Effects of polymicrobial communities on host immunity and response

Microorganisms grow as members of microbial communities in unique niches, such as the mucosal surfaces of the human body. These microbial communities, containing both commensals and opportunistic pathogens, serve to keep individual pathogens 'in check' through a variety of mechanisms and complex interactions, both between the microorganisms themselves and the microorganisms and the host. Recent studies shed new light on the diversity of microorganisms that form the human microbial communities and the interactions these microbial communities have with the host to stimulate immune responses. This occurs through their recognition by dendritic cells or their ability to induce differential cytokine and defensin profiles. The differential induction of defensins by commensals and pathogens and the ability of the induced defensins to interact with the antigens from these microorganisms may attenuate proinflammatory signaling and trigger adaptive immune responses to microbial antigens in a multistep process. Such an activity may be a mechanism that the host uses to sense what is on its mucosal surfaces, as well as to differentiate among commensals and pathogens.     

Ganoderma atrum polysaccharide induces anti-tumor activity via the mitochondrial apoptotic pathway related to activation of host immune response

Ganoderma atrum polysaccharide (PSG-1), the major active ingredient isolated from Ganoderma atrum, has been suggested as a candidate for cancer therapy. The aim of this study was to investigate the anti-tumor effect of PSG-1 using sarcoma 180 (S-180) transplanted mice and further to examine the molecular mechanisms of PSG-1-induced anti-tumor effect. Results showed that PSG-1 significantly inhibited tumor growth in S-180-bearing mice. PSG-1-induced tumor apoptosis was associated with the alteration of Bcl-2 family proteins, increase of reactive oxygen species generation, loss of mitochondrial membrane potential (Δψ(m) ), release of cytochrome c from the mitochondria into cytosol, and activation of caspase-3 and -9. Elevation of immune function was also shown during PSG-1-induced tumor apoptosis, as evidenced by increase of spleen and thymus indexes, lymphocyte proliferation, concentrations of tumor necrosis factor (TNF)-α, and interleukin-2 in serum. Furthermore, the combined treatment of PSG-1 and cyclophosphamide (CTX) results in an enhancement of the anti-tumor effect of CTX alone via increased host immune response. These results suggested that PSG-1 had a potent anti-tumor activity by induction of tumor apoptosis through mitochondrial pathways, and immunoenhancement effect of PSG-1 was related to its anti-tumor effect. In addition, PSG-1 enhanced CTX-induced anti-tumor activity in S-180-bearing mice.     

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.     

Variation in DNA damage response pathway activity

Comment on: Kabacik S, et al. Cell Cycle 2011; 10:1152-61.     

Determinants of immunogenic response to protein therapeutics

Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation.     

Bacterial adaptation to host innate immunity responses

Several recent reports show that different bacterial components trigger innate and inflammatory responses in host organisms. In parallel, selected bacterial virulence factors have been identified that interfere with corresponding responses. In many cases, this involves interference with host proinflammatory signal transduction pathways, whereas in selected cases bacterial virulence factors interfere with host antibacterial mechanisms. This indicates that bacteria, besides activating cellular responses, also have the capacity to directly interact with branches of the innate defence.     

A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity

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Metabolic regulation of leaf respiration and alternative pathway activity in response to phosphate supply

In this study the question whether the alternative respiratory pathway acts as an electron bypass for the cytochrome pathway under conditions of growth on limited phosphorus in leaves of bean (Phaseolus vulgaris L.), tobacco (Nicotiana tabacum L.) and Gliricidia sepium Walp was investigated. The oxygen isotope fractionation technique was used to assess the in vivo activities of the cytochrome and alternative respiratory pathways in the absence of added inhibitors. The response of respiration to low phosphorus supply varied among species. Growth at low phosphorus reduced cytochrome pathway activity in bean and tobacco. Alternative pathway activity increased only in bean leaves in response to low phosphorus and not in tobacco. In the case of G. sepium, cytochrome pathway activity remained unchanged whereas the alternative pathway activity increased with low nutritional phosphorus. At low phosphorus, alternative oxidase protein levels increased in the leaves of bean and G. sepium but not in tobacco, suggesting a dependence of alternative pathway activity on protein level. Alternative pathway activity was also not correlated with soluble carbohydrate concentration in bean or tobacco at any phosphorus level. These results show that the alternative pathway does not always act as an electron bypass in response to the downstream restriction of the cytochrome pathway imposed by low phosphorus supply. These results suggest that factors in addition to cellular carbohydrate level and adenylate control can act to regulate alternative pathway activity.     

DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway

Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics.     

Measles virus neurovirulence and host immunity

Measles virus is highly neuroinvasive, yet host immune responses are highly effective at limiting neurovirulence in humans. We know that neurons are an important target of infection and that both IFN-γ and -β expression are observed in the measles virus-infected human brain. Rodent models can be used to understand how this response is orchestrated. Constitutive expression of the major inducible 70-kDa heat-shock protein is a feature of primate tissues that is lacking in mice. This article examines the importance of addressing this difference when modeling outcomes of brain infection in mice, particularly in terms of understanding how infected neurons may activate uninfected brain macrophages to produce IFN-β and support T-cell production of IFN-γ, a mediator of noncytolytic viral clearance. New and historical data suggest that the virus heat-shock protein 70 relationship is key to a protective host immune response and has potential broad relevance.     

Enhanced regulatory T cell activity is an element of the host response to injury

CD4+CD25+ regulatory T cells (Tregs) play a critical role in suppressing the development of autoimmune disease, in controlling potentially harmful inflammatory responses, and in maintaining immune homeostasis. Because severe injury triggers both excessive inflammation and suppressed adaptive immunity, we wished to test whether injury could influence Treg activity. Using a mouse burn injury model, we demonstrate that injury significantly enhances Treg function. This increase in Treg activity is apparent at 7 days after injury and is restricted to lymph node CD4+CD25+ T cells draining the injury site. Moreover, we show that this injury-induced increase in Treg activity is cell-contact dependent and is mediated in part by increased cell surface TGF-beta1 expression. To test the in vivo significance of these findings, mice were depleted of CD4+CD25+ T cells before sham or burn injury and then were immunized to follow the development of T cell-dependent Ag-specific immune reactivity. We observed that injured mice, which normally demonstrate suppressed Th1-type immunity, showed normal Th1 responses when depleted of CD4+CD25+ T cells. Taken together, these observations suggest that injury can induce or amplify CD4+CD25+ Treg function and that CD4+CD25+ T cells contribute to the development of postinjury immune suppression.     

The epidemiological feedbacks critical to the evolution of host immunity

We examine in detail how epidemiological feedbacks combine with costs and benefits to determine the evolution of resistance by systematically analysing continuously stable strategies (CSS) for different host–parasite frameworks. The mode of resistance (innate versus acquired), the nature of the host (i.e. life‐history and immunological memory) and the nature of the disease (effects on fertility or mortality) all impact on the feedbacks that are critical to the evolution of resistance. By identifying relationships between CSS investment and the underlying epidemiological feedback for each mode of resistance in each framework, we distil complex feedbacks into simple combinations of selection pressures. When the parasite does not affect fertility, CSS investment reflects only the benefit of resistance and we explain why this is markedly different for innate and acquired resistance. If infection has no effect on host fertility, CSS investment in acquired immunity increases with the square of disease prevalence. While in contrast for evolving innate resistance, CSS investment is greatest at intermediate prevalence. When disease impacts fertility, only a fraction of the host population reproduce, and this introduces new ecological feedbacks to both the cost of resistance and the damage from infection. The multiple feedbacks in this case lead to the alternative result that the higher the abundance of infecteds, the higher the investment in innate resistance. A key insight is that maximal investment occurs at intermediate lifespans in a range of different host–parasite interactions, but for disparate reasons which can only be understood by a detailed analysis of the feedbacks. We discuss the extension of our approach to structured host populations and parasite community dynamics.     

Multivariate phenotype analysis enables genome-wide inference of mammalian gene function

The function of the majority of genes in the human and mouse genomes is unknown. Investigating and illuminating this dark genome is a major challenge for the biomedical sciences. The International Mouse Phenotyping Consortium (IMPC) is addressing this through the generation and broad-based phenotyping of a knockout (KO) mouse line for every protein-coding gene, producing a multidimensional data set that underlies a genome-wide annotation map from genes to phenotypes. Here, we develop a multivariate (MV) statistical approach and apply it to IMPC data comprising 148 phenotypes measured across 4,548 KO lines.There are 4,256 (1.4% of 302,997 observed data measurements) hits called by the univariate (UV) model analysing each phenotype separately, compared to 31,843 (10.5%) hits in the observed data results of the MV model, corresponding to an estimated 7.5-fold increase in power of the MV model relative to the UV model. One key property of the data set is its 55.0% rate of missingness, resulting from quality control filters and incomplete measurement of some KO lines. This raises the question of whether it is possible to infer perturbations at phenotype–gene pairs at which data are not available, i.e., to infer some in vivo effects using statistical analysis rather than experimentation. We demonstrate that, even at missing phenotypes, the MV model can detect perturbations with power comparable to the single-phenotype analysis, thereby filling in the complete gene–phenotype map with good sensitivity.A factor analysis of the MV model’s fitted covariance structure identifies 20 clusters of phenotypes, with each cluster tending to be perturbed collectively. These factors cumulatively explain 75% of the KO-induced variation in the data and facilitate biological interpretation of perturbations. We also demonstrate that the MV approach strengthens the correspondence between IMPC phenotypes and existing gene annotation databases. Analysis of a subset of KO lines measured in replicate across multiple laboratories confirms that the MV model increases power with high replicability.

The function of the majority of genes in the human and mouse genomes is unknown, and illuminating this "dark genome" is a major challenge for the biomedical sciences. This study shows that multi-dimensional phenotypes from single-gene knockout mouse lines can be analysed at a genome-wide scale both to increase power and infer missing phenotypes.