@article{zhu_scholle_kisthardt_xie_2022, title={<p>Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E</p>}, volume={571}, ISSN={["1089-862X"]}, DOI={10.1016/j.virol.2022.04.005}, abstractNote={Since December 2019, the deadly novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 pandemic. To date, vaccines are available in the developed countries to prevent the infection of this virus; however, medicines are necessary to help control COVID-19. Human coronavirus 229E (HCoV-229E) causes the common cold. The main protease (Mpro) is an essential enzyme required for the multiplication of these two viruses in the host cells, and thus is an appropriate candidate to screen potential medicinal compounds. Flavonols and dihydroflavonols are two groups of plant flavonoids. In this study, we report docking simulation with two Mpro enzymes and five flavonols and three dihydroflavonols, in vitro inhibition of the SARS-CoV-2 Mpro, and in vitro inhibition of the HCoV 229E replication. The docking simulation results predicted that (+)-dihydrokaempferol, (+)- dihydroquercetin, (+)-dihydromyricetin, kaempferol, quercetin, myricentin, isoquercitrin, and rutin could bind to at least two subsites (S1, S1', S2, and S4) in the binding pocket and inhibit the activity of SARS-CoV-2 Mpro. Their affinity scores ranged from -8.8 to -7.4 (kcal/mol). Likewise, these compounds were predicted to bind and inhibit the HCoV-229E Mpro activity with affinity scores ranging from -7.1 to -7.8 (kcal/mol). In vitro inhibition assays showed that seven available compounds effectively inhibited the SARS-CoV-2 Mpro activity and their IC50 values ranged from 0.125 to 12.9 μM. Five compounds inhibited the replication of HCoV-229E in Huh-7 cells. These findings indicate that these antioxidative flavonols and dihydroflavonols are promising candidates for curbing the two viruses.}, journal={VIROLOGY}, author={Zhu, Yue and Scholle, Frank and Kisthardt, Samantha C. and Xie, De-Yu}, year={2022}, month={Jun}, pages={21–33} }
 @article{wang_amanah_ali_payne_kisthardt_scholle_ormond_mathur_gluck_2022, title={A standardized procedure for quantitative evaluation of residual viral activity on antiviral treated textiles}, volume={11}, ISSN={["1746-7748"]}, url={https://doi.org/10.1177/00405175221126532}, DOI={10.1177/00405175221126532}, abstractNote={The SARS-CoV-2 pandemic has increased the demand for antiviral technologies to mitigate or prevent the risk of viral transmission. Antiviral treated textiles have the potential to save lives, especially in healthcare settings that rely on reusable patient-care textiles and personal protective equipment. Currently, little is known about the role of textiles in cross-contamination and pathogen transmission, despite the wealth of information on hard surfaces and fomites harboring viruses that remain viable in certain circumstances. In addition, there is no international standard method for evaluating residual viral activity on textiles, which would allow a thorough investigation of the efficacy of antiviral textile products. Therefore, this pilot study aims to develop and refine a standardized protocol to quantitatively evaluate residual viral activity on antiviral textiles. Specifically, we focused on general textiles, such as bed linens, commonly used in healthcare settings for patient care. The Tissue Culture Infectious Dose 50 (TCID 50 ) method is frequently used to quantitatively evaluate viral infectivity on textiles, but has not been established as a standard. This procedure involves observing the cytopathic effect of a given virus on cells grown in a 96-well plate after several days of incubation to determine the infectivity titer. We used HCoV-229E and Huh-7 human liver cancer cells for this investigation. We worked to improve the TCID 50 method through variations of different steps within the protocol to attain reproducible results. Our proposed optimized hybrid protocol has shown evidence that the protocol is technically simpler and more efficient, and provides successful, consistent results. The analysis showed a significant difference between the treated fabric compared with controls.}, journal={TEXTILE RESEARCH JOURNAL}, author={Wang, Ziyu and Amanah, Alaowei Y. and Ali, Kiran M. and Payne, Lucy C. and Kisthardt, Samantha and Scholle, Frank and Ormond, R. Bryan and Mathur, Kavita and Gluck, Jessica M.}, year={2022}, month={Nov} }
 @article{mottin_caesar_brodsky_mesquita_oliveira_noske_sousa_ramos_jarmer_loh_et al._2022, title={Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins}, volume={120}, ISSN={["1090-2120"]}, DOI={10.1016/j.bioorg.2022.105649}, abstractNote={• Docking studies suggested chalcones could inhibit the ZIKV NS3 protease and NS5 polymerase. • The chalcones 4-HD, XA, and XA-E inhibited the ZIKV NS3 protease. • XA displayed inhibitory activity in an assay designed to measure the activity of the ZIKV NS5 RdRp. • The chalcones 4-HD and XA-E displayed anti-ZIKV activity and low cytotoxicity. Zika virus (ZIKV) is a dangerous human pathogen and no antiviral drugs have been approved to date. The chalcones are a group of small molecules that are found in a number of different plants, including Angelica keiskei Koidzumi, also known as ashitaba. To examine chalcone anti-ZIKV activity, three chalcones, 4-hydroxyderricin (4HD), xanthoangelol (XA), and xanthoangelol-E (XA-E), were purified from a methanol-ethyl acetate extract from A. keiskei . Molecular and ensemble docking predicted that these chalcones would establish multiple interactions with residues in the catalytic and allosteric sites of ZIKV NS2B-NS3 protease, and in the allosteric site of the NS5 RNA-dependent RNA-polymerase (RdRp). Machine learning models also predicted 4HD, XA and XA-E as potential anti-ZIKV inhibitors. Enzymatic and kinetic assays confirmed chalcone inhibition of the ZIKV NS2B-NS3 protease allosteric site with IC 50 s from 18 to 50 µM. Activity assays also revealed that XA, but not 4HD or XA-E, inhibited the allosteric site of the RdRp, with an IC 50 of 6.9 µM. Finally, we tested these chalcones for their anti-viral activity in vitro with Vero cells. 4HD and XA-E displayed anti-ZIKV activity with EC 50 values of 6.6 and 22.0 µM, respectively, while XA displayed relatively weak anti-ZIKV activity with whole cells. With their simple structures and relative ease of modification, the chalcones represent attractive candidates for hit-to-lead optimization in the search of new anti-ZIKV therapeutics.}, journal={BIOORGANIC CHEMISTRY}, author={Mottin, Melina and Caesar, Lindsay K. and Brodsky, David and Mesquita, Nathalya C. M. R. and Oliveira, Ketllyn Zagato and Noske, Gabriela Dias and Sousa, Bruna K. P. and Ramos, Paulo R. P. S. and Jarmer, Hannah and Loh, Bonnie and et al.}, year={2022}, month={Mar} }
 @article{frias-de-diego_gilbertie_scholle_dejarnette_crisci_2022, title={Effect of BIO-PLYTM, a Platelet-Rich Plasma Derived Biologic on PRRSV-2-Infected Macrophages}, volume={14}, ISSN={1999-4915}, url={http://dx.doi.org/10.3390/v14122666}, DOI={10.3390/v14122666}, abstractNote={Porcine Reproductive and Respiratory Syndrome (PRRS) is the one of the most devastating diseases impacting the swine industry worldwide. Control and prevention methods rely on biosafety measures and vaccination. As an RNA virus with a high rate of mutation, vaccines are only partially effective against circulating and newly emerging strains. To reduce the burden of this disease, research on alternative control methods is needed. Here, we assess the in vitro antiviral effect of a novel platelet-rich plasma-derived biologic termed BIO-PLYTM (for the BIOactive fraction of Platelet-rich plasma LYsate) from both swine and equine origin. Our results show that BIO-PLYTM significantly reduces the amount of PRRSV viral load determined by RT-qPCR and the number of infectious viral particles measured by TCID50 in infected porcine alveolar and parenchymal macrophages. This study also showed limited toxicity of BIO-PLYTM in vitro and aspects of its immunomodulatory capacity evaluating the regulation of reactive oxygen species and cytokines production in infected cells. Finally, this study presents promising data on the effect of BIO-PLYTM on other RNA viruses such as human A influenza viruses and coronavirus.}, number={12}, journal={Viruses}, publisher={MDPI AG}, author={Frias-De-Diego, Alba and Gilbertie, Jessica M. and Scholle, Frank and Dejarnette, Sarah and Crisci, Elisa}, year={2022}, month={Nov}, pages={2666} }
 @article{wang_sun_vallabhuneni_pawlowski_vahabi_nellenbach_brown_scholle_zhao_kota_2022, title={On-demand, remote and lossless manipulation of biofluid droplets}, ISSN={["2051-6355"]}, DOI={10.1039/d2mh00695b}, abstractNote={The recent global outbreaks of epidemics and pandemics have shown us that we are severely under-prepared to cope with infectious agents. Exposure to infectious agents present in biofluids (e.g., blood, saliva, urine etc.) poses a severe risk to clinical laboratory personnel and healthcare workers, resulting in hundreds of millions of hospital-acquired and laboratory-acquired infections annually. Novel technologies that can minimize human exposure through remote and automated handling of infectious biofluids will mitigate such risk. In this work, we present biofluid manipulators, which allow on-demand, remote and lossless manipulation of virtually any liquid droplet. Our manipulators are designed by integrating thermo-responsive soft actuators with superomniphobic surfaces. Utilizing our manipulators, we demonstrate on-demand, remote and lossless manipulation of biofluid droplets. We envision that our biofluid manipulators will not only reduce manual operations and minimize exposure to infectious agents, but also pave the way for developing inexpensive, simple and portable robotic systems, which can allow point-of-care operations, particularly in developing nations.}, journal={MATERIALS HORIZONS}, author={Wang, Wei and Sun, Jiefeng and Vallabhuneni, Sravanthi and Pawlowski, Benjamin and Vahabi, Hamed and Nellenbach, Kimberly and Brown, Ashley C. and Scholle, Frank and Zhao, Jianguo and Kota, Arun K.}, year={2022}, month={Sep} }
 @article{puhl_gomes_damasceno_fritch_levi_johnson_scholle_premkumar_hurst_lee-montiel_et al._2022, title={Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice}, volume={7}, ISSN={["2470-1343"]}, DOI={10.1021/acsomega.2c02794}, abstractNote={The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC50 0.79 μM) while also showing a reduction of >3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1β caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.}, number={36}, journal={ACS OMEGA}, author={Puhl, Ana C. and Gomes, Giovanni F. and Damasceno, Samara and Fritch, Ethan J. and Levi, James A. and Johnson, Nicole J. and Scholle, Frank and Premkumar, Lakshmanane and Hurst, Brett L. and Lee-Montiel, Felipe and et al.}, year={2022}, month={Sep}, pages={31935–31944} }
 @article{kwon_cheeseman_frias‐de‐diego_hong_yang_jung_yin_murdoch_scholle_crook_et al._2021, title={A Liquid Metal Mediated Metallic Coating for Antimicrobial and Antiviral Fabrics}, volume={33}, ISSN={0935-9648 1521-4095}, url={http://dx.doi.org/10.1002/adma.202104298}, DOI={10.1002/adma.202104298}, abstractNote={Abstract Fabrics are widely used in hospitals and many other settings for bedding, clothing, and face masks; however, microbial pathogens can survive on surfaces for a long time, leading to microbial transmission. Coatings of metallic particles on fabrics have been widely used to eradicate pathogens. However, current metal particle coating technologies encounter numerous issues such as nonuniformity, processing complexity, and poor adhesion. To overcome these issues, an easy‐to‐control and straightforward method is reported to coat a wide range of fabrics by using gallium liquid metal (LM) particles to facilitate the deposition of liquid metal copper alloy (LMCu) particles. Gallium particles coated on the fabric provide nucleation sites for forming LMCu particles at room temperature via galvanic replacement of Cu 2+ ions. The LM helps promote strong adhesion of the particles to the fabric. The presence of the LMCu particles can eradicate over 99% of pathogens (including bacteria, fungi, and viruses) within 5 min, which is significantly more effective than control samples coated with only Cu. The coating remains effective over multiple usages and against contaminated droplets and aerosols, such as those encountered in facemasks. This facile coating method is promising for generating robust antibacterial, antifungal, and antiviral fabrics and surfaces.}, number={45}, journal={Advanced Materials}, publisher={Wiley}, author={Kwon, Ki Yoon and Cheeseman, Samuel and Frias‐De‐Diego, Alba and Hong, Haeleen and Yang, Jiayi and Jung, Woojin and Yin, Hong and Murdoch, Billy J. and Scholle, Frank and Crook, Nathan and et al.}, year={2021}, month={Sep}, pages={2104298} }
 @article{peddinti_downs_yan_smith_ghiladi_mhetar_tocchetto_griffiths_scholle_spontak_2021, title={Rapid and Repetitive Inactivation of SARS-CoV-2 and Human Coronavirus on Self-Disinfecting Anionic Polymers}, volume={8}, ISSN={["2198-3844"]}, DOI={10.1002/advs.202003503}, abstractNote={Abstract While the ongoing COVID‐19 pandemic affirms an urgent global need for effective vaccines as second and third infection waves are spreading worldwide and generating new mutant virus strains, it has also revealed the importance of mitigating the transmission of SARS‐CoV‐2 through the introduction of restrictive social practices. Here, it is demonstrated that an architecturally‐ and chemically‐diverse family of nanostructured anionic polymers yield a rapid and continuous disinfecting alternative to inactivate coronaviruses and prevent their transmission from contact with contaminated surfaces. Operating on a dramatic pH‐drop mechanism along the polymer/pathogen interface, polymers of this archetype inactivate the SARS‐CoV‐2 virus, as well as a human coronavirus surrogate (HCoV‐229E), to the minimum detection limit within minutes. Application of these anionic polymers to frequently touched surfaces in medical, educational, and public‐transportation facilities, or personal protection equipment, can provide rapid and repetitive protection without detrimental health or environmental complications.}, number={11}, journal={ADVANCED SCIENCE}, author={Peddinti, Bharadwaja S. T. and Downs, Sierra N. and Yan, Jiaqi and Smith, Steven D. and Ghiladi, Reza A. and Mhetar, Vijay and Tocchetto, Roger and Griffiths, Anthony and Scholle, Frank and Spontak, Richard J.}, year={2021}, month={Jun} }
 @article{puhl_fritch_lane_tse_yount_sacramento_fintelman-rodrigues_tavella_costa_weston_et al._2021, title={Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms}, volume={6}, ISSN={["2470-1343"]}, DOI={10.1021/acsomega.0c05996}, abstractNote={Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with Kd values of 339 and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic.}, number={11}, journal={ACS OMEGA}, author={Puhl, Ana C. and Fritch, Ethan J. and Lane, Thomas R. and Tse, Longping V and Yount, Boyd L. and Sacramento, Carolina Q. and Fintelman-Rodrigues, Natalia and Tavella, Tatyana Almeida and Costa, Fabio Trindade Maranhao and Weston, Stuart and et al.}, year={2021}, month={Mar}, pages={7454–7468} }
 @article{ghareeb_peddinti_kisthardt_scholle_spontak_ghiladi_2021, title={Toward Universal Photodynamic Coatings for Infection Control}, volume={8}, ISSN={["2296-858X"]}, DOI={10.3389/fmed.2021.657837}, abstractNote={The dual threats posed by the COVID-19 pandemic and hospital-acquired infections (HAIs) have emphasized the urgent need for self-disinfecting materials for infection control. Despite their highly potent antimicrobial activity, the adoption of photoactive materials to reduce infection transmission in hospitals and related healthcare facilities has been severely hampered by the lack of scalable and cost-effective manufacturing, in which case high-volume production methods for fabricating aPDI-based materials are needed. To address this issue here, we examined the antimicrobial efficacy of a simple bicomponent spray coating composed of the commercially-available UV-photocrosslinkable polymer N -methyl-4(4'-formyl-styryl)pyridinium methosulfate acetal poly(vinyl alcohol) (SbQ-PVA) and one of three aPDI photosensitizers (PSs): zinc-tetra(4- N -methylpyridyl)porphine (ZnTMPyP 4+ ), methylene blue (MB), and Rose Bengal (RB). We applied these photodynamic coatings, collectively termed SbQ-PVA/PS, to a variety of commercially available materials. Scanning electron microscopy (SEM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) confirmed the successful application of the coatings, while inductively coupled plasma-optical emission spectroscopy (ICP-OES) revealed a photosensitizer loading of 0.09-0.78 nmol PS/mg material. The antimicrobial efficacy of the coated materials was evaluated against methicillin-susceptible Staphylococcus aureus ATCC-29213 and human coronavirus strain HCoV-229E. Upon illumination with visible light (60 min, 400-700 nm, 65 ± 5 mW/cm 2 ), the coated materials inactivated S. aureus by 97-99.999% and HCoV-229E by 92-99.999%, depending on the material and PS employed. Photobleaching studies employing HCoV-229E demonstrated detection limit inactivation (99.999%) even after exposure for 4 weeks to indoor ambient room lighting. Taken together, these results demonstrate the potential for photodynamic SbQ-PVA/PS coatings to be universally applied to a wide range of materials for effectively reducing pathogen transmission.}, journal={FRONTIERS IN MEDICINE}, author={Ghareeb, C. Roland and Peddinti, Bharadwaja S. T. and Kisthardt, Samantha C. and Scholle, Frank and Spontak, Richard J. and Ghiladi, Reza A.}, year={2021}, month={Jul} }
 @article{peddinti_morales-gagnon_pourdeyhimi_scholle_spontak_ghiladi_2020, title={Photodynamic Coatings on Polymer Microfibers for Pathogen Inactivation: Effects of Application Method and Composition}, volume={13}, ISSN={1944-8244 1944-8252}, url={http://dx.doi.org/10.1021/acsami.0c16953}, DOI={10.1021/acsami.0c16953}, abstractNote={A substantial increase in the risk of hospital-acquired infections (HAIs) has greatly impacted the global healthcare industry. Harmful pathogens adhere to a variety of surfaces and infect personnel on contact, thereby promoting transmission to new hosts. This is particularly worrisome in the case of antibiotic-resistant pathogens, which constitute a growing threat to human health worldwide and require new preventative routes of disinfection. In this study, we have incorporated different loading levels of a porphyrin photosensitizer capable of generating reactive singlet oxygen in the presence of O2 and visible light in a water-soluble, photo-cross-linkable polymer coating, which was subsequently deposited on polymer microfibers. Two different application methods are considered, and the morphological and chemical characteristics of these coated fibers are analyzed to detect the presence of the coating and photosensitizer. To discern the efficacy of the fibers against pathogenic bacteria, photodynamic inactivation has been performed on two different bacterial strains, Staphylococcus aureus and antibiotic-resistant Escherichia coli, with population reductions of >99.9999 and 99.6%, respectively, after exposure to visible light for 1 h. In response to the current COVID-19 pandemic, we also confirm that these coated fibers can inactivate a human common cold coronavirus serving as a surrogate for the SARS-CoV-2 virus.}, number={1}, journal={ACS Applied Materials & Interfaces}, publisher={American Chemical Society (ACS)}, author={Peddinti, Bharadwaja S. T. and Morales-Gagnon, Nicolas and Pourdeyhimi, Behnam and Scholle, Frank and Spontak, Richard J. and Ghiladi, Reza A.}, year={2020}, month={Dec}, pages={155–163} }
 @article{alvarado_argyropoulos_scholle_peddinti_ghiladi_2019, title={A facile strategy for photoactive nanocellulose-based antimicrobial materials}, volume={21}, ISSN={1463-9262 1463-9270}, url={http://dx.doi.org/10.1039/C9GC00551J}, DOI={10.1039/c9gc00551j}, abstractNote={Anti-infective materials based upon renewable nanocellulose–porphyrin conjugates photodynamically inactivated four strains of drug-resistant bacteria and two viruses by 99.999+%.}, number={12}, journal={Green Chemistry}, publisher={Royal Society of Chemistry (RSC)}, author={Alvarado, David Ramirez and Argyropoulos, Dimitris S. and Scholle, Frank and Peddinti, Bharadwaja S. T. and Ghiladi, Reza A.}, year={2019}, pages={3424–3435} }
 @article{stoll_scholle_zhu_zhang_ghiladi_2019, title={BODIPY-embedded electrospun materials in antimicrobial photodynamic inactivation}, volume={18}, ISSN={1474-905X 1474-9092}, url={http://dx.doi.org/10.1039/C9PP00103D}, DOI={10.1039/c9pp00103d}, number={8}, journal={Photochemical & Photobiological Sciences}, publisher={Royal Society of Chemistry (RSC)}, author={Stoll, Kevin R. and Scholle, Frank and Zhu, Jiadeng and Zhang, Xiangwu and Ghiladi, Reza A.}, year={2019}, pages={1923–1932} }
 @article{peddinti_scholle_vargas_smith_ghiladi_spontak_2019, title={Inherently self-sterilizing charged multiblock polymers that kill drug-resistant microbes in minutes}, volume={6}, ISSN={2051-6347 2051-6355}, url={http://dx.doi.org/10.1039/C9MH00726A}, DOI={10.1039/c9mh00726a}, abstractNote={To combat the growing global healthcare threat from drug-resistant pathogens, we demonstrate that midblock-sulfonated block polymers can kill 99.9999% of “superbugs,” including bacteria and viruses, in just 5 minutes due to an abrupt pH reduction.}, number={10}, journal={Materials Horizons}, publisher={Royal Society of Chemistry (RSC)}, author={Peddinti, Bharadwaja S. T. and Scholle, Frank and Vargas, Mariana G. and Smith, Steven D. and Ghiladi, Reza A. and Spontak, Richard J.}, year={2019}, pages={2056–2062} }
 @article{peddinti_scholle_ghiladi_spontak_2018, title={Photodynamic Polymers as Comprehensive Anti-Infective Materials: Staying Ahead of a Growing Global Threat}, volume={10}, ISSN={1944-8244 1944-8252}, url={http://dx.doi.org/10.1021/ACSAMI.8B09139}, DOI={10.1021/ACSAMI.8B09139}, abstractNote={To combat the global threat posed by surface-adhering pathogens that are becoming increasingly drug-resistant, we explore the anti-infective efficacy of bulk thermoplastic elastomer films containing ∼1 wt % zinc-tetra(4-N-methylpyridyl)porphine (ZnTMPyP4+), a photoactive antimicrobial that utilizes visible light to generate singlet oxygen. This photodynamic polymer is capable of inactivating five bacterial strains and two viruses with at least 99.89% and 99.95% success, respectively, after exposure to noncoherent light for 60 min. Unlike other anti-infective methodologies commonly requiring oxidizing chemicals, carcinogenic radiation, or toxic nanoparticles, our approach is nonspecific and safe/nontoxic, and sustainably relies on the availability of just oxygen and visible light.}, number={31}, journal={ACS Applied Materials & Interfaces}, publisher={American Chemical Society (ACS)}, author={Peddinti, Bharadwaja S.T. and Scholle, Frank and Ghiladi, Reza A. and Spontak, Richard J.}, year={2018}, month={Jul}, pages={25955–25959} }
 @article{alayli_scholle_2016, title={Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells}, volume={496}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2016.06.008}, abstractNote={Dengue virus (DV) has become the most prevalent arthropod borne virus due to globalization and climate change. It targets dendritic cells during infection and leads to production of pro-inflammatory cytokines and chemokines. Several DV non-structural proteins (NS) modulate activation of human dendritic cells. We investigated the effect of DV NS1 on human monocyte-derived dendritic cells (mo-DCs) during dengue infection. NS1 is secreted into the serum of infected individuals where it interacts with various immune mediators and cell types. We purified secreted DV1 NS1 from supernatants of 293T cells that over-express the protein. Upon incubation with mo-DCs, we observed NS1 uptake and enhancement of early DV1 replication. As a consequence, mo-DCs that were pre-exposed to NS1 produced more pro-inflammatory cytokines in response to subsequent DV infection compared to DCs exposed to heat-inactivated NS1 (HNS1). Therefore the presence of exogenous NS1 is able to modulate dengue infection in mo-DCs.}, journal={VIROLOGY}, author={Alayli, Farah and Scholle, Frank}, year={2016}, month={Sep}, pages={227–236} }
 @article{stanley_scholle_zhu_lu_zhang_situ_ghiladi_2016, title={Photosensitizer-Embedded Polyacrylonitrile Nanofibers as Antimicrobial Non-Woven Textile}, volume={6}, ISSN={2079-4991}, url={http://dx.doi.org/10.3390/nano6040077}, DOI={10.3390/nano6040077}, abstractNote={Toward the objective of developing platform technologies for anti-infective materials based upon photodynamic inactivation, we employed electrospinning to prepare a non-woven textile comprised of polyacrylonitrile nanofibers embedded with a porphyrin-based cationic photosensitizer; termed PAN-Por(+). Photosensitizer loading was determined to be 34.8 nmol/mg material; with thermostability to 300 °C. Antibacterial efficacy was evaluated against four bacteria belonging to the ESKAPE family of pathogens (Staphylococcus aureus; vancomycin-resistant Enterococcus faecium; Acinetobacter baumannii; and Klebsiella pneumonia), as well as Escherichia coli. Our results demonstrated broad photodynamic inactivation of all bacterial strains studied upon illumination (30 min; 65 ± 5 mW/cm2; 400–700 nm) by a minimum of 99.9996+% (5.8 log units) regardless of taxonomic classification. PAN-Por(+) also inactivated human adenovirus-5 (~99.8% reduction in PFU/mL) and vesicular stomatitis virus (>7 log units reduction in PFU/mL). When compared to cellulose-based materials employing this same photosensitizer; the higher levels of photodynamic inactivation achieved here with PAN-Por(+) are likely due to the combined effects of higher photosensitizer loading and a greater surface area imparted by the use of nanofibers. These results demonstrate the potential of photosensitizer-embedded polyacrylonitrile nanofibers to serve as scalable scaffolds for anti-infective or self-sterilizing materials against both bacteria and viruses when employing a photodynamic inactivation mode of action.}, number={4}, journal={Nanomaterials}, publisher={MDPI AG}, author={Stanley, Sarah and Scholle, Frank and Zhu, Jiadeng and Lu, Yao and Zhang, Xiangwu and Situ, Xingci and Ghiladi, Reza}, year={2016}, month={Apr}, pages={77} }
 @article{jayaraman_devlin_miller_scholle_2016, title={The adaptor molecule Trif contributes to murine host defense during Leptospiral infection}, volume={221}, ISSN={["0171-2985"]}, DOI={10.1016/j.imbio.2016.05.006}, abstractNote={Leptospirosis is a zoonotic disease and is caused by pathogenic species of the Leptospira genus, including Leptospira interrogans (L. interrogans). Humans, domestic and wild animals are susceptible to acute or chronic infection. The innate immune response is a critical defense mechanism against Leptospira interrogans, and has been investigated in mouse models. Murine Toll-like receptors (TLRs) have been shown to be key factors in sensing and responding to L. interrogans infection. Specifically, TLR2, TLR4 and the TLR adaptor molecule MyD88 are essential for host defense against L. interrogans; however, the role of the TLR adaptor molecule TIR-domain-containing adaptor-inducing interferon β (TRIF) in the response to L. interrogans has not been previously determined. In the present study, TRIF was found to play an important role during leptospiral infection. Following challenge with L. interrogans, Trif(-/-) mice exhibited delayed weight gain compared to wild-type mice. Moreover, Trif(-/-) mice exhibited an increase in L. interrogans burden in the kidneys, lungs, and blood at early time points (less than 7days post infection). Multiple components of the innate immune responses were dampened in response to leptospiral infection including transcription and production of cytokines, and the humoral response, which suggested that TRIF contributes to expression and production of cytokines important for the host defense against L. interrogans.}, number={9}, journal={IMMUNOBIOLOGY}, author={Jayaraman, Priya A. and Devlin, Amy A. and Miller, Jennifer C. and Scholle, Frank}, year={2016}, month={Sep}, pages={964–974} }
 @article{carpenter_situ_scholle_bartelmess_weare_ghiladi_2015, title={Antiviral, antifungal and antibacterial activities of a BODIPY-based photosensitizer}, volume={20}, number={6}, journal={Molecules}, author={Carpenter, B. L. and Situ, X. C. and Scholle, F. and Bartelmess, J. and Weare, W. W. and Ghiladi, R. A.}, year={2015}, pages={10604–10621} }
 @article{callaway_smith_widman_mckinnon_scholle_sempowski_dittmer_crowe_silva_ting_2015, title={Source and Purity of Dengue-Viral Preparations Impact Requirement for Enhancing Antibody to Induce Elevated IL-1 beta Secretion: A Primary Human Monocyte Model}, volume={10}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0136708}, abstractNote={Dengue virus is a major global health threat and can lead to life-threatening hemorrhagic complications due to immune activation and cytokine production. Cross-reactive antibodies to an earlier dengue virus infection are a recognized risk factor for severe disease. These antibodies bind heterologous dengue serotypes and enhance infection into Fc-receptor-bearing cells, a process known as antibody-dependent enhancement of infection. One crucial cytokine seen elevated in severe dengue patients is IL-1β, a potent inflammatory cytokine matured by the inflammasome. We used a highly-physiologic system by studying antibody-dependent enhancement of IL-1β in primary human monocytes with anti-dengue human monoclonal antibodies isolated from patients. Antibody-enhancement increased viral replication in primary human monocytes inoculated with supernatant harvested from Vero cells infected with dengue virus serotype 2 (DENV-2) 16681. Surprisingly, IL-1β secretion induced by infectious supernatant harvested from two independent Vero cell lines was not enhanced by antibody. Secretion of multiple other inflammatory cytokines was also independent of antibody signaling. However, IL-1β secretion did require NLRP3 and caspase-1 activity. Immunodepletion of dengue virions from the infectious supernatant confirmed that virus was not the main IL-1β-inducing agent, suggesting that a supernatant component(s) not associated with the virion induced IL-1β production. We excluded RNA, DNA, contaminating LPS, viral NS1 protein, complement, and cytokines. In contrast, purified Vero-derived DENV-2 16681 exhibited antibody-enhancement of both infection and IL-1β induction. Furthermore, C6/36 mosquito cells did not produce such an inflammatory component, as crude supernatant harvested from insect cells infected with DENV-2 16681 induced antibody-dependent IL-1β secretion. This study indicates that Vero cells infected with DENV-2 16681 may produce inflammatory components during dengue virus propagation that mask the virus-specific immune response. Thus, the choice of host cell and viral purity should be carefully considered, while insect-derived virus represents a system that elicits antibody-dependent cytokine responses to dengue virus with fewer confounding issues.}, number={8}, journal={PLOS ONE}, author={Callaway, Justin B. and Smith, Scott A. and Widman, Douglas G. and McKinnon, Karen P. and Scholle, Frank and Sempowski, Gregory D. and Dittmer, Dirk P. and Crowe, James E., Jr. and Silva, Aravinda M. and Ting, Jenny P. -Y.}, year={2015}, month={Aug} }
 @article{carpenter_scholle_sadeghifar_francis_boltersdorf_weare_argyropoulos_maggard_ghiladi_2015, title={Synthesis, Characterization, and Antimicrobial Efficacy of Photomicrobicidal Cellulose Paper}, volume={16}, ISSN={["1526-4602"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84938937944&partnerID=MN8TOARS}, DOI={10.1021/acs.biomac.5b00758}, abstractNote={Toward our goal of scalable, antimicrobial materials based on photodynamic inactivation, paper sheets comprised of photosensitizer-conjugated cellulose fibers were prepared using porphyrin and BODIPY photosensitizers, and characterized by spectroscopic (infrared, UV–vis diffuse reflectance, inductively coupled plasma optical emission) and physical (gel permeation chromatography, elemental, and thermal gravimetric analyses) methods. Antibacterial efficacy was evaluated against Staphylococcus aureus (ATCC-2913), vancomycin-resistant Enterococcus faecium (ATCC-2320), Acinetobacter baumannii (ATCC-19606), Pseudomonas aeruginosa (ATCC-9027), and Klebsiella pneumoniae (ATCC-2146). Our best results were achieved with a cationic porphyrin–paper conjugate, Por(+)-paper, with inactivation upon illumination (30 min, 65 ± 5 mW/cm2, 400–700 nm) of all bacterial strains studied by 99.99+% (4 log units), regardless of taxonomic classification. Por(+)-paper also inactivated dengue-1 virus (>99.995%), influenza A (∼99.5%), and human adenovirus-5 (∼99%). These results demonstrate the potential of cellulose materials to serve as scalable scaffolds for anti-infective or self-sterilizing materials against both bacteria and viruses when employing a photodynamic inactivation mode of action.}, number={8}, journal={BIOMACROMOLECULES}, author={Carpenter, Bradley L. and Scholle, Frank and Sadeghifar, Hasan and Francis, Aaron J. and Boltersdorf, Jonathan and Weare, Walter W. and Argyropoulos, Dimitris S. and Maggard, Paul A. and Ghiladi, Reza A.}, year={2015}, month={Aug}, pages={2482–2492} }
 @article{morrison_scholle_2014, title={Abrogation of TLR3 inhibition by discrete amino acid changes in the C-terminal half of the West Nile virus NS1 protein}, volume={456}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2014.03.017}, abstractNote={West Nile virus (WNV) is a mosquito-transmitted pathogen, which causes significant disease in humans. The innate immune system is a first-line defense against invading microorganism and many flaviviruses, including WNV, have evolved multifunctional proteins, which actively suppress its activation and antiviral actions. The WNV non-structural protein 1 (NS1) inhibits signal transduction originating from Toll-like receptor 3 (TLR3) and also critically contributes to virus genome replication. In this study we developed a novel FACS-based screen to attempt to separate these two functions. The individual amino acid changes P320S and M333V in NS1 restored TLR3 signaling in virus-infected HeLa cells. However, virus replication was also attenuated, suggesting that the two functions are not easily separated and may be contained within overlapping domains. The residues we identified are completely conserved among several mosquito- and tick-borne flaviviruses, indicating that they are of biological importance to the virus.}, journal={VIROLOGY}, author={Morrison, Clayton R. and Scholle, Frank}, year={2014}, month={May}, pages={96–107} }
 @article{crook_miller-kittrell_morrison_scholle_2014, title={Modulation of innate immune signaling by the secreted form of the West Nile virus NS1 glycoprotein}, volume={458}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2014.04.036}, abstractNote={West Nile virus (WNV) employs several different strategies to escape the innate immune response. We have previously demonstrated that the WNV NS1 protein interferes with signal transduction from Toll-like receptor 3 (TLR3). NS1 is a glycoprotein that can be found intracellularly or associated with the plasma membrane. In addition, NS1 is secreted to high levels during flavivirus infections. We investigated whether the secreted form of NS1 inhibits innate immune signaling pathways in uninfected cells. Secreted NS1 (sNS1) was purified from supernatants of cells engineered to express the protein. Purified sNS1 associated with and repressed TLR3-induced cytokine production by HeLa cells, and inhibited signaling from TLR3 and other TLRs in bone marrow-derived macrophages and dendritic cells. Footpad administration of sNS1 showed the protein associated predominantly with macrophages and dendritic cells in the draining lymph node. Additionally, sNS1 significantly reduced TLR3 signaling and WNV replicon particle-mediated cytokine transcription in popliteal lymph nodes.}, journal={VIROLOGY}, author={Crook, Kristen R. and Miller-Kittrell, Mindy and Morrison, Clayton R. and Scholle, Frank}, year={2014}, month={Jun}, pages={172–182} }
 @article{bogerd_skalsky_kennedy_furuse_whisnant_flores_schultz_putnam_barrows_sherry_et al._2014, title={Replication of Many Human Viruses Is Refractory to Inhibition by Endogenous Cellular MicroRNAs}, volume={88}, ISSN={["1098-5514"]}, DOI={10.1128/jvi.00985-14}, abstractNote={ABSTRACT The issue of whether viruses are subject to restriction by endogenous microRNAs (miRNAs) and/or by virus-induced small interfering RNAs (siRNAs) in infected human somatic cells has been controversial. Here, we address this question in two ways. First, using deep sequencing, we demonstrate that infection of human cells by the RNA virus dengue virus (DENV) or West Nile virus (WNV) does not result in the production of any virus-derived siRNAs or viral miRNAs. Second, to more globally assess the potential of small regulatory RNAs to inhibit virus replication, we used gene editing to derive human cell lines that lack a functional Dicer enzyme and that therefore are unable to produce miRNAs or siRNAs. Infection of these cells with a wide range of viruses, including DENV, WNV, yellow fever virus, Sindbis virus, Venezuelan equine encephalitis virus, measles virus, influenza A virus, reovirus, vesicular stomatitis virus, human immunodeficiency virus type 1, or herpes simplex virus 1 (HSV-1), failed to reveal any enhancement in the replication of any of these viruses, although HSV-1, which encodes at least eight Dicer-dependent viral miRNAs, did replicate somewhat more slowly in the absence of Dicer. We conclude that most, and perhaps all, human viruses have evolved to be resistant to inhibition by endogenous human miRNAs during productive replication and that dependence on a cellular miRNA, as seen with hepatitis C virus, is rare. How viruses have evolved to avoid inhibition by endogenous cellular miRNAs, which are generally highly conserved during metazoan evolution, remains to be determined. IMPORTANCE Eukaryotic cells express a wide range of small regulatory RNAs, including miRNAs, that have the potential to inhibit the expression of mRNAs that show sequence complementarity. Indeed, previous work has suggested that endogenous miRNAs have the potential to inhibit viral gene expression and replication. Here, we demonstrate that the replication of a wide range of pathogenic viruses is not enhanced in human cells engineered to be unable to produce miRNAs, indicating that viruses have evolved to be resistant to inhibition by miRNAs. This result is important, as it implies that manipulation of miRNA levels is not likely to prove useful in inhibiting virus replication. It also focuses attention on the question of how viruses have evolved to resist inhibition by miRNAs and whether virus mutants that have lost this resistance might prove useful, for example, in the development of attenuated virus vaccines.}, number={14}, journal={JOURNAL OF VIROLOGY}, author={Bogerd, Hal P. and Skalsky, Rebecca L. and Kennedy, Edward M. and Furuse, Yuki and Whisnant, Adam W. and Flores, Omar and Schultz, Kimberly L. W. and Putnam, Nicole and Barrows, Nicholas J. and Sherry, Barbara and et al.}, year={2014}, month={Jul}, pages={8065–8076} }
 @article{winkelmann_widman_xia_ishikawa_miller-kittrell_nelson_bourne_scholle_mason_milligan_2012, title={Intrinsic adjuvanting of a novel single-cycle flavivirus vaccine in the absence of type I interferon receptor signaling}, volume={30}, ISSN={["1873-2518"]}, DOI={10.1016/j.vaccine.2011.12.103}, abstractNote={Type I interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-α and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1-3 post-infection in type I IFN receptor knockout mice (IFNAR(-/-)) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR(-/-) mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4(+) T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8(+) T cells were produced by IFNAR(-/-) mice and a significantly greater percentage of these T cells from IFNAR(-/-) mice produced only IFN-γ following antigen-specific re-stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8(+) effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8(+) effector T cells elicited by this SCFV.}, number={8}, journal={VACCINE}, author={Winkelmann, Evandro R. and Widman, Douglas G. and Xia, Jingya and Ishikawa, Tomohiro and Miller-Kittrell, Mindy and Nelson, Michelle H. and Bourne, Nigel and Scholle, Frank and Mason, Peter W. and Milligan, Gregg N.}, year={2012}, month={Feb}, pages={1465–1475} }
 @article{skalsky_vanlandingham_scholle_higgs_cullen_2010, title={Identification of microRNAs expressed in two mosquito vectors, Aedes albopictus and Culex quinquefasciatus}, volume={11}, ISSN={["1471-2164"]}, DOI={10.1186/1471-2164-11-119}, abstractNote={MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression in a variety of organisms, including insects, vertebrates, and plants. miRNAs play important roles in cell development and differentiation as well as in the cellular response to stress and infection. To date, there are limited reports of miRNA identification in mosquitoes, insects that act as essential vectors for the transmission of many human pathogens, including flaviviruses. West Nile virus (WNV) and dengue virus, members of the Flaviviridae family, are primarily transmitted by Aedes and Culex mosquitoes. Using high-throughput deep sequencing, we examined the miRNA repertoire in Ae. albopictus cells and Cx. quinquefasciatus mosquitoes.We identified a total of 65 miRNAs in the Ae. albopictus C7/10 cell line and 77 miRNAs in Cx. quinquefasciatus mosquitoes, the majority of which are conserved in other insects such as Drosophila melanogaster and Anopheles gambiae. The most highly expressed miRNA in both mosquito species was miR-184, a miRNA conserved from insects to vertebrates. Several previously reported Anopheles miRNAs, including miR-1890 and miR-1891, were also found in Culex and Aedes, and appear to be restricted to mosquitoes. We identified seven novel miRNAs, arising from nine different precursors, in C7/10 cells and Cx. quinquefasciatus mosquitoes, two of which have predicted orthologs in An. gambiae. Several of these novel miRNAs reside within a ~350 nt long cluster present in both Aedes and Culex. miRNA expression was confirmed by primer extension analysis. To determine whether flavivirus infection affects miRNA expression, we infected female Culex mosquitoes with WNV. Two miRNAs, miR-92 and miR-989, showed significant changes in expression levels following WNV infection.Aedes and Culex mosquitoes are important flavivirus vectors. Recent advances in both mosquito genomics and high-throughput sequencing technologies enabled us to interrogate the miRNA profile in these two species. Here, we provide evidence for over 60 conserved and seven novel mosquito miRNAs, expanding upon our current understanding of insect miRNAs. Undoubtedly, some of the miRNAs identified will have roles not only in mosquito development, but also in mediating viral infection in the mosquito host.}, journal={BMC GENOMICS}, author={Skalsky, Rebecca L. and Vanlandingham, Dana L. and Scholle, Frank and Higgs, Stephen and Cullen, Bryan R.}, year={2010}, month={Feb} }
 @article{oyegunwa_sikes_wilson_scholle_laster_2010, title={Tetra-O-methyl nordihydroguaiaretic acid (Terameprocol) inhibits the NF-kappa B-dependent transcription of TNF-alpha and MCP-1/CCL2 genes by preventing RelA from binding its cognate sites on DNA}, volume={7}, ISSN={["1476-9255"]}, DOI={10.1186/1476-9255-7-59}, abstractNote={Abstract Background Tetra-O-methyl nordihydroguaiaretic acid, also known as terameprocol (TMP), is a naturally occurring phenolic compound found in the resin of the creosote bush. We have shown previously that TMP will suppress production of certain inflammatory cytokines, chemokines and lipids from macrophages following stimulation with LPS or infection with H1N1 influenza virus. In this study our goal was to elucidate the mechanism underlying TMP-mediated suppression of cytokine and chemokine production. We focused our investigations on the response to LPS and the NF-κB protein RelA, a transcription factor whose activity is critical to LPS-responsiveness. Methods Reporter assays were performed with HEK293 cells overexpressing either TLR-3, -4, or -8 and a plasmid containing the luciferase gene under control of an NF-κB response element. Cells were then treated with LPS, poly(I:C), or resiquimod, and/or TMP, and lysates measured for luciferase activity. RAW 264.7 cells treated with LPS and/or TMP were used in ChIP and EMSA assays. For ChIP assays, chromatin was prepared and complexes precipitated with anti-NF-κB RelA Ab. Cross-links were reversed, DNA purified, and sequence abundance determined by Q-PCR. For EMSA assays, nuclear extracts were incubated with radiolabeled probes, analyzed by non-denaturing PAGE and visualized by autoradiography. RAW 264.7 cells treated with LPS and/or TMP were also used in fluorescence microscopy and western blot experiments. Translocation experiments were performed using a primary Ab to NF-κB RelA and a fluorescein-conjugated secondary Ab. Western blots were performed using Abs to IκB-α and phospho-IκB-α. Bands were visualized by chemiluminescence. Results In reporter assays with TLR-3, -4, and -8 over-expressing cells, TMP caused strong inhibition of NF-κB-dependent transcription. ChIP assays showed TMP caused virtually complete inhibition of RelA binding in vivo to promoters for the genes for TNF-α, MCP-1/CCL2, and RANTES/CCL5 although the LPS-dependent synthesis of IκB-α was not inhibited. EMSA assays did not reveal an effect of TMP on the binding of RelA to naked DNA templates in vitro. TMP did not inhibit the nuclear translocation of NF-κB RelA nor the phosphorylation of IκB-α. Conclusion TMP acts indirectly as an inhibitor of NF-κB-dependent transcription by preventing RelA from binding the promoters of certain key cytokine and chemokine genes.}, journal={JOURNAL OF INFLAMMATION-LONDON}, author={Oyegunwa, Akinbolade O. and Sikes, Michael L. and Wilson, Jason R. and Scholle, Frank and Laster, Scott M.}, year={2010}, month={Dec} }
 @article{eads_hansen_oyegunwa_cecil_culver_scholle_petty_laster_2009, title={Terameprocol, a methylated derivative of nordihydroguaiaretic acid, inhibits production of prostaglandins and several key inflammatory cytokines and chemokines}, volume={6}, ISSN={["1476-9255"]}, DOI={10.1186/1476-9255-6-2}, abstractNote={Abstract Background Extracts of the creosote bush, Larrea tridentata , have been used for centuries by natives of western American and Mexican deserts to treat a variety of infectious diseases and inflammatory disorders. The beneficial activity of this plant has been linked to the compound nordihydroguaiaretic acid (NDGA) and its various substituted derivatives. Recently, tetra-O-methyl NDGA or terameprocol (TMP) has been shown to inhibit the growth of certain tumor-derived cell lines and is now in clinical trials for the treatment of human cancer. In this report, we ask whether TMP also displays anti-inflammatory activity. TMP was tested for its ability to inhibit the LPS-induced production of inflammatory lipids and cytokines in vitro . We also examined the effects of TMP on production of TNF-α in C57BL6/J mice following a sublethal challenge with LPS. Finally, we examined the molecular mechanisms underlying the effects we observed. Methods RAW 264.7 cells and resident peritoneal macrophages from C57BL6/J mice, stimulated with 1 μg/ml LPS, were used in experiments designed to measure the effects of TMP on the production of prostaglandins, cytokines and chemokines. Prostaglandin production was determined by ELISA. Cytokine and chemokine production were determined by antibody array and ELISA. Western blots, q-RT-PCR, and enzyme assays were used to assess the effects of TMP on expression and activity of COX-2. q-RT-PCR was used to assess the effects of TMP on levels of cytokine and chemokine mRNA. C57BL6/J mice injected i.p. with LPS were used in experiments designed to measure the effects of TMP in vivo . Serum levels of TNF-α were determined by ELISA. Results TMP strongly inhibited the production of prostaglandins from RAW 264.7 cells and normal peritoneal macrophages. This effect correlated with a TMP-dependent reduction in levels of COX-2 mRNA and protein, and inhibition of the enzymatic activity of COX-2. TMP inhibited, to varying degrees, the production of several cytokines, and chemokines from RAW 264.7 macrophages and normal peritoneal macrophages. Affected molecules included TNF-α and MCP-1. Levels of cytokine mRNA were affected similarly, suggesting that TMP is acting to prevent gene expression. TMP partially blocked the production of TNF-α and MCP-1 in vivo in the serum of C57BL6/J mice that were challenged i.p . with LPS. Conclusion TMP inhibited the LPS-induced production of lipid mediators and several key inflammatory cytokines and chemokines, both in vitro and in vivo , raising the possibility that TMP might be useful as a treatment for a variety of inflammatory disorders.}, journal={JOURNAL OF INFLAMMATION-LONDON}, author={Eads, D. and Hansen, R. L. and Oyegunwa, A. O. and Cecil, C. E. and Culver, C. A. and Scholle, F. and Petty, I. T. D. and Laster, S. M.}, year={2009}, month={Jan} }
 @article{wilson_sessions_leon_scholle_2008, title={West Nile virus nonstructural protein 1 inhibits TLR3 signal transduction}, volume={82}, ISSN={["1098-5514"]}, DOI={10.1128/JVI.00226-08}, abstractNote={ABSTRACT The innate immune response is the first line of defense against foreign pathogens. The recognition of virus-associated molecular patterns, including double- and single-stranded RNA, by pattern recognition receptors initiates a cascade of signaling reactions. These result in the transcriptional upregulation and secretion of proinflammatory cytokines that induce an antiviral state. Many viruses have evolved mechanisms to antagonize these responses in order to help them establish a productive infection. We have previously shown that West Nile virus (WNV) is able to inhibit Toll-like receptor 3 (TLR3)-mediated activation of interferon (IFN) regulatory factor 3 (IRF3) (F. Scholle and P. W. Mason, Virology 342:77-87, 2005). In the present study, the WNV nonstructural (NS) proteins were analyzed individually for their ability to antagonize signal transduction mediated by TLR3. We report that expression of WNV NS1 inhibits TLR3-induced transcriptional activation of the IFN-β promoter and of an NF-κB-responsive promoter. This inhibition was due to a failure of the TLR3 ligand poly(I:C) to induce nuclear translocation of IRF3 and NF-κB. Furthermore, NS1 expression also inhibited TLR3-dependent production of interleukin-6 and the establishment of an antiviral state. The function of NS1 in flavivirus infection is not well understood. NS1 is required for viral RNA replication and is also secreted from mammalian cells but not from insect cells. Here, we identify a previously unrecognized role for NS1 in the modulation of signaling pathways of the innate immune response to WNV infection.}, number={17}, journal={JOURNAL OF VIROLOGY}, author={Wilson, Jason R. and Sessions, Paola Florez and Leon, Megan A. and Scholle, Frank}, year={2008}, month={Sep}, pages={8262–8271} }
 @article{bourne_scholle_silva_rossi_dewsbury_judy_de aguiar_leon_estes_fayzulin_et al._2007, title={Early production of type I interferon during West Nile virus infection: Role for lymphoid tissues in IRF3-independent interferon production}, volume={81}, DOI={10.1128/JVI.00316-07}, abstractNote={ABSTRACT Infection of cells with flaviviruses in vitro is reduced by pretreatment with small amounts of type I interferon (IFN-α/β). Similarly, pretreatment of animals with IFN and experiments using mice defective in IFN signaling have indicated a role for IFN in controlling flavivirus disease in vivo. These data, along with findings that flavivirus-infected cells block IFN signaling, suggest that flavivirus infection can trigger an IFN response. To investigate IFN gene induction by the very first cells infected during in vivo infection with the flavivirus West Nile virus (WNV), we infected mice with high-titer preparations of WNV virus-like particles (VLPs), which initiate viral genome replication in cells but fail to spread. These studies demonstrated a brisk production of IFN in vivo, with peak levels of over 1,000 units/ml detected in sera between 8 and 24 h after inoculation by either the intraperitoneal or footpad route. The IFN response was dependent on genome replication, and WNV genomes and WNV antigen-positive cells were readily detected in the popliteal lymph nodes (pLN) of VLP-inoculated mice. High levels of IFN mRNA transcripts and functional IFN were also produced in VLP-inoculated IFN regulatory factor 3 null (IRF3 −/− ) mice, indicating that IFN production was independent of the IRF3 pathways to IFN gene transcription, consistent with the IFN type produced (predominantly α).}, number={17}, journal={Journal of Virology}, author={Bourne, N. and Scholle, F. and Silva, M. C. and Rossi, S. L. and Dewsbury, N. and Judy, B. and De Aguiar, J. B. and Leon, M. A. and Estes, D. M. and Fayzulin, R. and et al.}, year={2007}, pages={9100–9108} }
 @article{fayzulin_scholle_petrakova_frolov_mason_2006, title={Evaluation of replicative capacity and genetic stability of West Nile virus replicons using highly efficient packaging cell lines}, volume={351}, ISSN={0042-6822}, url={http://dx.doi.org/10.1016/j.virol.2006.02.036}, DOI={10.1016/j.virol.2006.02.036}, abstractNote={A stable cell system for high-efficiency packaging of West Nile virus (WNV) subgenomic replicons into virus-like particles (VLPs) was developed. VLPs could be propagated on these packaging cells and produced infectious foci similar to foci produced by WNV. Focus size correlated with the replicative capacity of WNV replicons, indicating that genome copy number, rather than amount of trans-complementing structural proteins, was rate-limiting in packaging of VLPs. Comparison of VLP production from replicon genomes encoding partial or complete C genes indicated that portions of C downstream of the cyclization sequence could improve genome replication or that cis expression of C could enhance packaging. Interestingly, a rapid loss of replicon-encoded reporter gene activity was detected within two serial passages of reporter gene-containing VLPs. The loss of reporter activity correlated with gene deletion and better VLP growth, indicating a powerful selection pressure for WNV genomes lacking reporter genes.}, number={1}, journal={Virology}, publisher={Elsevier BV}, author={Fayzulin, Rafik and Scholle, Frank and Petrakova, Olga and Frolov, Ilya and Mason, Peter W.}, year={2006}, month={Jul}, pages={196–209} }
 @article{scholle_mason_2005, title={West Nile virus replication interferes with both poly(I:C)-induced interferon gene transcription and response to interferon treatment}, volume={342}, ISSN={0042-6822}, url={http://dx.doi.org/10.1016/j.virol.2005.07.021}, DOI={10.1016/j.virol.2005.07.021}, abstractNote={West Nile virus (WNV), the leading cause of viral encephalitis in the United States, is an arthropod-transmitted member of the family Flaviviridae. We have explored the interaction of this positive-strand RNA virus with signaling pathways involved in induction of the host's innate immune response. Phosphorylation of STAT-1 in response to interferon (IFN) treatment and the ability of IFN to establish an antiviral state were reduced in WNV replicon-bearing cell lines. Similarly, the activation of IRF3 and stimulation of IFN-beta transcription in response to the double-stranded RNA (dsRNA) mimetic poly(I:C) were inhibited in replicon-bearing and WNV-infected HeLa cells. In contrast, WNV replicons did not affect IRF3 activation by Sendai virus infection, suggesting that not all IRF3 activating pathways are inhibited by WNV. Taken together, these findings demonstrate that WNV replication in cultured cells interferes with both the response to IFN and synthesis of IFN-beta in response to dsRNA.}, number={1}, journal={Virology}, publisher={Elsevier BV}, author={Scholle, Frank and Mason, Peter W.}, year={2005}, month={Nov}, pages={77–87} }