Search

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the largest single‐stranded RNA virus known to date. Its genome contains multiple accessory protein genes that act against host immune responses but are not required for progeny virus production. The functions of the accessory proteins in the viral life cycle have been examined, but their involvement in viral pathogenicity remains unclear. Here, we investigated the roles of the accessory proteins in viral immunopathogenicity. To this end, recombinant SARS‐CoV‐2 possessing nonsense mutations in the seven accessory protein open reading frames (ORFs) (ORF3a, ORF3b, ORF6, ORF7a, ORF8, ORF9b, and ORF10) was de novo generated using an early pandemic SARS‐CoV‐2 strain as a backbone. We confirmed that the resultant virus (termed ORF3–10 KO) did not express accessory proteins in infected cells and retained the desired mutations in the viral genome. In cell culture, the ORF3–10 KO virus exhibited similar virus growth kinetics as the parental virus. In hamsters, ORF3–10 KO virus infection resulted in mild weight loss and reduced viral replication in the oral cavity and lung tissue. ORF3–10 KO virus infection led to mild inflammation, indicating that an inability to evade innate immune sensing because of a lack of accessory proteins impairs virus growth in vivo and results in quick elimination from the body. Overall, we showed that SARS‐CoV‐2 accessory proteins are involved in immunopathogenicity. [ABSTRACT FROM AUTHOR]

Summary: Prolonged SARS‐CoV‐2 infection in immunocompromised individuals has been scattered, but the details remain unclear. We conducted a prospective study with 26 COVID‐19 patients with haematological malignancies to determine viral shedding kinetics and characteristics. We obtained nasopharyngeal swabs from the patients 21–28 days post‐onset for a PCR test and performed virus isolation from the PCR‐positive samples. A viable virus was detected in five patients (19.2%), all of whom had malignant lymphoma. Those patients had significantly lower CD4+ T‐cell counts than the PCR‐negative patients. A comparison of previous chemotherapy showed that anti‐CD20 antibodies and bendamustine may be risk factors for prolonged viral shedding. [ABSTRACT FROM AUTHOR]

Smoking is one of the risk factors most closely related to the severity of coronavirus disease 2019 (COVID‐19). However, the relationship between smoking history and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infectivity is unknown. In this study, we evaluated the ACE2 expression level in the lungs of current smokers, ex‐smokers, and nonsmokers. The ACE2 expression level of ex‐smokers who smoked cigarettes until recently (cessation period shorter than 6 months) was higher than that of nonsmokers and ex‐smokers with a long history of nonsmoking (cessation period longer than 6 months). We also showed that the efficiency of SARS‐CoV‐2 infection was enhanced in a manner dependent on the angiotensin‐converting enzyme 2 (ACE2) expression level. Using RNA‐seq analysis on the lungs of smokers, we identified that the expression of inflammatory signaling genes was correlated with ACE2 expression. Notably, with increasing duration of smoking cessation among ex‐smokers, not only ACE2 expression level but also the expression levels of inflammatory signaling genes decreased. These results indicated that smoking enhances the expression levels of ACE2 and inflammatory signaling genes. Our data suggest that the efficiency of SARS‐CoV‐2 infection is enhanced by smoking‐mediated upregulation of ACE2 expression level. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage should be considered as a possible adverse event in patients with anaphylactic shock who are treated with adrenaline administration, especially in those at high risk of serious bleeding events. Although prompt intramuscular injection of adrenaline is the first‐line treatment for anaphylactic shock, physicians should recognize that adrenaline injection can lead to intracerebral hemorrhage, especially in high bleeding risk patients. [ABSTRACT FROM AUTHOR]

Chronic infection with hepatitis B virus (HBV) sometime induces lethal cirrhosis and hepatocellular carcinoma. Although nucleot(s)ide analogs are used as main treatment for HBV infection, the emergence of the drug‐resistant viruses has become a problem. To discover novel antivirals with low side effects and low risk of emergence of resistant viruses, screening for anti‐HBV compounds was performed with compound libraries of inhibitors targeting G‐protein‐coupled receptors (GPCRs). HepG2‐hNTCP C4 cells infected with HBV were treated with various GPCR inhibitors and harvested at 14 day postinfection for quantification of core protein in the first screening or relaxed circular DNA in the second screening. Finally, we identified a cannabinoid receptor 1 inhibitor, rimonabant, as a candidate showing anti‐HBV effect. In HepG2‐hNTCP C4 cells, treatment with rimonabant suppressed HBV propagation at the viral RNA transcription step but had no effect on entry or covalently closed circular DNA level. The values of half maximal inhibitory concentration, half maximal effective concentration, and selectivity index of rimonabant in primary human hepatocyte (PHH) are 2.77 μm, 40.4 μm, and 14.6, respectively. Transcriptome analysis of rimonabant‐treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of hepatocyte nuclear factor 4α (HNF4α), which is known to stimulate viral RNA synthesis, was depressed. By treatment of PHH with rimonabant, the expression level of HNF4α protein and the production of the messenger RNAs (mRNAs) of downstream factors promoted by HNF4α were reduced while the amount of HNF4α mRNA was not altered. These results suggest that treatment with rimonabant suppresses HBV propagation through the inhibition of HNF4α activity. [ABSTRACT FROM AUTHOR]

Approximately 2% of healthy persons are infected with human pegivirus (HPgV). HPgV is transmitted via vertical, sexual, and blood‐borne routes. Recently, the association of HPgV infection with the risk of lymphoma was reported. Here, we examined the prevalence of chronic HPgV infection in liver transplantation (LT) recipients and patients with hepatectomy and the influence of HPgV infection after LT on clinical and perioperative factors. We enrolled 313 LT recipients and 187 patients with hepatectomy who received care at the Kyusyu University Hospital between May 1997 and September 2017. Of the 313 recipients and 187 patients enrolled in this study, 44 recipients (14.1%) and 2 patients (1.1%) had HPgV viremia, respectively. There was no significant association between HPgV infection and LT outcomes. Interestingly, one recipient was infected with HPgV during the peritransplant period, which was likely transmitted via blood transfusion because HPgV RNA was detected from the blood bag transfused to the recipient during LT. We reviewed the available literature on the prevalence HPgV infections in other organ‐transplanted patients and whether they impacted clinical outcomes. They also had the higher prevalence of HPgV infection, while it appears to be of low or no consequences. In addition, HPgV infection induced the upregulation of interferon‐stimulated gene (ISG) expression in peripheral blood mononuclear cells. LT recipients had higher HPgV viremia compared to patients with hepatectomy. Although HPgV infection was not associated with LT‐related outcomes, it induced ISG expression in recipients. Highlight: HPgV infection induced the upregulation of interferon‐stimulated gene (ISG) expression in peripheral blood mononuclear cells. [ABSTRACT FROM AUTHOR]

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population., (© 2024 The Author(s). Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd.)