Viral Sequences Are Repurposed for Controlling Antiviral Responses as Non-Retroviral Endogenous Viral Elements

Eukaryotic genomes contain numerous copies of endogenous viral elements (EVEs), most of which are considered endogenous retrovirus (ERV) sequences. Over the past decade, non-retroviral endogenous viral elements (nrEVEs) derived from ancient RNA viruses have been discovered. Several functions have been proposed for these elements, including antiviral defense. This review summarizes the current understanding of nrEVEs derived from RNA viruses, particularly endogenous bornavirus-like elements (EBLs) and endogenous filovirus-like elements (EFLs). EBLs are one of the most extensively studied nrEVEs. The EBL derived from bornavirus nucleoprotein (EBLN) is thought to function as a non-coding RNA or protein that regulates host gene expression or inhibits virus propagation. Ebolavirus and marburgvirus, which are filoviruses, induce severe hemorrhagic fever in humans and nonhuman primates. Although the ecology of filoviruses remains unclear, bats are believed to be potential reservoirs. Based on the knowledge from EBLs, it is postulated that EFLs in the bat genome help to maintain the balance between filovirus infection and the bat’s defense system, which may partially explain why bats act as potential reservoirs. Further research into the functions of nrEVEs could reveal novel antiviral systems and inspire novel antiviral approaches

Suppression of Borna Disease Virus Replication during Its Persistent Infection Using the CRISPR/Cas13b System

Borna disease virus (BoDV-1) is a bornavirus that infects the central nervous systems of various animal species, including humans, and causes fatal encephalitis. BoDV-1 also establishes persistent infection in neuronal cells and causes neurobehavioral abnormalities. Once neuronal cells or normal neural networks are lost by BoDV-1 infection, it is difficult to regenerate damaged neural networks. Therefore, the development of efficient anti-BoDV-1 treatments is important to improve the outcomes of the infection. Recently, one of the clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) systems, CRISPR/Cas13, has been utilized as antiviral tools. However, it is still unrevealed whether the CRISPR/Cas13 system can suppress RNA viruses in persistently infected cells. In this study, we addressed this question using persistently BoDV-1-infected cells. The CRISPR/Cas13 system targeting viral mRNAs efficiently decreased the levels of target viral mRNAs and genomic RNA (gRNA) in persistently infected cells. Furthermore, the CRISPR/Cas13 system targeting viral mRNAs also suppressed BoDV-1 infection if the system was introduced prior to the infection. Collectively, we demonstrated that the CRISPR/Cas13 system can suppress BoDV-1 in both acute and persistent infections. Our findings will open the avenue to treat prolonged infection with RNA viruses using the CRISPR/Cas13 system

Interferon-α enhances biological defense activities against oxidative stress in cultured rat hepatocytes and hepatic stellate cells

Oxidative stress has been implicated as a cause of hepatic fibrosis, and hepatic stellate cells (HSCs), which are the most important collagen-producing cell types, have been reported to be activated by lipid peroxidation products. Antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) provide a defense system that plays a critical role in protecting the cell from free radical damage, particularly lipid peroxidation. To elucidate the antioxidant activity of interferon-α (IFN-α), the effects of IFN-α on rat hepatocytes undergoing oxidative stress and HSCs in primary culture as well as isolated rat liver mitochondria were examined. IFN-α was observed to dose-dependently increase the immunoreactive protein levels of copper, zinc-and manganese-dependent SOD as well as the enzyme activities of GPx, and decrease the lipid peroxidation product levels and oxidative burst both in stressed hepatocytes and activated HSCs GPx activities, however, were not detected in the latter cells. IFN-α also inhibited HSC activation and lipid peroxidation in liver mitochondria. These findings suggest that IFN-α may enhance biological defense activities against oxidative stress and function as a potent fibrosuppressant by protecting hepatocytes and hepatic stellate cells from lipid peroxidation in vivo

Study of the causes of higher mortality rates from chronic liver diseases in Tokushima Prefecture

Mortality rates from chronic liver diseases (CLD) such as liver cirrhosis and hepatocellular carcinoma have been reported to be higher in Tokushima prefecture, although its causes remain unclear. To clarify the causes of CLD in Tokushima prefecture, we evaluated the positive rates of HBs antigen and anti-HCV antibody and the mortality rates from CLD in patients with liver diseases and blood donors after dividing the entire Tokushima prefecture into 8 district boundaries of health centers. In addition, to evaluate the causes of the higher frequency of CLD and the relationship between the development of CLD and viruses, medical examinations were performed in 2 mountain villages in Tokushima prefecture where the drift of population was limited and the mortality rates from CLD differed from each other. As a result, it was found that HCV infection was the major cause of the higher mortality rates from CLD in Tokushima prefecture. Although there were marked regional differences in the mortality rates from CLD, they were mainly due to different rates of HCV infection

An incident involving blood sucking by a tick in a suburb in Japan

We encountered a patient whose blood was sucked by Haemaphysalis longicornis in the suburb of a business city in Tokushima prefecture in Japan. The tick, which had been attached to the lower limb of the patient for one week, measured 10 mm in length. There were no notable objective or subjective findings after the complete extirpation of the tick. The area had not been known in recent history to be a habitat of ticks, and, thus, this case is of importance in terms of predicting future trends of tick-borne diseases in Japan

Cガタカンエン ウイルス ジゾク カンセン カンジャ ノ カンセンイカ ニオケル ジョセイ ホルモン ノ ヤクワリ

The most common cause of hepatic fibrosis is chronic hepatitis C virus infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory stimuli, and produce extracellular matrix components. Clinical observations and death statistics support the view that chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. It should be noted in this respect that estradiol (E2) is a potent endogenous antioxidant. Our studies showed that E2 suppressed hepatic fibrosis in hepatic fibrosis models, and attenuated HSC activation in primary culture. Recently, variant estrogen receptors (ERs) were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. We also demonstrated decreased levels of ERs in postmenopausal women and cirrhotic patients of both genders. The present review summarizes our current knowledge of the biological functions of E2 and ER status as it relates to fibrogenesis in the liver

Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study

Background/Aims Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody. Methods We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn’s disease (CD, n=46) compared with healthy controls (HCs, n=64). Results FCP levels in UC patients strongly correlated with the Disease Activity Index (rs=0.676, P<0.0001) and Mayo endoscopic subscore (MES; rs=0.677, P<0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P<0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P<0.001), except those with proctitis. The Crohn’s Disease Activity Index tended to correlate with the FCP level (rs=0.283, P=0.0565). Conclusions Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC

Clinical value of the determination of serum guanase activity in patients with chronic hepatitis type C

The study examines the clinical significance of guanase (GU) measurement inpatients with hepatitis C. 688 patients in whom either ALT was abnormal, or in whom HBsAg or HCVAb was detected in the serum, were enrolled into this study. The percentage of cases in which normal ALT while elevated GU was compared among the different disease groups. Then, the percentage of cases with normal ALT but elevated GU was compared between HBV and HCV groups. For the entire population, a significant correlation was observed between ALT and GU (r=0.872). The overall percentage of cases with normal ALT but elevated GU activity was 11.4%. In HCV group, 449 cases had normal ALT. Of these cases, 20.3% had elevated GU, while ALT was normal. Before 1989, no test to check donated blood for HCV antibody was available. However, screening of donated blood for high GU was associated with a reduced incidence of post-transfusion hepatitis. This is probably because following the screening, blood donated by patients with hepatitis C who had normal ALT but elevated GU was rejected. After the introduction of HCV antibody measurement, GU measurement is still useful to reveal the pathophysiological condition in-patients with chronic hepatitis type C

APOBコドン4311遺伝子多型は脂質代謝を変化させることによりC型肝炎ウイルスの感染性に関与する

Background: It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. Methods: Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequencespecific oligonucleotide probe-Luminex method. Results: An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). Conclusion: An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR