The Impact of the Gut Microbiota on Human Health: An Integrative View

Chronic viral infections represent major challenges in contemporary medicine, virology and pharmacology. The virus-bearing hosts are commonly found in every parts of the world and it is extremely difficult to manage these patients. In addition, considerable numbers of these patients develop progressive diseases and severe complications. Finally, most of these patients act as permanent reservoirs of virus. Understandings of viral life cycle during the last decade of 20th century and the first decade of 21st century have allowed development of hundreds of antiviral agents for different diseases. But, the clinical efficacy of these drugs is not yet satisfactory. In addition, virologists have provided conclusive evidences suggesting that eradication of most chronic virus from infected hosts may an unachievable goal. In this context, it is essential to develop alternative, novel, and evidence-based therapeutic maneuver for these patients. Manipulation of host immune system may be one of these approaches. We would discuss about scopes, limitations, and strategies for manipulation for controlling of chronic viral infections. The primary function of the host's immune system is to mount responses that protect the individual from various microbial infections including viruses. Host's immune responses also control the spread and virulence of the viruses [1]. This is applicable to viruses that cause acute infection. After entering the hosts, these viruses are localized in host's tissues, proliferate and induce antiviral immunity. These cellular events may cause damage and destruction of tissues and the host exhibit features of acute inflammatory diseases. However, the viruses are either almost completely eliminated from the hosts or adequately controlled in situ by host's immune systems. However, chronic infection is established by many viruses because the hosts induce improper and uncoordinated immune responses against these viruses. Most viruses cause persistent infection by evading the host immune surveillance mechanism. Both virus-related factors and host-dependent factors are primarily responsible for viral persistency in subjects with chronic viral infections. doi: 10.3329/blj.v1i1.2620 Bangladesh Liver Journal Vol.1(1) 2009 p.13-19

In internal parasitism, the respiration strategy within the host's body is as essential as evading attack from the host's immune system. Tachinid flies are parasitoids of terrestrial arthropods, mostly insects, during their larval stage. To obtain oxygen while living in the host body, they build a cylindrical structure known as the respiratory funnel at the aperture opened by the tachinid larva on the host integument or trachea. These funnels can be divided morphologically into sheath and cone types. Previous research on sheath-type funnels revealed that they are derived from the encapsulating substance produced by the host's immune system. In contrast, the cone-type funnels cover part of the body of the larval tachinid and may be constructed independently from the host immune system. To determine the mechanisms of cone-type funnel formation, histological observations were carried out on Gymnosoma rotundatum (L.) (Diptera: Tachinidae), which possesses this type of funnel. The respiratory funnel of G. rotundatum was found to be derived from the tube-shaped faeces wrapped with the peritrophic membrane and excreted by the fly larva, not from host tissue or haemocytes. Additionally, secretory glands putatively involved in the funnel formation were discovered around the larval anal plate of G. rotundatum. A comparison of funnel types within Tachinidae revealed that Phasiinae and Dexiinae have cone-type funnels, which may be created by the same mechanism as in G. rotundatum. These new findings suggest that funnel formation that does not use the host immune system is relevant to tachinid phylogeny.

Developing worms need the host immune system.

Chapter 12 - Polydnavirus Gene Products that Interact with the Host Immune System

Virus infected host cells serve as a central immune ecological niche during viral infection and replication and stimulate the host immune response via molecular signaling. The viral infection and multiplication process involves complex intracellular molecular interactions between viral components and the host factors. Various types of host cells are also involved to modulate immune factors in delicate and dynamic equilibrium to maintain a balanced immune ecosystem in an infected host tissue. Antiviral host arsenals are equipped to combat or eliminate viral invasion. However, viruses have evolved with strategies to counter against antiviral immunity or hijack cellular machinery to survive inside host tissue for their multiplication. However, host immune systems have also evolved to neutralize the infection; which, in turn, either clears the virus from the infected host or causes immune-mediated host tissue injury. A complex relationship between viral pathogenesis and host antiviral defense could define the immune ecosystem of virus-infected host tissues. Understanding of the molecular mechanism underlying this ecosystem would uncover strategies to modulate host immune function for antiviral therapeutics. This review presents past and present updates of immune-ecological components of virus infected host tissue and explains how viruses subvert the host immune surveillances.

The Gut Microbiome in Health and Disease

As an important receptor in a host's immune and metabolic systems, NOD1 is usually activated by Gram-negative bacteria having meso-diaminopimelic acid (m-DAP) in their peptidoglycan (PGN). But some atypical Gram-positive bacteria also contain m-DAP in their PGN, giving them the potential to activate NOD1. The prevalence of m-DAP-type Gram-positive bacteria in the gut, however, remains largely unknown. Here, we report a stem-peptide-based m-DAP-containing tetrapeptide probe for labeling and identifying m-DAP-type Gram-positive microbiota. The probe was synthesized via a five-step convergent approach and demonstrated moderate selectivity toward m-DAP-type bacteria in vitro. In vivo labeling revealed that ∼13.7% of the mouse gut microbiota (mostly Gram-positive) was selectively labeled. We then identified Oscillibacter and several other Gram-positive genera in this population, most of which were previously unknown m-DAP-type bacteria. The following functional assay showed that Oscillibacter's PGN could indeed activate NOD1, suggesting an overlooked NOD1-activating role for these Gram-positive bacteria. These findings deepen our understanding of the structural diversity of gut microbes and their interactions with the host's immune system.

Schistosomiasis is a parasitic disease caused by trematodes that affects more than 200 million people worldwide, mostly children in developing countries. Annually, 200 000 deaths are estimated to be associated with schistosomiasis (van der Werf et al., 2002). Until now, attempts to control infection and disease have mostly failed but the disease can be effectively treated by chemotherapy (Praziquantel ). One of the most striking features of schistosomiasis is that the worms are experts in modulation and evasion of the host immune response, to enable their survival, migration and development in different host tissues. It is becoming increasingly clear that schistosome glycoconjugates play a crucial role in the evasion mechanisms that are exploited by the parasites. Here we will summarize our studies that aim to increase our molecular understanding of the role of specific schistosome glycan antigens in immune modulation. We will focus on the interactions of schistosome glycans with the host immune system that result in the mounting of T helper cell 2 (Th2) responses.

The transplanted allogeneic multipotent mesenchymal stromal cells (MMSC) were previously thought to be poorly recognized by host immune system; the prolonged survival of these cells in host tissues was explained by their privileged immune status. As long as this concept is currently being revised, the understanding of MMSC routes should be reconsidered given the emerging role of host immune system in their gradual elimination. The study was focused upon elimination of PKH26-labeled MMSC, derived from umbilical cord, analyzed in animal models for two distinct pathologies: subtotal liver resection and critical skeletal muscle ischemia. Specific patterns of PKH26-positive macrophages (defined as CD68+ cells) were described for intact spleen and regenerating liver, and for the ischemic skeletal muscle, respectively. The PKH26-positive cells were observed in spleen of the subtotally hepatectomized model animals at 24 h. after surgery combined with MMSC transplantation; 83,2±4,6% of these were CD68+; the ratio reached 100% 3 days after transplantation. The PKH26-positive cells were also detected in regenerating liver starting from 3 days after transplantation, the great majority of them were CD68+ (96,8±2,2% and 96,3±2,6% for 3 and 10 days after transplantation, respectively). A different sort of host environment was provided by the damaged skeletal muscle model: productive phase of aseptic inflammation triggered by ischemia. The PKH26-positive fraction in the pool of macrophages significantly increased from 48,1 ±3,2% 3 days to 76,2±3,9% 30 days after transplantation. Thus, transplanted allogeneic MMSC are recognized and eliminated by host immune system. The rates of elimination depend on site of injection and time elapsed since the injection; the efficacy may reach 100%. The presence of РКН26 vital label (as well as any other exogenous label) in living cell can by no means solely prove its exogenous origin. The massive elimination of MMSC by host macrophages leads to impregnation of the latter with the dye that is masking the true presence of the former. The study accentuates the need of additional criteria for correct data interpretation.

Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis

During evolution Herpesviridae have developed glycoproteins, which interact with essential components of the immune system. Besides immunoglobulin-binding proteins (= Fc-receptors), expressed by several members of the herpesfamily, the interaction with the complement system plays a role in the pathogenicity of herpes simplex virus. Here we report that the ability to interact with the third complement component (C3), the central mediator of complement activation, was also found among several animal alphaherpesviruses. This interaction appeared to be species-selective as the viral proteins preferentially bound to the C3 originated from the respective host. That could provide a possible explanation for the evolution of a variety of herpesviruses as the species tropism observed among Herpesviridae may be influenced by specific adaptation of protective virus-proteins to the immune system of the different hosts. The data have critical implications for the studies of virus host interactions in heterologous systems and support a role for the C3-binding proteins in pathogenesis. Since the C3-binding proteins are conserved among different herpesviruses they could serve as suitable subunit-vaccine candidates.

The intricate and dynamic interactions between the host immune system and its microbiome constituents undergo dynamic shifts in response to perturbations to the intestinal tissue environment. Our ability to study these events on the systems level is significantly limited by in situ approaches capable of generating simultaneous insights from both host and microbial communities. Here, we introduce Microbiome Cartography (MicroCart), a framework for simultaneous in situ probing of host features and its microbiome across multiple spatial modalities. We demonstrate MicroCart by comprehensively investigating the alterations in both gut host and microbiome components in a murine model of colitis by coupling MicroCart with spatial proteomics, transcriptomics, and glycomics platforms. Our findings reveal a global but systematic transformation in tissue immune responses, encompassing tissue-level remodeling in response to host immune and epithelial cell state perturbations, and bacterial population shifts, localized inflammatory responses, and metabolic process alterations during colitis. MicroCart enables a deep investigation of the intricate interplay between the host tissue and its microbiome with spatial multiomics.

Posttransfusion graft-versus-host disease (PTGVHD) is known to develop in immunocompetent patients exhibiting clinical symptoms such as erythroderma, fever, liver dysfunction, diarrhea and pancytopenia. It is speculated that transfused blood donors' lymphocytes might recognize the recipients' HLAs as alloantigens. The thus stimulated lymphocytes might proliferate, expand and finally attack the host's immune system or tissues. However, details regarding these expanded donor cells such as: (1) whether they represent one clone or more, (2) the composition of lymphocyte subsets, and (3) the target HLA antigens of recipients, are not clear, since T-cell lines derived from PTGVHD patients have not yet been obtained. The aim of this study is to characterize T-cells responsible for PTGVHD and to identify their target molecules. For that purpose, we attempted to establish T-cell lines derived from a PTGVHD patient. We show that the established T-cell line, proven to be derived from donor lymphocytes, showed a CD4+ phenotype and had cytotoxic activities. Furthermore, we describe that the target of the cytotoxic T-cell line (CTL) is an HLA-DRB1*0405-related molecule of the patient.

The gut microbiota has been referred to as the hidden metabolic “organ” due to its enormous impact on host metabolism, physiology, nutrition, and immune system. The relationship between the gut microbiota and the animal host is complex, changing, and generally mutually beneficial. As this relationship is complex, strategies have been studied to help modulate the microbiota to result in greater health and performance. Feed supplementation with biotic products is one of these strategies. These supplements have indirect effects via the manipulation of the quality of the microbiota and an improvement in the intestinal epithelial barrier. In addition to these functions, a stimulation of the host's immune system, a decrease in the colonization of pathogens and relief from stress have also been reported. Therefore, these supplements are presented as a safe alternative to the use of antibiotic growth promoters. The objective of this review is to know what biotic products are and how they work, as well as their application in animal production.

Genotypic diversity and immunological implications of porcine circovirus: Inspiration from PCV1 to PCV4