Members of the tripartite motif (TRIM) family are a part of the innate immune system to counter intracellular pathogens. TRIM22 has been reported to possess antiretroviral activity. Here we report that TRIM22 is involved in antiviral immunity against hepatitis B virus (HBV). Our results showed that TRIM22, being a strongly induced gene by interferons in human hepatoma HepG2 cells, could inhibit HBV gene expression and replication in a cell culture system as well as in a mouse model system. Importantly, it was found that TRIM22 could inhibit the activity of HBV core promoter (CP) in a dose-dependent manner. However, TRIM22 lacking the C terminal SPRY domain lost this activity. Further study showed that the SPRY domain deletion mutant was localized exclusively to the cytoplasm of HepG2 cells. In contrast, the wild-type TRIM22 was localized to the nucleus, as expected for a transcriptional suppressor. Interestingly, although RING domain mutants of TRIM22 were localized to the nucleus, they could not inhibit HBV CP activity, indicating that TRIM22-mediated anti-HBV activity was dependent on the nuclear-located RING domain. W ith over 300 million carriers, hepatitis B virus (HBV) infection remains a major public health problem worldwide. 1 Classified in the Hepadnaviridae family, HBV is a small, enveloped DNA virus with a genome size of 3.2 kb. HBV replicates its partially double-stranded DNA genome within core particles by reverse transcription of encapsulated 3.5-kb pregenomic RNA (pgRNA), and thus is related to retroviruses. 2 The core promoter (CP) is responsible for the synthesis of pgRNA, and therefore the regulation of this promoter is important in the viral life cycle. It is well established that resolution of HBV infection is critically dependent on adaptive immunity, especially on HBVspecific cytotoxic T lymphocytes response. However, many studies also indicate that an innate immune response is crucial for early clearance of HBV infection. 3 For example, activation of Toll-like receptor signaling can inhibit HBV replication in vivo, and overexpression of an innate antiviral molecule, APOBEC3G, has also been shown to interfere with HBV replication efficiently. 4,5 Recent studies show that many members of the tripartite motif (TRIM) superfamily are expressed in response to interferons (IFNs) and display antiviral properties, targeting retroviruses in particular. 6,7 TRIM5␣, TRIM19, TRIM22, and TRIM28 were all demonstrated to play important roles in antiretroviral activities. [8][9][10][11][12] It has been speculated that the TRIM proteins may represent a new and widespread class of antiviral molecules involved in innate immunity. 6,7 The TRIM family is characterized by a combination of RING, B-Box, and coiled-coil domains, followed by one of several C-terminal domains. 13 To date, nearly 70 TRIM family members have been identified, yet the most intensively studied TRIM protein may be

Phage-coded lysin is an enzyme that destroys the cell walls of bacteria. Phage lysin could be an alternative to conventional antibiotic therapy against pathogens that are resistant to multiple antibiotics. In this study, a novel staphylococcal phage, GH15, was isolated, and the endogenous lytic enzyme (LysGH15) was expressed and purified. The lysin LysGH15 displayed a broad lytic spectrum; in vitro treatment killed a number of Staphylococcus aureus strains rapidly and completely, including methicillinresistant S. aureus (MRSA). In animal experiments, a single intraperitoneal injection of LysGH15 (50 g) administered 1 h after MRSA injections at double the minimum lethal dose was sufficient to protect mice (P < 0.01). Bacteremia in unprotected mice reached colony counts of about 10 7 CFU/ml within 3.5 h after challenge, whereas the mean colony count in lysin-protected mice was less than 10 4 CFU/ml (and ultimately became undetectable). These results indicate that LysGH15 can kill S. aureus in vitro and can protect mice efficiently from bacteremia in vivo. The phage lysin LysGH15 might be an alternative treatment strategy for infections caused by MRSA.Staphylococcus aureus is a common and dangerous pathogen that causes various infectious diseases, including skin abscesses, wound infections, endocarditis, osteomyelitis, pneumonia, and toxic shock syndrome (2, 23). Treatment of these infections has become ever more difficult due to the emergence of multidrug-resistant strains, especially methicillin-resistant S. aureus (MRSA) (15,25,26,36,37). Vancomycin was effective against MRSA, but certain MRSA strains have already acquired resistance to vancomycin as well (vancomycin-resistant S. aureus [VRSA]), raising serious concerns within the medical community (17,18,37). Therefore, there is an urgent need for novel therapeutic agents directed against this formidable pathogen (2, 9).The phage lysin is encoded by the bacteriophage genome and is synthesized at the end of the phage lytic life cycle to lyse the host cell (30). Lysins belong to the family of mureolytic enzymes that directly destroy peptidoglycans in the bacterial cell wall. Previous studies have suggested that lysins from certain phages were highly efficient in lysing bacteria, especially when applied exogenously (11,14,21,22,29,35). As a potential antibacterial agent, lysins possess several promising features, namely, a distinct mode of action, species or type specificity, and bactericidal activity independent of the antibiotic susceptibility pattern (1). Indeed, there is a low probability that bacteria will develop resistance against lysin (12, 21).Some Staphylococcus phage lysins have been isolated and studied, including LysK, ClyS, MV-L, LysWMY, and ⌽H5; however, only MV-L and ClyS have been studied in in vivo assays (6, 33). In this study, a novel myovirus phage infecting S. aureus was isolated. The lysin derived from this phage, LysGH15, was expressed and refined. The lysin LysGH15 demonstrated a very broad host range and strong lytic activity. We evaluate...

The Tp-e/QT ratio may serve as a prognostic predictor of adverse outcomes after successful pPCI treatment in STEMI patients.

Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

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BackgroundCardiac fibrogenesis in the late stage of viral myocarditis causing contractile dysfunction and ventricular dilatation, is a major pathogenic factor for the progression of myocarditis to serious cardiovascular diseases including dilated cardiomyopathy (DCM) and congestive heart failure (HF). Recent studies indicate that regulatory T cells (Tregs) are involved in the fibrotic process of liver and lung fibosis. However, the role of Tregs in the development of viral myocarditis-caused cardiac fibrosis and their therapeutic potential remains unclear.Methodology/Principal FindingsMyocardial fibrosis was induced in BALB/c mice by intraperitoneal injection of Coxsackievirus B3 (CVB3) assessed by picrosirius red staining and detection of expression levels of collagen I, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Myocardial Treg frequency was down-regulated during the course of viral myocarditis and a negative correlation with the severity of cardiac fibrosis was found. To explore the role of Tregs in CVB-induced cardiac fibrosis, Treg was in vivo depleted by injecting anti-CD25 mAb which resulted in aggravation of cardiac fibrosis. In consistent with that, after adoptive transfer of isolated Tregs into mice, significant amelioration of CVB3-induced cardiac fibrosis was confirmed. Interleukin-10 (IL-10) neutralizing antibodies were used in vivo and in vitro to explore the molecular mechanism of the therapeutic effect of Treg. It was found that administration of anti-IL-10 mAb after Treg transfer abrogated Treg’s treating effect and the inhibition of Treg on collagen production by cardiac fibroblasts was mediated mainly through IL-10.Conclusion/SignificanceOur data suggested that Tregs have a protective role in the fibrotic process of CVB3-induced cardiac fibrosis via secreting IL-10 and might provide an alternative option for the future treatment of cardiac fibrosis.

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