion of Enterobacteriaceae, particularly Escherichia coli. Adherent-invasive E. coli (AIEC) strains are frequently isolated from the biopsies of Crohn's patients, where their ability to elicit inflammation suggests a possible role in Crohn's pathology. Here, we consider the origins of the AIEC pathovar and discuss how risk factors associated with Crohn's disease might influence AIEC colonization dynamics within the host to alter the overall disease potential of the microbial community.

Formação de biofilmes monotípicos e heterotípicos por Enterococcus faecalis E Enterococcus faecium em dentina radicular / Formation of monotypic and heterotypic biofilm by Enterococcus faecalis E Enterococcus faecium in root dentin

E. faecalis e E. faecium possuem grande relevância nas infecções hospitalares por apresentarem facilidade em adquirir resistência aos antibióticos. E. faecalis também apresentam alta prevalência nas infecções endodônticas, entretanto a importância de E. faecium para a odontologia ainda precisa ser esclarecida. Assim, o objetivo desse estudo foi comparar cepas clínicas de E. faecium com as cepas de E. faecalis em relação a capacidade de formação de biofilme na dentina radicular e penetração nos túbulos dentinários. Além disso, foi avaliada a interação dessas espécies em biofilmes mistos. Para a realização desse estudo, foram utilizadas cepas clínicas, previamante, isoladas de canais radiculares com infecções endodõnticas e identificadas pelo PCR multiplex. Entre as cepas isoladas, foram selecionadas 4 cepas de E. faecalis e 2 cepas de E. faecium. Primeiramente, foi realizado a formação dos biofilmes monotípicos das cepas de E. faecalis e E. faecium sobre dentinas radiculares de dentes bovinos. Os biofilmes foram formados em placas de microtitulação por diferentes tempos: 2, 4, 6, 24, 48, 72, 96 e 120 horas. Os biofilmes formados foram, então, analisados pela contagem de células viáveis (UFC/mL) e quantificação da biomassa total (método do cristal violeta). Além disso, os biofilmes foram analisados por Microscopia Eletrônica de Varredura (MEV) procurando-se observar a penetração das células de E. faecalis e E. faecium nos túbulos dentinários. A seguir foram formados biofilmes heterotípicos de E. faecalis e E. faecium para estudo das interações ecológicas estabelecidas entre as espécies. A análise dos biofilmes heterotípicos foi feita pela quantificação da biomassa total (cristal violeta) procurando-se detectar a presença de relações sinérgicas ou antagônicas. Os resultados foram submetidos à Análise de Variância (ANOVA) e teste de Tukey, considerando-se nível de 5%. Os resultados obtidos na contagem de UFC/mL dos biofilmes monotípicos, revelaram que as 6 cepas testadas apresentam grande capacidade para formar biofilmes na dentina radicular, alcançando valores de UFC/mL entre 8 a 12 log de acordo com o tempo de observação. Em relação a análise das imagens de MEV, as cepas clínicas de E. faecalis e E. faecium demonstraram capacidade semelhante para formar biofilmes e penetrar nos túbulos dentinários. Na comparação da quantificação da biomassa dos biofilmes monotípicos e heterotípicos, observamos que a interação das cepas clínicas E. faecalis e E. faecium favoreceu a adesão e crescimento do biofilme. Assim, concluiuse que as cepas de E. faecalis e E. faecium apresentam a mesma capacidade de formar biofilmes sobre a superfície radicular. Além disso, em biofilmes mistos, essas duas espécies estabelecem relações ecológicas sinérgicas, aumentando significativamente a formação de biofilmes(AU)

E. faecalis and E. faecium have a high relevance in hospital infections because they are easy to acquire resistance to antibiotics. E. faecalis also present high prevalence in endodontic infections, however the importance of E. faecium for dentistry still needs to be clarified. Thus, the objective of this study was to compare clinical strains of E. faecium with strains of E. faecalis in relation to the capacity of biofilm formation in root dentin and penetration into the dentin tubules. In addition, the interaction of these species in mixed biofilms was evaluated. In order to perform this study, clinical strains were used, pre-determined, isolated from root canals with endodontic infections and identified by multiplex PCR. Among the isolated strains, 4 strains of E. faecalis and 2 strains of E. faecium were selected. Firstly, the formation of the monotypic biofilms of the strains of E. faecalis and E. faecium on root dentin of bovine teeth was carried out. The biofilms were formed in microtiter plates at different times: 2, 4, 6, 24, 48, 72, 96 and 120 hours. The biofilms formed were then analyzed by counting viable cells (CFU / mL) and quantification of total biomass (violet crystal method). In addition, the biofilms were analyzed by Scanning Electron Microscopy (SEM), aiming to observe the penetration of E. faecalis and E. faecium cells into the dentin tubules. Then, heterophilic biofilms of E. faecalis and E. faecium were formed to study the ecological interactions established between the species. The analysis of the heterotypic biofilms was made by quantifying the total biomass (violet crystal) in order to detect the presence of synergistic or antagonistic relationships The results were submitted to Analysis of Variance (ANOVA) and Tukey test, considering a level of 5%. The results obtained in the CFU / mL count of the monotypic biofilms revealed that the six strains tested had a great capacity to form biofilms in the root dentin, reaching values of CFU / mL between 8 and 12 log according to the time of observation. In relation to SEM images, the clinical strains of E. faecalis and E. faecium demonstrated similar capacity to form biofilms and to penetrate the dentinal tubules. In the comparison of the biomass quantification of the monotypic and heterotypic biofilms, we observed that the interaction of the clinical strains E. faecalis and E. faecium favored the adhesion and growth of the biofilm. Thus, it was concluded that strains of E. faecalis and E. faecium have the same ability to form biofilms on the root surface. In addition, in mixed biofilms, these two species establish synergistic ecological relationships, significantly increasing the formation of biofilms(AU)