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Numerous natural phytochemicals such as resveratrol are acknowledged as potent botanical agents in regulating immune responses. However, it is less understood whether such immunomodulatory phytochemicals are appropriate for use as direct treatments in veterinary viral diseases. In the present study, we investigated the efficacy of resveratrol in suppressing vesicular stomatitis virus (VSV) infection. Outbreaks of VSV can cause massive economic loss in poultry and livestock husbandry farming, and VSV treatment is in need of therapeutic development. We utilized a recombinant VSV that expresses green fluorescent protein (GFP) to measure viral replication in cells treated with resveratrol. Our findings revealed that resveratrol treatment affords a protective effect, shown by increased viability and reduced viral replication, as indicated by a reduction in fluorescent signals. Additionally, we found that resveratrol inhibition of VSV infection occurs via suppression of the caspase cascade. Structural analysis also indicated that resveratrol potentially interacts with the active sites of caspase-3 and -7, facilitating antiviral activity. The potential effect of resveratrol on reducing VSV infection in vitro suggests that resveratrol should be further investigated as a potential veterinary therapeutic or prophylactic agent.
Shih-Chao Lin; Xiang Zhang; Caitlin Lehman; Han-Chi Pan; Ya Wen; Shiow-Yi Chen. A Natural Botanical Product, Resveratrol, Effectively Suppresses Vesicular Stomatitis Virus Infection In Vitro. Plants 2021, 10, 1231 .
AMA StyleShih-Chao Lin, Xiang Zhang, Caitlin Lehman, Han-Chi Pan, Ya Wen, Shiow-Yi Chen. A Natural Botanical Product, Resveratrol, Effectively Suppresses Vesicular Stomatitis Virus Infection In Vitro. Plants. 2021; 10 (6):1231.
Chicago/Turabian StyleShih-Chao Lin; Xiang Zhang; Caitlin Lehman; Han-Chi Pan; Ya Wen; Shiow-Yi Chen. 2021. "A Natural Botanical Product, Resveratrol, Effectively Suppresses Vesicular Stomatitis Virus Infection In Vitro." Plants 10, no. 6: 1231.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.
Victoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses 2021, 13, 1062 .
AMA StyleVictoria Callahan, Seth Hawks, Matthew Crawford, Caitlin Lehman, Holly Morrison, Hannah Ivester, Ivan Akhrymuk, Niloufar Boghdeh, Rafaela Flor, Carla Finkielstein, Irving Allen, James Weger-Lucarelli, Nisha Duggal, Molly Hughes, Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses. 2021; 13 (6):1062.
Chicago/Turabian StyleVictoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. 2021. "The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner." Viruses 13, no. 6: 1062.
Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response (UPR) pathway. Loss of PERK prevented EGR1 induction and decreased VEEV-induced death. The results presented within show that loss of PERK in human primary astrocytes dramatically reduced VEEV and eastern equine encephalitis virus (EEEV) infectious titers by 4–5 log10. Loss of PERK also suppressed VEEV replication in primary human pericytes and human umbilical vein endothelial cells, but it had no impact on VEEV replication in transformed U87MG and 293T cells. A significant reduction in VEEV RNA levels was observed as early as 3 h post-infection, but viral entry assays indicated that the loss of PERK minimally impacted VEEV entry. In contrast, the loss of PERK resulted in a dramatic reduction in viral nonstructural protein translation and negative-strand viral RNA production. The loss of PERK also reduced the production of Rift Valley fever virus and Zika virus infectious titers. These data indicate that PERK is an essential factor for the translation of alphavirus nonstructural proteins and impacts multiple RNA viruses, making it an exciting target for antiviral development.
Bibha Dahal; Caitlin Lehman; Ivan Akhrymuk; Nicole Bracci; Lauren Panny; Michael Barrera; Nishank Bhalla; Jonathan Jacobs; Jonathan Dinman; Kylene Kehn-Hall. PERK Is Critical for Alphavirus Nonstructural Protein Translation. Viruses 2021, 13, 892 .
AMA StyleBibha Dahal, Caitlin Lehman, Ivan Akhrymuk, Nicole Bracci, Lauren Panny, Michael Barrera, Nishank Bhalla, Jonathan Jacobs, Jonathan Dinman, Kylene Kehn-Hall. PERK Is Critical for Alphavirus Nonstructural Protein Translation. Viruses. 2021; 13 (5):892.
Chicago/Turabian StyleBibha Dahal; Caitlin Lehman; Ivan Akhrymuk; Nicole Bracci; Lauren Panny; Michael Barrera; Nishank Bhalla; Jonathan Jacobs; Jonathan Dinman; Kylene Kehn-Hall. 2021. "PERK Is Critical for Alphavirus Nonstructural Protein Translation." Viruses 13, no. 5: 892.
The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Therefore, we attempted to explore whether it exerts any antiviral activity against VEEV. In this study, we utilized green fluorescent protein (GFP)- and luciferase-encoding recombinant VEEV to determine the cytotoxicity and antiviral efficacy via luciferase reporter assays, flow cytometry, and immunofluorescent assays. Our results indicate that resveratrol treatment is capable of inhibiting VEEV replication, resulting in increased viability of Vero and U87MG cells as well as reduced virion production and viral RNA contents within host cells for at least 48 h with a single treatment. Furthermore, the suppression of apoptotic signaling adaptors, caspase-3, caspase-7, and annexin V may also be implicated in resveratrol-mediated antiviral activity. We found that decreased phosphorylation of the AKT/GSK-3 pathway, mediated by resveratrol, can be triggered during the early stages of VEEV infection, suggesting that resveratrol disrupts the viral replication cycle and consequently promotes cell survival. Finally, molecular docking and dynamics simulation studies revealed that resveratrol can directly bind to VEEV glycoproteins, which may interfere with virus attachment and entry. In conclusion, our results suggest that resveratrol exerts inhibitory activity against VEEV infection and upon further modification could be a useful compound to study in neuroprotective research and veterinary sciences.
Caitlin Lehman; Kylene Kehn-Hall; Megha Aggarwal; Nicole Bracci; Han-Chi Pan; Lauren Panny; Robert Lamb; Shih-Chao Lin. Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway. Plants 2021, 10, 346 .
AMA StyleCaitlin Lehman, Kylene Kehn-Hall, Megha Aggarwal, Nicole Bracci, Han-Chi Pan, Lauren Panny, Robert Lamb, Shih-Chao Lin. Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway. Plants. 2021; 10 (2):346.
Chicago/Turabian StyleCaitlin Lehman; Kylene Kehn-Hall; Megha Aggarwal; Nicole Bracci; Han-Chi Pan; Lauren Panny; Robert Lamb; Shih-Chao Lin. 2021. "Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway." Plants 10, no. 2: 346.
In light of the COVID-19 pandemic, studies that work to understand SARS-CoV-2 are urgently needed. In turn, the less severe human coronaviruses such as HCoV-229E and OC43 are drawing newfound attention. These less severe coronaviruses can be used as a model to facilitate our understanding of the host immune response to coronavirus infection. SARS-CoV-2 must be handled under biosafety level 3 (BSL-3) conditions. Therefore, HCoV-229E and OC43, which can be handled at BSL-2 provide an alternative to SARS-CoV-2 for preclinical screening and designing of antivirals. However, to date, there is no published effective and efficient method to titrate HCoVs other than expensive indirect immunostaining. Here we present an improved approach using an agarose-based conventional plaque assay to titrate HCoV 229E and OC43 with mink lung epithelial cells, Mv1Lu. Our results indicate that titration of HCoV 229E and OC43 with Mv1Lu is consistent and reproducible. The titers produced are also comparable to those produced using human rhabdomyosarcoma (RD) cells. More importantly, Mv1Lu cells display a higher tolerance for cell-cell contact stress, decreased temperature sensitivity, and a faster growth rate. We believe that our improved low-cost plaque assay can serve as an easy tool for researchers conducting HCoV research.
Nicole Bracci; Han-Chi Pan; Caitlin Lehman; Kylene Kehn-Hall; Shih-Chao Lin. Improved plaque assay for human coronaviruses 229E and OC43. PeerJ 2020, 8, e10639 .
AMA StyleNicole Bracci, Han-Chi Pan, Caitlin Lehman, Kylene Kehn-Hall, Shih-Chao Lin. Improved plaque assay for human coronaviruses 229E and OC43. PeerJ. 2020; 8 ():e10639.
Chicago/Turabian StyleNicole Bracci; Han-Chi Pan; Caitlin Lehman; Kylene Kehn-Hall; Shih-Chao Lin. 2020. "Improved plaque assay for human coronaviruses 229E and OC43." PeerJ 8, no. : e10639.
The coronavirus disease 2019 (COVID-19) has created an acute worldwide demand for sustained broadband pathogen suppression in households, hospitals, and public spaces. The US recently passed a new sad milestone of 500,000 deaths due to COVID-19, the highest rate anywhere in the world. In response, we have created a rapid-acting, self-sterilizing PPE configurations capable of killing SARS-CoV-2 and other microbes in seconds. The highly active material destroys pathogens faster than any conventional copper configuration. The material maintains its antimicrobial efficacy over sustained use and is shelf stable. We have performed rigorous testing in accordance with guidelines from U.S. governing authorities and believe that the material could offer broad spectrum, non-selective defense against most microbes via integration into masks and other protective equipment.
Alfred A. Zinn; Mina Izadjoo; Hosan Kim; Kylene Kehn-Hall; Caitlin Lehman; Rachel L. Brody; Robert R. Roth; Augustin Vega; Khanh K. Nguyen; Nhi T. Ngo; Hannah T. Zinn; Lauren Panny; Rafaela Flor; Nicholas Antonopoulos; Randall M. Stoltenberg. Rapidly self-sterilizing PPE capable of 99.9% SARS-CoV-2 deactivation in 30 seconds. 2020, 1 .
AMA StyleAlfred A. Zinn, Mina Izadjoo, Hosan Kim, Kylene Kehn-Hall, Caitlin Lehman, Rachel L. Brody, Robert R. Roth, Augustin Vega, Khanh K. Nguyen, Nhi T. Ngo, Hannah T. Zinn, Lauren Panny, Rafaela Flor, Nicholas Antonopoulos, Randall M. Stoltenberg. Rapidly self-sterilizing PPE capable of 99.9% SARS-CoV-2 deactivation in 30 seconds. . 2020; ():1.
Chicago/Turabian StyleAlfred A. Zinn; Mina Izadjoo; Hosan Kim; Kylene Kehn-Hall; Caitlin Lehman; Rachel L. Brody; Robert R. Roth; Augustin Vega; Khanh K. Nguyen; Nhi T. Ngo; Hannah T. Zinn; Lauren Panny; Rafaela Flor; Nicholas Antonopoulos; Randall M. Stoltenberg. 2020. "Rapidly self-sterilizing PPE capable of 99.9% SARS-CoV-2 deactivation in 30 seconds." , no. : 1.
Crotonoside, a guanosine analog originally isolated from Croton tiglium, is reported to be a potent tyrosine kinase inhibitor with immunosuppressive effects on immune cells. Due to its potential immunotherapeutic effects, we aimed to evaluate the anti-arthritic activity of crotonoside and explore its immunomodulatory properties in alleviating the severity of arthritic symptoms. To this end, we implemented the treatment of crotonoside on collagen-induced arthritic (CIA) DBA/1 mice and investigated its underlying mechanisms towards pathogenic dendritic cells (DCs). Our results suggest that crotonoside treatment remarkably improved clinical arthritic symptoms in this CIA mouse model as indicated by decreased pro-inflammatory cytokine production in the serum and suppressed expression of co-stimulatory molecules, CD40, CD80, and MHC class II, on CD11c+ DCs from the CIA mouse spleens. Additionally, crotonoside treatment significantly reduced the infiltration of CD11c+ DCs into the synovial tissues. Our in vitro study further demonstrated that bone marrow-derived DCs (BMDCs) exhibited lower yield in numbers and expressed lower levels of CD40, CD80, and MHC-II when incubated with crotonoside. Furthermore, LPS-stimulated mature DCs exhibited limited capability to prime antigen-specific CD4+ and T-cell proliferation, cytokine secretions, and co-stimulatory molecule expressions when treated with crotonoside. Our pioneer study highlights the immunotherapeutic role of crotonoside in the alleviation of the CIA via modulation of pathogenic DCs, thus creating possible applications of crotonoside as an immunosuppressive agent that could be utilized and further explored in treating autoimmune disorders in the future.
Shih-Chao Lin; Chi-Chien Lin; Shiming Li; Wan-Yi Lin; Caitlin W. Lehman; Nicole R. Bracci; Sen-Wei Tsai. Alleviation of Collagen-Induced Arthritis by Crotonoside through Modulation of Dendritic Cell Differentiation and Activation. Plants 2020, 9, 1535 .
AMA StyleShih-Chao Lin, Chi-Chien Lin, Shiming Li, Wan-Yi Lin, Caitlin W. Lehman, Nicole R. Bracci, Sen-Wei Tsai. Alleviation of Collagen-Induced Arthritis by Crotonoside through Modulation of Dendritic Cell Differentiation and Activation. Plants. 2020; 9 (11):1535.
Chicago/Turabian StyleShih-Chao Lin; Chi-Chien Lin; Shiming Li; Wan-Yi Lin; Caitlin W. Lehman; Nicole R. Bracci; Sen-Wei Tsai. 2020. "Alleviation of Collagen-Induced Arthritis by Crotonoside through Modulation of Dendritic Cell Differentiation and Activation." Plants 9, no. 11: 1535.
Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the COVID-19 pandemic, remains viable and therefore potentially infectious on several materials. One strategy to discourage the fomite-mediated spread of COVID-19 is the development of materials whose surface chemistry can spontaneously inactivate SARS-CoV-2. Silicon nitride (Si3N4), a material used in spine fusion surgery, is one such candidate because it has been shown to inactivate several bacterial species and viral strains. This study hypothesized that contact with Si3N4would inactivate SARS-CoV-2, while mammalian cells would remain unaffected. Materials SARS-CoV-2 virions (2×104PFU/mL diluted in growth media) were exposed to 5, 10, 15, and 20% (w/v) of an aqueous suspension of sintered Si3N4particles for durations of 1, 5, and 10 minutes, respectively. Before exposure to the virus, cytotoxicity testing of Si3N4alone was assessed in Vero cells at 24 and 48 hour post-exposure times. Following each exposure to Si3N4, the remaining infectious virus was quantitated by plaque assay. Results Vero cell viability increased at 5% and 10% (w/v) concentrations of Si3N4at exposure times up to 10 minutes, and there was only minimal impact on cell health and viability up to 20% (w/v). However, the SARS-CoV-2 titers were markedly reduced when exposed to all concentrations of Si3N4; the reduction in viral titers was between 85% - 99.6%, depending on the dose and duration of exposure. Conclusions Si3N4was non-toxic to the Vero cells while showing strong antiviral activity against SARS-CoV-2. The viricidal effect increased with increasing concentrations of Si3N4and longer duration of exposure. Surface treatment strategies based on Si3N4may offer novel methods to discourage SARS-CoV-2 persistence and infectivity on surfaces and discourage the spread of COVID-19.
Caitlin W. Lehman; Rafaela Flur; Kylene Kehn-Hall; Bryan J. McEntire; B. Sonny Bal; Ryan M. Bock. Silicon Nitride Inactivates SARS-CoV-2in vitro. 2020, 1 .
AMA StyleCaitlin W. Lehman, Rafaela Flur, Kylene Kehn-Hall, Bryan J. McEntire, B. Sonny Bal, Ryan M. Bock. Silicon Nitride Inactivates SARS-CoV-2in vitro. . 2020; ():1.
Chicago/Turabian StyleCaitlin W. Lehman; Rafaela Flur; Kylene Kehn-Hall; Bryan J. McEntire; B. Sonny Bal; Ryan M. Bock. 2020. "Silicon Nitride Inactivates SARS-CoV-2in vitro." , no. : 1.