Genotype-specific acquisition, evolution and adaptation of characteristic mutations in hepatitis E virus

Hepatitis E virus (HEV) infection is a major cause of acute hepatitis but also provokes chronic infection in immunocompromised patients. Although the pathogenesis and treatment outcome involve complex interplay between the virus and host, the nature of adaptive responses of HEV to the host immune system remain obscure at best. In this study, we used large-scale proteomic bioinformatics to profile characteristic mutations in human HEV isolates associated to ribavirin treatment failure, chronic hepatitis, hepatic failure or altered immunoreactivity. The prevalence of specific mutations was examined in a large number of protein sequences of ORF1 and ORF2 regions of the 3 major human-derived HEV genotypes (1, 3 and 4). By analyzing potential B, CD4+ and CD8+ T cell epitopes, we found that many of these mutations overlap with the predicted epitopes and are frequently present among the 3 HEV genotypes. These overlapping mutations mediate reduced antigenicity. Finally, by delineation of diversification and evolution of the underlying epitopes, we observe that most of these variants apparently evolved earlier in genotype 1 when compared with genotypes 3 and 4. These results indicate that HEV is under substantial evolutionary pressure to develop mutations enabling evasion of the host immune response and resistance to antiviral treatment. This indicates the existence of an ongoing evolutionary arms race between human immunity, antiviral medication and HEV

Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response

Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.</p

The interplay between host innate immunity and hepatitis E virus

Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies

MDA5 against enteric viruses through induction of interferon-like response partially via the JAK-STAT cascade

Enteric viruses including hepatitis E virus (HEV), human norovirus (HuNV), and rotavirus are causing global health issues. The host interferon (IFN) response constitutes the first-line defense against viral infections. Melanoma Differentiation-Associated protein 5 (MDA5) is an important cytoplasmic receptor sensing viral infection to trigger IFN production, and on the other hand it is also an IFN-stimulated gene (ISG). In this study, we investigated the effects and mode-of-action of MDA5 on the infection of enteric viruses. We found that MDA5 potently inhibited HEV, HuNV and rotavirus replication in multiple cell models. Overexpression of MDA5 induced transcription of important antiviral ISGs through IFN-like response, without triggering of functional IFN production. Interestingly, MDA5 activates the expression and phosphorylation of STAT1, which is a central component of the JAK-STAT cascade and a hallmark of antiviral IFN response. However, genetic silencing of STAT1 or pharmacological inhibition of the JAK-STAT cascade only partially attenuated the induction of ISG transcription and the antiviral function of MDA5. Thus, we have demonstrated that MDA5 effectively inhibits HEV, HuNV and rotavirus replication through provoking a non-canonical IFN-like response, which is partially dependent on JAK-STAT cascade

PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target

Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, an

Recombinant identification, molecular classification and proposed reference genomes for hepatitis delta virus

Hepatitis delta virus (HDV), as a defective sub-virus that co-infects with hepatitis B virus, imposes an emerging global health burden. However, genetic characteristics and molecular classification of HDV remain under investigated. In this study, we have systematically retrieved and analysed a large set of HDV full-length genome sequences and identified novel recombinants. Based on phylogenetic and genetic analyses, we have established an updated classification system for HDV when recombinants were excluded. Furthermore, we have mapped the global distribution of different genotypes and subtypes. Finally, we have compiled a complete set of reference genomes for each subtype and proposed criteria for future identification of novel genotypes and subtypes. Of note, the global distribution map indicates that currently available HDV genetic data remain limited, and thus our proposed classification will likely evolve as future epidemiological data will accumulate. These results will facilitate the future research on the diagnosis, screening, epidemiology, evolution, prevention and clinical management of HDV infection

Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV

IFN-α has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for

Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids

Rotavirus (RV) primarily infects enterocytes and results in severe diarrhea, particularly in children. It is known that the host immune responses determine the outcome of viral infections. Following infections, interferons (IFNs) are produced as the first and the main anti-viral cytokines to combat the virus. Here we showed that RV predominantly induced type III IFNs (IFN-λ1), and to a less extent, type I IFNs (IFN-α and IFN-β) in human intestinal cells. However, it did not produce detectable IFN proteins and thus, was not sufficient to inhibit RV replication. In contrast, we revealed the essential roles of the basal IFN signaling in limiting RV replication by silencing STAT1, STAT2 and IRF9 genes. In addition, exogenous IFN treatment demonstrated that RV replication was able to be inhibited by all types of IFNs, both in human intestinal Caco2 cell line and in primary intestinal organoids. In these models, IFNs significantly upregulated a panel of well-known anti-viral IFN-stimulated genes (ISGs). Importantly, inhibition of the JAK-STAT cascade abrogated ISG induction and the anti-RV effects of IFNs. Thus, our study shall contribute to better understanding of the complex RV-host interactions and provide rationale for therapeutic development of IFN-based treatment against RV infection

Phylogeography and Genetic Ancestry of Tigers (Panthera tigris)

Eight traditional subspecies of tiger (Panthera tigris), of which three recently became extinct, are commonly recognized on the basis of geographic isolation and morphological characteristics. To investigate the species' evolutionary history and to establish objective methods for subspecies recognition, voucher specimens of blood, skin, hair, and/or skin biopsies from 134 tigers with verified geographic origins or heritage across the whole distribution range were examined for three molecular markers: (1) 4.0 kb of mitochondrial DNA (mtDNA) sequence; (2) allele variation in the nuclear major histocompatibility complex class II DRB gene; and (3) composite nuclear microsatellite genotypes based on 30 loci. Relatively low genetic variation with mtDNA, DRB, and microsatellite loci was found, but significant population subdivision was nonetheless apparent among five living subspecies. In addition, a distinct partition of the Indochinese subspecies P. t. corbetti into northern Indochinese and Malayan Peninsula populations was discovered. Population genetic structure would suggest recognition of six taxonomic units or subspecies: (1) Amur tiger P. t. altaica; (2) northern Indochinese tiger P. t. corbetti; (3) South China tiger P. t. amoyensis; (4) Malayan tiger P. t. jacksoni, named for the tiger conservationist Peter Jackson; (5) Sumatran tiger P. t. sumatrae; and (6) Bengal tiger P. t. tigris. The proposed South China tiger lineage is tentative due to limited sampling. The age of the most recent common ancestor for tiger mtDNA was estimated to be 72,000–108,000 y, relatively younger than some other Panthera species. A combination of population expansions, reduced gene flow, and genetic drift following the last genetic diminution, and the recent anthropogenic range contraction, have led to the distinct genetic partitions. These results provide an explicit basis for subspecies recognition and will lead to the improved management and conservation of these recently isolated but distinct geographic populations of tigers