Impairment Of Host Immunity Research Articles

Withaferin A Protects against Primary and Recurrent Tuberculosis by Modulating Mycobacterium-Specific Host Immune Responses.

The fate of Mycobacterium tuberculosis infection is governed by immune signaling pathways that can either eliminate the pathogen or result in tuberculosis (TB). Anti-TB therapy (ATT) is extensive and is efficacious only against active, drug-sensitive strains of M. tuberculosis. Due to severe side effects, ATT often causes impairment of host immunity, making it imperative to use novel immunotherapeutics for better clinical outcomes. In this study, we have explored the immunomodulatory potential of withaferin A (WA) as an immunotherapeutic against TB. Here, we demonstrate that WA can constrain intracellular drug-sensitive and -resistant strains of M. tuberculosis by augmenting host immune responses. We also established the potential of WA treatment in conjunction with isoniazid. We show that WA directs the host macrophages toward defensive M1 polarization and enhances TH1 and TH17 immune responses against M. tuberculosis infection. The reduced bacterial burden upon T cell adoptive transfer further corroborated the augmented T cell responses. Interestingly, WA stimulated the generation of T cell memory populations by instigating STAT signaling, thereby reducing the rate of TB recurrence due to reactivation and reinfection. We substantiate the prospects of WA as a potent adjunct immunomodulator that enriches protective memory cells by prompting STAT signaling and improves host defense against M. tuberculosis. IMPORTANCE Despite being extensive, conventional antituberculosis therapy (ATT) is barely proficient in providing sterile immunity to tuberculosis (TB). Failure to constrain the escalating global TB burden due to the emergence of drug-resistant bacterial strains and immune dampening effects of ATT necessitates adjunct immunotherapeutics for better clinical outcomes. We evaluated the prospects of withaferin A (WA), an active constituent of Withania somnifera, as an adjunct immunomodulator against diverse M. tuberculosis strains. WA efficiently restricts the progression of TB by stimulating antimycobacterial host responses, protective immune signaling, and activation of diverse immune cell populations. Protective effects of WA can be attributed to the enrichment of memory T cells by induction of STAT signaling, thereby enhancing resistance to reinfections and reactivation of disease. We ascertained the immunotherapeutic potential of WA in boosting host immune responses against M. tuberculosis.

THE DEGREE OF SECRETORY IMMUNOGLOBULIN A IN BURN PATIENTS WITH PROBIOTIC THERAPY

Background: One of the problems with burn patients is the impairment of host immunity, which makes difficult to treat. In burns, immunoglobulinA has demonstrated to decrease. Immunoglobulin A is the main product of mucous immune system, which increases viral clearance and decreasesbacterial adhesion in the intestine. Probiotics consist of living microflora, which control the balance of lactobacilli and bifidobacteria in the intestine.Instead of producing organic component, increasing the acidity of intestine, mucin and bacteriocin, they also activate the intestinal immune systemand secretory immunoglobulin A (sIgA). The goal of this study was to propose that regular intake of probiotic might help to improve the mucousimmune system, especially sIgA in intestines in burn patients.Methods: An experimental, double-blind, controlled clinical trial was carried out in 33 burn patients. Those patients were divided into two groups.The first group was given daily probiotic and the second group was given only placebo for 10 days. The treatment began on the 4th day admission, andthen, the degree of sIgA was evaluated before treatment and day 14 from fecal specimen.Results: Significant differences between probiotic and control group were observed (p<0.0001). The degree of sIgA in the probiotic group increased61.25%, and in the control group, it decreased to 36.80%.Conclusion: The mucous immune system, especially sIgA, increases by probiotic intake.

Gene-metabolite profile integration to understand the cause of spaceflight induced immunodeficiency

Spaceflight presents a spectrum of stresses very different from those associated with terrestrial conditions. Our previous study (BMC Genom. 15: 659, 2014) integrated the expressions of mRNAs, microRNAs, and proteins and results indicated that microgravity induces an immunosuppressive state that can facilitate opportunistic pathogenic attack. However, the existing data are not sufficient for elucidating the molecular drivers of the given immunosuppressed state. To meet this knowledge gap, we focused on the metabolite profile of spaceflown human cells. Independent studies have attributed cellular energy deficiency as a major cause of compromised immunity of the host, and metabolites that are closely associated with energy production could be a robust signature of atypical energy fluctuation. Our protocol involved inoculation of human endothelial cells in cell culture modules in spaceflight and on the ground concurrently. Ten days later, the cells in space and on the ground were exposed to lipopolysaccharide (LPS), a ubiquitous membrane endotoxin of Gram-negative bacteria. Nucleic acids, proteins, and metabolites were collected 4 and 8 h post-LPS exposure. Untargeted profiling of metabolites was followed by targeted identification of amino acids and knowledge integration with gene expression profiles. Consistent with the past reports associating microgravity with increased energy expenditure, we identified several markers linked to energy deficiency, including various amino acids such as tryptophan, creatinine, dopamine, and glycine, and cofactors such as lactate and pyruvate. The present study revealed a molecular architecture linking energy metabolism and immunodeficiency in microgravity. The energy-deficient condition potentially cascaded into dysregulation of protein metabolism and impairment of host immunity. This project is limited by a small sample size. Although a strict statistical screening was carefully implemented, the present results further emphasize the need for additional studies with larger sample sizes. Validating this hypothesis using an in vivo model is essential to extend the knowledge towards identifying markers of diagnostic and therapeutic value.

Abstract 4901: Clostridium cluster XIVa species an early biomarker in radiation injury

Abstract Radiation therapy is being used in the treatment of nearly 60% of the current cancer patients. In spite of the best efforts to provide special care in minimizing radiation exposure, significant radiation injury remains a common side-effect particularly to the gastro intestinal tract. Severe injury to GI tract may lead to multiple organ dysfunction syndrome. The status of fecal microbiota has been proposed as a rapid diagnostic platform in radiation injury. Gut microbes play a role in immunity, health, and disease. Imbalances in gut microbiota are related to numerous disorders, such as inflammatory bowel disease, colorectal cancer (CRC), and atopy. In patients with immune suppression due to high-dose chemotherapy or that undergoing radiation therapy, disruption of the microbiota through antibiotics and impairment of host immunity gives rise to perturbations favoring intestinal domination by pathogenic species, resulting in increased bacterial translocation and susceptibility to systemic infection. Here, using real-time PCR assays, we assessed the immediate changes and quantitative alterations to fecal microbiota in response to radiation injury. Swiss-albino Mice were subjected to 10 Gy X-ray whole body irradiation doses using commercially available X-RAD 320 irradiator (1Gy/min; F2 beam hardening filter 1.5mm Al, 0.25mm Cu, 0.75mm Sn; Precision X-ray inc, USA). Fecal samples collected immediately after the radiation exposure were analyzed. We show that Clostridium cluster XIVa that accounts for almost 60% of the mucin-adhered microbiota is significantly increased (11.71 +/- 0.29 fold n=6) in the fecal samples, compared to the total bacteria and other bacteria that tend to enrich in the luminal region. Along with the Bacteroidetes and Proteobacteria from the luminal region, minimal changes in the levels of Firmicutes that colonize the mucin layer were observed. Further, these changes varied considerably between the subjects and were inconsistent compared to the Clostridium cluster species. Clostridium cluster XIVa has been proposed to be the mucosal butyrate producers producing butyrate close to the epithelium. This enhances butyrate bioavailability required in treating diseases such as inflammatory bowel disease. These findings provide opportunities to evaluate the potential use of intestinal microbiota as biomarkers in radiation injury. Also, provides insights into the microbial changes tantamount to the radiation induced GI injury. Citation Format: Ishfaq Ahmed, William McLauglin, Shrikant Anant, Shahid Umar, Rao V. Papineni. Clostridium cluster XIVa species an early biomarker in radiation injury. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4901. doi:10.1158/1538-7445.AM2014-4901

Management of Strongyloides stercoralis: a puzzling parasite.

Strongyloides stercoralis is one of the common parasites in tropical areas. It can result in severe clinical syndromes, hyperinfection syndrome or disseminated strongyloidiasis in immunocompromised patients. The treatment of strongyloidiasis is a challenge for clinicians in clinical practice. Failure of treatment is due to autoinfection caused by the parasite life cycle and impairment of host immunity. Ivermectin currently is the treatment of choice. When compared with thiabendazole, it has shown a similar efficacy with better tolerability. However, there is neither consensus in duration of treatment nor in repetition of doses. The keys for management of this tough parasite include proper evaluation and prevention. Stool examination with high sensitivity techniques such as Baermann technique, filter-paper culture and agar-plate culture and specific IgG serology should be used in evaluation for 1 to 2 years. Screening, both stool examination and serology, before patients have immunosuppressive treatment is needed to prevent the severe form of strongyloidiasis.

Spot light on intestinal microbiota

Microbes in human body play an essential role in immunity, health, and disease. The gut microbes have been found to be the most diverse and constitute the densest cell number in the human microbiota and studies continue to support the premise that commensal bacteria, largely anaerobic, serve to maintain microbial stability and colonization resistance by preventing overgrowth or domination with more pathogenic bacteria, through interactions within the microbial community and with the host. Early results have indicated that the imbalances in gut microbiota are related to numerous disorders, such as inflammatory bowel disease, colorectal cancer (CRC), diabetes, and atopy. In patients with immune suppression due to high-dose chemotherapy or hematopoietic stem cell transplantation or in patients undergoing radiation therapy, disruption of the microbiota through antibiotics as well as impairment of host immunity gives rise to perturbations favoring intestinal domination by pathogenic species, leading to increased bacterial translocation and susceptibility to systemic infection. Randomized and double blind placebo-controlled human studies using pro- pre- or synbiotics, with adequate follow-up are needed to formulate directions for prevention and therapy. Nano-formulation of phytonutrients for delivery to specific targets could revolutionize personalized medicine.

The intestinal microbiota and susceptibility to infection in immunocompromised patients.

Many infections of immunocompromised patients originate from the gastrointestinal tract. The pathogenesis of these infections often begins with alteration of the intestinal microbiota. Understanding the microbiota and how it can either cause or prevent infection is vital for the development of more effective prevention and treatment of these infections. This article reviews and discusses recent work providing insight into the intestinal microbiota of these at-risk immunocompromised patients. Studies continue to support the premise that commensal bacteria, largely anaerobic, serve to maintain microbial stability and colonization resistance by preventing overgrowth or domination with more pathogenic bacteria, through interactions within the microbial community and with the host. In patients with immune suppression due to high-dose chemotherapy or hematopoietic stem cell transplantation, disruption of the microbiota through antibiotics as well as impairment of host immunity gives rise to perturbations favoring intestinal domination by pathogenic species, leading to increased bacterial translocation and susceptibility to systemic infection. An understanding of the intestinal microbiota and the impact of antibiotics will help to guide our treatment of these gut-originating infections.

CD40 ligand enhances immunogenicity of vector-based vaccines in immunocompetent and CD4+ T cell deficient individuals

Impairment of host immunity, particularly CD4+ T cell deficiency, presents significant complications for vaccine immunogenicity and efficacy. CD40 ligand (CD40L or CD154), a member of the tumor necrosis factor superfamily (TNFSF), is an important co-stimulatory molecule and, through interactions with its cognate receptor CD40, plays a pivotal role in the generation of host immune responses. Exploitation of CD40L and its receptor CD40 could provide a means to enhance and potentially restore protective immune responses in CD4+ T cell deficiency. To investigate the potential adjuvanticity of CD40L, we constructed recombinant plasmid DNA and adenoviral (Ad) vaccine vectors expressing murine CD40L and the mycobacterial protein antigen 85B (Ag85B). Co-immunization of mice with CD40L and Ag85B by intranasal or intramuscular prime-boosting led to route-dependent enhancement of the magnitude of vaccine-induced circulating and lung mucosal CD4+ and CD8+ T cell responses in both normal (CD4-replete) and CD4+ T cell deficient animals, including polyfunctional T cell responses. The presence of CD40L alone was insufficient to enhance or restore CD4+ T cell responses in CD4-ablated animals; however, in partially depleted animals, co-immunization with Ag85B and CD40L was capable of eliciting enhanced T cell responses, similar to those observed in normal animals, when compared to those given vaccine antigen alone. In summary, these findings show that CD40L has the capacity to enhance the magnitude of vaccine-induced polyfunctional T cell responses in CD4+ T cell deficient mice, and warrants further study as an adjuvant for immunization against opportunistic pathogens in individuals with CD4+ T cell deficiency.

Advanced gastric cancer associated with acute myelocytic leukemia —Report of a case—

A case of advanced gastric cancer associated with acute myelocytic leukemia (AML) is reported. Synchronous double malignancies of gastric cancer and AML are very rare. Combination chemotherapy (BHAC-DMP) was used as the method for induction and consolidation therapy for AML and a complete remission was obtained. However, it failed to show any therapeutic effect on the gastric cancer. A radical subtotal gastrectomy was performed with lymphadenectomy. During the postoperative course, both respiratory failure and severe thrombocytopenia progressed. Fortunately, the patient responded well to mechanical ventilation and the administration of heparin. She was discharged on day 52 after surgery, and no sign of recurrence of either gastric cancer or AML has been observed over the one-year period following the gastrectomy. In principle, in order to achieve a good prognosis, a radical resection should be carried out for gastric cancer associated with AML. However, chemotherapy for AML might make the patient vulnerable to surgical stress, although we could not demonstrate any concrete evidence which could prove the impairment of host immunity in this case. It is, therefore, possible that not only the relapse of AML but also the impairment of host immunity may cause some other difficulties during the post-gastrectomy course.