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Porcine deltacoronavirus (PDCoV) is an emerging infectious disease of swine with zoonotic potential. Phylogenetic analysis suggests that PDCoV originated recently from a host-switching event between birds and mammals. Little is known about how PDCoV interacts with its differing hosts. Human-derived cell lines are susceptible to PDCoV infection. Herein, we compare the gene expression profiles of an established host swine cells to potential emerging host human cells after infection with PDCoV. Cell lines derived from intestinal lineages were used to reproduce the primary sites of viral infection in the host. Porcine intestinal epithelial cells (IPEC-J2) and human intestinal epithelial cells (HIEC) were infected with PDCoV. RNA-sequencing was performed on total RNA extracted from infected cells. Human cells exhibited a more pronounced response to PDCoV infection in comparison to porcine cells with more differentially expressed genes (DEGs) in human, 7486, in comparison to pig cells, 1134. On the transcriptional level, the adoptive host human cells exhibited more DEGs in response to PDCoV infection in comparison to the primary pig host cells, where different types of cytokines can control PDCoV replication and virus production. Key immune-associated DEGs and signaling pathways are shared between human and pig cells during PDCoV infection. These included genes related to the NF-kappa-B transcription factor family, the interferon (IFN) family, the protein-kinase family, and signaling pathways such as the apoptosis signaling pathway, JAK-STAT signaling pathway, inflammation/cytokine–cytokine receptor signaling pathway. MAP4K4 was unique in up-regulated DEGs in humans in the apoptosis signaling pathway. While similarities exist between human and pig cells in many pathways, our research suggests that the adaptation of PDCoV to the porcine host required the ability to down-regulate many response pathways including the interferon pathway. Our findings provide an important foundation that contributes to an understanding of the mechanisms of PDCoV infection across different hosts. To our knowledge, this is the first report of transcriptome analysis of human cells infected by PDCoV.
Diana Cruz-Pulido; Patricia A. Boley; Wilberforce Zachary Ouma; Moyasar Alhamo; Linda J. Saif; Scott P. Kenney. Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells after Porcine Deltacoronavirus Infection. Viruses 2021, 13, 292 .
AMA StyleDiana Cruz-Pulido, Patricia A. Boley, Wilberforce Zachary Ouma, Moyasar Alhamo, Linda J. Saif, Scott P. Kenney. Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells after Porcine Deltacoronavirus Infection. Viruses. 2021; 13 (2):292.
Chicago/Turabian StyleDiana Cruz-Pulido; Patricia A. Boley; Wilberforce Zachary Ouma; Moyasar Alhamo; Linda J. Saif; Scott P. Kenney. 2021. "Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells after Porcine Deltacoronavirus Infection." Viruses 13, no. 2: 292.
Hepatitis E virus (HEV) can account for up to a 30% mortality rate in pregnant women, with highest incidences reported for genotype 1 (gt1) HEV. Reasons contributing to adverse maternal-fetal outcome during pregnancy in HEV-infected pregnant women remain elusive in part due to the lack of a robust tissue culture model for some strains. Open reading frame (ORF4) was discovered overlapping ORF1 in gt1 HEV whose protein expression is regulated via an IRES-like RNA element. To experimentally determine whether gt3 HEV contains an ORF4-like gt1, gt1 and gt3 sequence comparisons were performed between the gt1 and the homologous gt3 sequence. To assess whether ORF4 protein could enhance gt3 replication, Huh7 cell lines constitutively expressing ORF4 were created and used to assess the replication of the Kernow-C1 gt3 and sar55 gt1 HEV. Virus stocks from transfected Huh7 cells with or without ORF4 were harvested and infectivity assessed via infection of HepG2/C3A cells. We also studied the replication of gt1 HEV in the ORF4-expressing tunicamycin-treated cell line. To directly show that HEV transcripts have productively replicated in the target cells, we assessed events at the single-cell level using indirect immunofluorescence and flow cytometry. Despite not naturally encoding ORF4, replication of gt3 HEV was enhanced by the presence of gt1 ORF4 protein. These results suggest that the function of ORF4 protein from gt1 HEV is transferrable, enhancing the replication of gt3 HEV. ORF4 may be utilized to enhance replication of difficult to propagate HEV genotypes in cell culture. IMPORTANCE: HEV is a leading cause of acute viral hepatitis (AVH) around the world. The virus is a threat to pregnant women, particularly during the second and third trimester of pregnancy. The factors enhancing virulence to pregnant populations are understudied. Additionally, field strains of HEV remain difficult to culture in vitro. ORF4 was recently discovered in gt1 HEV and is purported to play a role in pregnancy related pathology and enhanced replication. We present evidence that ORF4 protein provided in trans enhances the viral replication of gt3 HEV even though it does not encode ORF4 naturally in its genome. These data will aid in the development of cell lines capable of supporting replication of non-cell culture adapted HEV field strains, allowing viral titers sufficient for studying these strains in vitro. Furthermore, development of gt1/gt3 ORF4 chimeric virus may shed light on the role that ORF4 plays during pregnancy.
Kush K. Yadav; Patricia A. Boley; Zachary Fritts; Scott P. Kenney. Ectopic Expression of Genotype 1 Hepatitis E Virus ORF4 Increases Genotype 3 HEV Viral Replication in Cell Culture. Viruses 2021, 13, 75 .
AMA StyleKush K. Yadav, Patricia A. Boley, Zachary Fritts, Scott P. Kenney. Ectopic Expression of Genotype 1 Hepatitis E Virus ORF4 Increases Genotype 3 HEV Viral Replication in Cell Culture. Viruses. 2021; 13 (1):75.
Chicago/Turabian StyleKush K. Yadav; Patricia A. Boley; Zachary Fritts; Scott P. Kenney. 2021. "Ectopic Expression of Genotype 1 Hepatitis E Virus ORF4 Increases Genotype 3 HEV Viral Replication in Cell Culture." Viruses 13, no. 1: 75.
Coronaviruses (CoVs) comprise a large group of positive stranded RNA viruses that infect a diverse host range including birds and mammals. Infection with CoVs typically presents as mild to severe respiratory or enteric disease, but CoVs have the potential to cause significant morbidity or mortality in highly susceptible age groups. CoVs have exhibited a penchant for jumping species barriers throughout history with devastating effects. The emergence of highly pathogenic or infectious CoVs in humans over the past 20 years, including severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and most recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underscores the significant threat that CoV spillovers pose to humans. Similar to the emergence of SARS-CoV-2, CoVs have been devastating to commercial animal production over the past century, including infectious bronchitis virus in poultry and bovine CoV, as well as the emergence and reemergence of multiple CoVs in swine including transmissible gastroenteritis virus, porcine epidemic diarrhea virus, and porcine deltacoronavirus. These naturally occurring animal CoV infections provide important examples for understanding CoV disease as many animal CoVs have complex pathogenesis similar to SARS-CoV-2 and can shed light on the ongoing SARS-CoV-2 outbreak. We provide an overview and update regarding selected existing animal CoVs and their primary host species, diseases caused by CoVs, how CoVs jump species, whether these CoVs pose an outbreak risk or risk to humans, and how we can mitigate these risks.
Scott P. Kenney; Qiuhong Wang; Anastasia Vlasova; Kwonil Jung; Linda Saif. Naturally Occurring Animal Coronaviruses as Models for Studying Highly Pathogenic Human Coronaviral Disease. Veterinary Pathology 2020, 58, 438 -452.
AMA StyleScott P. Kenney, Qiuhong Wang, Anastasia Vlasova, Kwonil Jung, Linda Saif. Naturally Occurring Animal Coronaviruses as Models for Studying Highly Pathogenic Human Coronaviral Disease. Veterinary Pathology. 2020; 58 (3):438-452.
Chicago/Turabian StyleScott P. Kenney; Qiuhong Wang; Anastasia Vlasova; Kwonil Jung; Linda Saif. 2020. "Naturally Occurring Animal Coronaviruses as Models for Studying Highly Pathogenic Human Coronaviral Disease." Veterinary Pathology 58, no. 3: 438-452.
A pneumonia outbreak with unknown etiology was reported in Wuhan, Hubei province, China, in December 2019, associated with the Huanan Seafood Wholesale Market. The causative agent of the outbreak was identified by the WHO as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), producing the disease named coronavirus disease-2019 (COVID-19). The virus is closely related (96.3%) to bat coronavirus RaTG13, based on phylogenetic analysis. Human-to-human transmission has been confirmed even from asymptomatic carriers. The virus has spread to at least 200 countries, and more than 1,700,000 confirmed cases and 111,600 deaths have been recorded, with massive global increases in the number of cases daily. Therefore, the WHO has declared COVID-19 a pandemic. The disease is characterized by fever, dry cough, and chest pain with pneumonia in severe cases. In the beginning, the world public health authorities tried to eradicate the disease in China through quarantine but are now transitioning to prevention strategies worldwide to delay its spread. To date, there are no available vaccines or specific therapeutic drugs to treat the virus. There are many knowledge gaps about the newly emerged SARS-CoV-2, leading to misinformation. Therefore, in this review, we provide recent information about the COVID-19 pandemic. This review also provides insights for the control of pathogenic infections in humans such as SARS-CoV-2 infection and future spillovers.
Yosra A. Helmy; Mohamed Fawzy; Ahmed Elaswad; Ahmed Sobieh; Scott P. Kenney; Awad A. Shehata. The COVID-19 Pandemic: A Comprehensive Review of Taxonomy, Genetics, Epidemiology, Diagnosis, Treatment, and Control. Journal of Clinical Medicine 2020, 9, 1225 .
AMA StyleYosra A. Helmy, Mohamed Fawzy, Ahmed Elaswad, Ahmed Sobieh, Scott P. Kenney, Awad A. Shehata. The COVID-19 Pandemic: A Comprehensive Review of Taxonomy, Genetics, Epidemiology, Diagnosis, Treatment, and Control. Journal of Clinical Medicine. 2020; 9 (4):1225.
Chicago/Turabian StyleYosra A. Helmy; Mohamed Fawzy; Ahmed Elaswad; Ahmed Sobieh; Scott P. Kenney; Awad A. Shehata. 2020. "The COVID-19 Pandemic: A Comprehensive Review of Taxonomy, Genetics, Epidemiology, Diagnosis, Treatment, and Control." Journal of Clinical Medicine 9, no. 4: 1225.
Coronaviruses cause respiratory and gastrointestinal diseases in diverse host species. Deltacoronaviruses (DCoVs) have been identified in various songbird species and in leopard cats in China. In 2009, porcine deltacoronavirus (PDCoV) was detected in fecal samples from pigs in Asia, but its etiologic role was not identified until 2014, when it caused major diarrhea outbreaks in swine in the United States. Studies have shown that PDCoV uses a conserved region of the aminopeptidase N protein to infect cell lines derived from multiple species, including humans, pigs, and chickens. Because PDCoV is a potential zoonotic pathogen, investigations of its prevalence in humans and its contribution to human disease continue. We report experimental PDCoV infection and subsequent transmission among poultry. In PDCoV-inoculated chicks and turkey poults, we observed diarrhea, persistent viral RNA titers from cloacal and tracheal samples, PDCoV-specific serum IgY antibody responses, and antigen-positive cells from intestines.
Patricia A. Boley; Moyasar A. Alhamo; Geoffrey Lossie; Kush Kumar Yadav; Marcia Vasquez-Lee; Linda J. Saif; Scott P. Kenney. Porcine Deltacoronavirus Infection and Transmission in Poultry, United States1. Emerging Infectious Diseases 2020, 26, 255 -265.
AMA StylePatricia A. Boley, Moyasar A. Alhamo, Geoffrey Lossie, Kush Kumar Yadav, Marcia Vasquez-Lee, Linda J. Saif, Scott P. Kenney. Porcine Deltacoronavirus Infection and Transmission in Poultry, United States1. Emerging Infectious Diseases. 2020; 26 (2):255-265.
Chicago/Turabian StylePatricia A. Boley; Moyasar A. Alhamo; Geoffrey Lossie; Kush Kumar Yadav; Marcia Vasquez-Lee; Linda J. Saif; Scott P. Kenney. 2020. "Porcine Deltacoronavirus Infection and Transmission in Poultry, United States1." Emerging Infectious Diseases 26, no. 2: 255-265.
Hepatitis E virus (HEV) is an emerging zoonotic pathogen transmitting both human to human via the fecal oral route and from animals to humans through feces, direct contact, and consumption of contaminated meat products. Understanding the host range of the virus is critical for determining where potential threats to human health may be emerging from and where potential reservoirs for viral persistence in the environment may be hiding. Initially thought to be a human specific disease endemic to developing countries, the identification of swine as a primary host for genotypes 3 and 4 HEV in industrialized countries has begun a long journey of discovering novel strains of HEV and their animal hosts. As we continue identifying new strains of HEV in disparate animal species, it is becoming abundantly clear that HEV has a broad host range and many of these HEV strains can cross between differing animal species. These cross-species transmitting strains pose many unique challenges to human health as they are often unrecognized as sources of viral transmission.
Scott P Kenney. The Current Host Range of Hepatitis E Viruses. Viruses 2019, 11, 452 .
AMA StyleScott P Kenney. The Current Host Range of Hepatitis E Viruses. Viruses. 2019; 11 (5):452.
Chicago/Turabian StyleScott P Kenney. 2019. "The Current Host Range of Hepatitis E Viruses." Viruses 11, no. 5: 452.
Hepatitis E virus (HEV) is an important human pathogen that historically has been difficult to study. Limited levels of replication in vitro hindered our understanding of the viral life cycle. Sporadic and low-level virus shedding, lack of standardized detection methods, and subclinical infections made the development of animal models difficult. Better diagnostic techniques and understanding of the virus increased our ability to identify and characterize animal strains and animals that are amenable to model human-relevant infection. These advances are translating into the development of useful HEV animal models so that some of the greatest concerns associated with HEV infection, including host immunology, chronic infection, severe pregnancy mortality, and extrahepatic manifestations, can now be studied. Continued development of these animal models will be instrumental in understanding the many complex questions associated with HEV infection and for assessing therapeutics and prevention strategies to minimize HEV becoming a greater risk to the human population.
Scott P. Kenney; Xiang-Jin Meng. Hepatitis E Virus: Animal Models and Zoonosis. Annual Review of Animal Biosciences 2019, 7, 427 -448.
AMA StyleScott P. Kenney, Xiang-Jin Meng. Hepatitis E Virus: Animal Models and Zoonosis. Annual Review of Animal Biosciences. 2019; 7 (1):427-448.
Chicago/Turabian StyleScott P. Kenney; Xiang-Jin Meng. 2019. "Hepatitis E Virus: Animal Models and Zoonosis." Annual Review of Animal Biosciences 7, no. 1: 427-448.
Hepatitis E virus (HEV) possesses many of the features of other positive-stranded RNA viruses but also adds HEV-specific nuances, making its virus–host interactions unique. Slow virus replication kinetics and fastidious growth conditions, coupled with the historical lack of an efficient cell culture system to propagate the virus, have left many gaps in our understanding of its structure and replication cycle. Recent advances in culturing selected strains of HEV and resolving the 3D structure of the viral capsid are filling in knowledge gaps, but HEV remains an extremely understudied pathogen. Many steps in the HEV life cycle and many aspects of HEV pathogenesis remain unknown, such as the host and viral factors that determine cross-species infection, the HEV-specific receptor(s) on host cells, what determines HEV chronicity and the ability to replicate in extrahepatic sites, and what regulates processing of the open reading frame 1 (ORF1) nonstructural polyprotein.
Scott P. Kenney; Xiang-Jin Meng. Hepatitis E Virus Genome Structure and Replication Strategy. Cold Spring Harbor Perspectives in Medicine 2018, 9, a031724 .
AMA StyleScott P. Kenney, Xiang-Jin Meng. Hepatitis E Virus Genome Structure and Replication Strategy. Cold Spring Harbor Perspectives in Medicine. 2018; 9 (1):a031724.
Chicago/Turabian StyleScott P. Kenney; Xiang-Jin Meng. 2018. "Hepatitis E Virus Genome Structure and Replication Strategy." Cold Spring Harbor Perspectives in Medicine 9, no. 1: a031724.
Porcine reproductive and respiratory syndrome virus (PRRSV) causes an economically important global swine disease, and has a complicated virus-host immunomodulation that often leads to a weak Th2 immune response and viral persistence. In this study, we identified a Src homology 3 (SH3) binding motif, PxxPxxP, that is conserved within the N protein of PRRSV strains. Subsequently, we identified five host cellular proteins [signal transducing adaptor molecule (STAM)I, TXK tyrosine kinase (TXK), protein tyrosine kinase fyn (Fyn), hematopoietic cell kinase (Hck), and cortactin] that interact with this SH3 motif. We demonstrated that binding of SH3 proteins with PRRSV N protein depends on at least one intact PxxP motif as disruption of P53 within the motif significantly reduced interaction of each of the 5 proteins. The first PxxP motif appears to be more important for STAMI-N protein interactions whereas the second PxxP motif was more important for Hck interaction. Both STAMI and Hck interactions with PRRSV N protein required an unhindered C-terminal domain as the interaction was only observed with STAMI and Hck proteins with N-terminal but not C-terminal fluorescent tags. We showed that the P56 residue within the SH3 motif is critical for virus lifecycle as mutation resulted in a loss of virus infectivity, however the P50 and P53 mutations did not abolish virus infectivity suggesting that these highly conserved proline residues within the SH3 motif may provide a selective growth advantage through interactions with the host rather than a vital functional element. These results have important implications in understanding PRRSV-host interactions.
Scott P. Kenney; Xiang-Jin Meng. An SH3 binding motif within the nucleocapsid protein of porcine reproductive and respiratory syndrome virus interacts with the host cellular signaling proteins STAMI, TXK, Fyn, Hck, and cortactin. Virus Research 2015, 204, 31 -39.
AMA StyleScott P. Kenney, Xiang-Jin Meng. An SH3 binding motif within the nucleocapsid protein of porcine reproductive and respiratory syndrome virus interacts with the host cellular signaling proteins STAMI, TXK, Fyn, Hck, and cortactin. Virus Research. 2015; 204 ():31-39.
Chicago/Turabian StyleScott P. Kenney; Xiang-Jin Meng. 2015. "An SH3 binding motif within the nucleocapsid protein of porcine reproductive and respiratory syndrome virus interacts with the host cellular signaling proteins STAMI, TXK, Fyn, Hck, and cortactin." Virus Research 204, no. : 31-39.