Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: a systematic review

Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened riskcould be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. 17 genes were classified as having “good” evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardised approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in patients with HCV infection

Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages

This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein–Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease

Sero-prevalence and risk factors for hepatitis B virus infection among health care workers in a tertiary hospital in Uganda

BACKGROUND: Hepatitis B virus (HBV) infection is a global public health challenge. Prevalence of current hepatitis B virus infection in the general population in Uganda is about 10%. Health care workers (HCW) have an extra risk of getting infected from their workplace and yet they are not routinely vaccinated against HBV infection. This study aimed at estimating prevalence of hepatitis B virus infection and associated risk factors among health care workers in a tertiary hospital in Uganda. METHODS: Data were obtained from a cross sectional survey conducted in Mulago, a national referral and teaching hospital in Uganda among health care workers in 2003. A proportionate to size random sample was drawn per health care worker category. A structured questionnaire was used to collect data on socio-demographic characteristics and risk factors. ELISA was used to test sera for HBsAg, anti-HBs and total anti-HBc. Descriptive and logistic regression models were used for analysis. RESULTS: Among the 370 participants, the sero-prevalence of current hepatitis B virus infection was 8.1%; while prevalence of life time exposure to hepatitis B virus infection was 48.1%. Prevalence of needle stick injuries and exposure to mucous membranes was 67.8% and 41.0% respectively. Cuts were also common with 31.7% of doctors reporting a cut in a period of one year preceding the survey. Consistent use of gloves was reported by 55.4% of respondents. The laboratory technicians (18.0% of respondents) were the least likely to consistently use gloves. Only 6.2% of respondents were vaccinated against hepatitis B virus infection and 48.9% were susceptible and could potentially be protected through vaccination. Longer duration in service was associated with a lower risk of current infection (OR = 0.13; p value = 0.048). Being a nursing assistant (OR = 17.78; p value = 0.007) or a laboratory technician (OR = 12.23; p value = 0.009) were associated with a higher risk of current hepatitis B virus infection. Laboratory technicians (OR = 3.99; p value = 0.023) and individuals with no training in infection prevention in last five years (OR = 1.85; p value = 0.015) were more likely to have been exposed to hepatitis B virus infection before. CONCLUSIONS: The prevalence of current and life time exposure to hepatitis B virus infection was high. Exposure to potentially infectious body fluids was high and yet only a small percentage of HCW were vaccinated. There is need to vaccinate all health care workers as a matter of policy and ensure a safer work environment

Parenteral Medication Prescriptions, Dispensing and Administration Habits in Mongolia

High levels of injection prescribing were reported in Mongolia. Understanding the factors influencing the injection prescribing is essential to reduce their inappropriate use. The study evaluated the views, experiences and attitudes of community members associated with the prescribing of injections in Mongolia. A structured questionnaire focusing on respondents’ characteristics, experiences and views about injections was developed and administered face-to-face to community members in Ulaanbaatar, Mongolia. Standard descriptive statistics were used to summarize demographic data and responses to the questionnaires. Dependant variables were compared using Kruskal-Wallis Tests for independence. Statistical analyses were performed using SPSS Version 21.0. Six hundred participants were approached and the response rate was 79% (n 474). Almost half of the respondents were aged between 31 and 50 (n 228, 48.1%) and 40.9% of respondents were male (n 194). Most respondents were from Ulaanbaatar city (n 407, 85.7%). All respondents had received injections in the past and 268 (56.5%) had received injection in the past year. The most common reason for having an injection in the past year was reported as treatment of a disease (n 163, 60.8%), or for administration of vitamins (n 70, 26.1%). Injections were prescribed by a doctor (n 353, 74.9%), dispensed by a pharmacist (n 283, 59.7%) and administered by a nurse (n 277, 54.9%). Only 16% of all respondents had the expectation of receiving injections when they visited a doctor (n 77). An important perception regarding injections was that they hastened the recovery process (n 269, 56.8%). When asked their opinion about therapeutic injections, 40% of all respondents agreed that injections were a better medicine (n 190) than oral medications, with older respondents strongly agreeing (p<0.001). Based on this total sample, approximately 1891 injections per 1000 patients were administered. The excessive injection use seems to be promoted by inappropriate prescribing, dispensing and administration of medication by doctors and others

VapC Toxins from Mycobacterium tuberculosis Are Ribonucleases that Differentially Inhibit Growth and Are Neutralized by Cognate VapB Antitoxins

The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as ‘non-toxic’. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of ‘non-toxic’ VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617 – VapC proteins with similarity to Rv0549c and Rv3320c, respectively – these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism

Brugia malayi Antigen (BmA) inhibits HIV-1 trans-infection but neither BmA nor ES-62 alter HIV-1 infectivity of DC induced CD4+ Th-cells

One of the hallmarks of HIV-1 disease is the association of heightened CD4+ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4+ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4+ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4+ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4+ Th-cells induced by exposed DCs

Differential Expression of Iron Acquisition Genes by Brucella melitensis and Brucella canis during Macrophage Infection

Brucella spp. cause chronic zoonotic disease often affecting individuals and animals in impoverished economic or public health conditions; however, these bacteria do not have obvious virulence factors. Restriction of iron availability to pathogens is an effective strategy of host defense. For brucellae, virulence depends on the ability to survive and replicate within the host cell where iron is an essential nutrient for the growth and survival of both mammalian and bacterial cells. Iron is a particularly scarce nutrient for bacteria with an intracellular lifestyle. Brucella melitensis and Brucella canis share ∼99% of their genomes but differ in intracellular lifestyles. To identify differences, gene transcription of these two pathogens was examined during infection of murine macrophages and compared to broth grown bacteria. Transcriptome analysis of B. melitensis and B. canis revealed differences of genes involved in iron transport. Gene transcription of the TonB, enterobactin, and ferric anguibactin transport systems was increased in B. canis but not B. melitensis during infection of macrophages. The data suggest differences in iron requirements that may contribute to differences observed in the lifestyles of these closely related pathogens. The initial importance of iron for B. canis but not for B. melitensis helps elucidate differing intracellular survival strategies for two closely related bacteria and provides insight for controlling these pathogens

Injection Drug Use Is a Risk Factor for HCV Infection in Urban Egypt

OBJECTIVE: To identify current risk factors for hepatitis C virus (HCV) transmission in Greater Cairo. DESIGN AND SETTING: A 1:1 matched case-control study was conducted comparing incident acute symptomatic hepatitis C patients in two "fever" hospitals of Greater Cairo with two control groups: household members of the cases and acute hepatitis A patients diagnosed at the same hospitals. Controls were matched on the same age and sex to cases and were all anti-HCV antibody negative. Iatrogenic, community and household exposures to HCV in the one to six months before symptoms onset for cases, and date of interview for controls, were exhaustively assessed. RESULTS: From 2002 to 2007, 94 definite acute symptomatic HCV cases and 188 controls were enrolled in the study. In multivariate analysis, intravenous injections (OR = 5.0; 95% CI = 1.2-20.2), medical stitches (OR = 4.2; 95% CI = 1.6-11.3), injection drug use (IDU) (OR = 7.9; 95% CI = 1.4-43.5), recent marriage (OR = 3.3; 95% CI = 1.1-9.9) and illiteracy (OR = 3.9; 95% CI = 1.8-8.5) were independently associated with an increased HCV risk. CONCLUSION: In urban Cairo, invasive health care procedures remain a source of HCV transmission and IDU is an emerging risk factor. Strict application of standard precautions during health care is a priority. Implementation of comprehensive infection prevention programs for IDU should be considered

Differential Producibility Analysis (DPA) of Transcriptomic Data with Metabolic Networks: Deconstructing the Metabolic Response of M. tuberculosis

A general paucity of knowledge about the metabolic state of Mycobacterium tuberculosis within the host environment is a major factor impeding development of novel drugs against tuberculosis. Current experimental methods do not allow direct determination of the global metabolic state of a bacterial pathogen in vivo, but the transcriptional activity of all encoded genes has been investigated in numerous microarray studies. We describe a novel algorithm, Differential Producibility Analysis (DPA) that uses a metabolic network to extract metabolic signals from transcriptome data. The method utilizes Flux Balance Analysis (FBA) to identify the set of genes that affect the ability to produce each metabolite in the network. Subsequently, Rank Product Analysis is used to identify those metabolites predicted to be most affected by a transcriptional signal. We first apply DPA to investigate the metabolic response of E. coli to both anaerobic growth and inactivation of the FNR global regulator. DPA successfully extracts metabolic signals that correspond to experimental data and provides novel metabolic insights. We next apply DPA to investigate the metabolic response of M. tuberculosis to the macrophage environment, human sputum and a range of in vitro environmental perturbations. The analysis revealed a previously unrecognized feature of the response of M. tuberculosis to the macrophage environment: a down-regulation of genes influencing metabolites in central metabolism and concomitant up-regulation of genes that influence synthesis of cell wall components and virulence factors. DPA suggests that a significant feature of the response of the tubercle bacillus to the intracellular environment is a channeling of resources towards remodeling of its cell envelope, possibly in preparation for attack by host defenses. DPA may be used to unravel the mechanisms of virulence and persistence of M. tuberculosis and other pathogens and may have general application for extracting metabolic signals from other “-omics” data