College of Science (COS)

Permanent URI for this community

https://hdl.handle.net/10919/5553

Browse

Now showing 1 - 20 of 29

Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure
Hrubec, Terry C.; Seguin, Ryan P.; Xu, L.; Cortopassi, G. A.; Datta, S.; Hanlon, Alexandra L.; Lozano, A. J.; McDonald, V. A.; Healy, C. A.; Anderson, T. C.; Musse, N. A.; Williams, R. T. (Elsevier, 2021-01-01)
Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. Main Findings: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.
Antibiotics ameliorate lupus-like symptoms in mice
Mu, Qinghui; Tavella, Vincent J.; Kirby, Jay L.; Cecere, Thomas E.; Chung, Matthias; Lee, Jiyoung; Li, Song; Ahmed, Sattar Ansar; Eden, Kristin; Allen, Irving C. (Nature, 2017-10-20)
Gut microbiota and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of systemic lupus erythematosus (SLE) is unclear. Here we report that oral antibiotics given during active disease removed harmful bacteria from the gut microbiota and attenuated SLE-like disease in lupus-prone mice. Using MRL/lpr mice, we showed that antibiotics given after disease onset ameliorated systemic autoimmunity and kidney histopathology. They decreased IL-17-producing cells and increased the level of circulating IL-10. In addition, antibiotics removed Lachnospiraceae and increased the relative abundance of Lactobacillus spp., two groups of bacteria previously shown to be associated with deteriorated or improved symptoms in MRL/lpr mice, respectively. Moreover, we showed that the attenuated disease phenotype could be recapitulated with a single antibiotic vancomycin, which reshaped the gut microbiota and changed microbial functional pathways in a time-dependent manner. Furthermore, vancomycin treatment increased the barrier function of the intestinal epithelium, thus preventing the translocation of lipopolysaccharide, a cell wall component of Gram-negative Proteobacteria and known inducer of lupus in mice, into the circulation. These results suggest that mixed antibiotics or a single antibiotic vancomycin ameliorate SLE-like disease in MRL/lpr mice by changing the composition of gut microbiota.
The Application of a Nanomaterial Optical Fiber Biosensor Assay for Identification of Brucella Nomenspecies
McCutcheon, Kelly; Bandara, Aloka B.; Zuo, Ziwei; Heflin, James R.; Inzana, Thomas J. (MDPI, 2019-05-21)
Bacteria in the genus Brucella are the cause of brucellosis in humans and many domestic and wild animals. A rapid and culture-free detection assay to detect Brucella in clinical samples would be highly valuable. Nanomaterial optical fiber biosensors (NOFS) are capable of recognizing DNA hybridization events or other analyte interactions with high specificity and sensitivity. Therefore, a NOFS assay was developed to detect Brucella DNA from cultures and in tissue samples from infected mice. An ionic self-assembled multilayer (ISAM) film was coupled to a long-period grating optical fiber, and a nucleotide probe complementary to the Brucella IS711 region and modified with biotin was bound to the ISAM by covalent conjugation. When the ISAM/probe duplex was exposed to lysate containing ≥100 killed cells of Brucella, or liver or spleen tissue extracts from Brucella-infected mice, substantial attenuation of light transmission occurred, whereas exposure of the complexed fiber to non-Brucella gram-negative bacteria or control tissue samples resulted in negligible attenuation of light transmission. Oligonucleotide probes specific for B. abortus, B. melitensis, and B. suis could also be used to detect and differentiate these three nomenspecies. In summary, the NOFS biosensor assay detected three nomenspecies of Brucella without the use of polymerase chain reaction within 30 min and could specifically detect low numbers of this bacterium in clinical samples.
Canine Cancer Screening Via Ultraviolet Absorbance And Fluorescence Spectroscopy Of Serum Proteins
Dickerson, Bryan Douglas; Geist, Brian L.; Spillman, William B. Jr.; Robertson, John L. (Optical Society of America, 2007-01-01)
A cost-effective optical cancer screening and monitoring technique was demonstrated in a pilot study of canine serum samples and was patented for commercialization. Compared to conventional blood chemistry analysis methods, more accurate estimations of the concentrations of albumin, globulins, and hemoglobin in serum were obtained by fitting the near UV absorbance and photoluminescence spectra of diluted serum as a linear combination of component reference spectra. Tracking these serum proteins over the course of treatment helped to monitor patient immune response to carcinoma and therapy. For cancer screening, 70% of dogs with clinical presentation of cancer displayed suppressed serum hemoglobin levels (below 20 mg/dL) in combination with atypical serum protein compositions, that is, albumin levels outside of a safe range (from 4 to 8 g/dL) and globulin levels above or below a more normal range (from 1.7 to 3.7 g/dL). Of the dogs that met these criteria, only 20% were given a false positive label by this cancer screening test. (C) 2007 Optical Society of America.
Complexity, fractals, disease time, and cancer
Spillman, William B. Jr.; Robertson, John L.; Huckle, William R.; Govindan, B. S.; Meissner, Kenith E. (American Physical Society, 2004-12)
Despite many years of research, a method to precisely and quantitatively determine cancer disease state remains elusive. Current practice for characterizing solid tumors involves the use of varying systems of tumor grading and staging and thus leaves diagnosis and clinical staging dependent on the experience and skill of the physicians involved. Although numerous disease markers have been identified, no combination of them has yet been found that produces a quantifiable and reliable measure of disease state. Newly developed genomic markers and other measures based on the developing sciences of complexity offer promise that this situation may soon be changed for the better. In this paper, we examine the potential of two measures of complexity, fractal dimension and percolation, for use as components of a yet to be determined "disease time" vector that more accurately quantifies disease state. The measures are applied to a set of micrographs of progressive rat hepatoma and analyzed in terms of their correlation with cell differentiation, ratio of tumor weight to rat body weight and tumor growth time. The results provide some support for the idea that measures of complexity could be important elements of any future cancer "disease time" vector.
Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury
Hazy, Amanda; Bochicchio, Lauren; Oliver, Andrea; Xie, Eric; Geng, Shuo; Brickler, Thomas; Xie, Hehuang David; Li, Liwu; Allen, Irving C.; Theus, Michelle H. (Springer Nature, 2019-06-12)
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naive neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.
Effect of Salmonella enterica serovar Typhimurium VNP20009 and VNP20009 with restored chemotaxis on 4T1 mouse mammary carcinoma progression
Coutermarsh-Ott, Sheryl; Broadway, Katherine M.; Scharf, Birgit E.; Allen, Irving C. (Impact Journals, 2017-05-16)
A variety of bacterial strains have been evaluated as bio-therapeutic and immunomodulatory agents to treat cancer. One such strain, Salmonella enterica serovar Typhimurium VNP20009, which is attenuated by a purine auxotrophic mutation and modified lipid A, is characterized in previous models as a safely administered, tumor colonizing agent. However, earlier work tended to use less aggressive cancer cell lines and immunocompromised animal models. Here, we investigated the safety and efficacy of VNP20009 in a highly malignant murine model of human breast cancer. Additionally, as VNP20009 has recently been found to have a defective chemotaxis system, we tested whether restoring chemotaxis would improve anti-cancer properties in this model system. Exposure to VNP20009 had no significant effect on primary mammary tumor size or pulmonary metastasis, and the tumor colonizing process appeared chemotaxis independent. Moreover, tumor-bearing mice exposed to Salmonella exhibited increased morbidity that was associated with significant liver disease. Our results suggest that VNP20009 may not be safe or efficacious when used in aggressive, metastatic breast cancer models utilizing immunocompetent animals.
EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
Sun, Zhixiong; Xu, Xiguang; He, Jianlin; Murray, Alexander; Sun, Ming-an; Wei, Xiaoran; Wang, Xia; McCoig, Emmarose; Xie, Evan; Jiang, Xi; Li, Liwu; Zhu, Jinsong; Chen, Jianjun; Morozov, Alexei; Pickrell, Alicia M.; Theus, Michelle H.; Xie, Hehuang David (2019-08-29)
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
EGR2 is elevated and positively regulates inflammatory IFNγ production in lupus CD4+ T cells
Dai, Rujuan; Heid, Bettina; Xu, Xiguang; Xie, Hehuang David; Reilly, Christopher M.; Ahmed, Sattar Ansar (2020-07-09)
Background Recent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions. In normal C57BL/6 (B6) mice, deletion of EGR2 in lymphocytes results in the development of lupus-like systemic autoimmune disease, which implies indirectly an autoimmune protective role of EGR2. Conversely, increased EGR2 gene expression is suggested to link with high risk of human lupus. In the present studies we sought to clarify the expression and inflammation regulatory role of EGR2 in murine lupus T cells directly. Results We performed RT-qPCR analysis and found a significant increase of EGR2 mRNA expression in human lupus PBMCs and in CD4+ T cells from three different murine lupus models including MRL-lpr, B6-lpr, and B6.sle123 mice at diseased stage when compared to age-matched control MRL or B6 mice. By performing intracellular flow cytometry analysis, we found that EGR2 protein expression was significantly increased in resting lupus (either MRL-lpr or B6.sle123) CD4+ T cells when compared to CD4+ T cells from their respective non-autoimmune controls. However, there was no difference of EGR2 protein expression in anti-CD3 and anti-CD28 stimulated control and lupus CD4+ T cells since there was a stronger induction of EGR2 in activated control CD4+ T cells. EGR2 expression was significantly increased in MRL-lpr mice at an age when lupus is manifested. To understand further the function of elevated EGR2 in lupus CD4+ T cells, we inhibited EGR2 with a specific siRNA in vitro in splenocytes from MRL-lpr and control MRL mice at 15 weeks-of-age. We found that EGR2 inhibition significantly reduced IFNγ production in PMA and ionomycin activated MRL-lpr lupus CD4+ T cells, but not control MRL CD4+ T cells. We also found that inhibition of EGR2 in vitro suppressed the Th1 differentiation in both MRL and MRL-lpr naïve CD4+ T cells. Conclusions EGR2 is highly upregulated in human and murine lupus cells. Our in vitro data suggest a positive role of EGR2 in the regulation of Th1 differentiation and IFNγ production in lupus effector CD4+ T cells.
Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M
Rothschild, Daniel E.; Zhang, Yao; Diao, Na; Lee, Christina K.; Chen, Keqiang; Caswell, Clayton C.; Slade, Daniel J.; Helm, Richard F.; LeRoith, Tanya; Li, Liwu; Allen, Irving C. (2016-12-03)
Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m(-/-) mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m(-/-) animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m(-/-) mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m(-/-) mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.
Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid
Jo, Ami; Ringel-Scaia, Veronica M.; McDaniel, Dylan K.; Thomas, Cassidy A.; Zhang, Rui; Riffle, Judy S.; Allen, Irving C.; Davis, Richey M. (2020-01-20)
Background The clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9 protein system is a revolutionary tool for gene therapy. Despite promising reports of the utility of CRISPR–Cas9 for in vivo gene editing, a principal problem in implementing this new process is delivery of high molecular weight DNA into cells. Results Using poly(lactic-co-glycolic acid) (PLGA), a nanoparticle carrier was designed to deliver a model CRISPR–Cas9 plasmid into primary bone marrow derived macrophages. The engineered PLGA-based carriers were approximately 160 nm and fluorescently labeled by encapsulation of the fluorophore 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS pentacene). An amine-end capped PLGA encapsulated 1.6 wt% DNA, with an encapsulation efficiency of 80%. Release studies revealed that most of the DNA was released within the first 24 h and corresponded to ~ 2–3 plasmid copies released per nanoparticle. In vitro experiments conducted with murine bone marrow derived macrophages demonstrated that after 24 h of treatment with the PLGA-encapsulated CRISPR plasmids, the majority of cells were positive for TIPS pentacene and the protein Cas9 was detectable within the cells. Conclusions In this work, plasmids for the CRISPR–Cas9 system were encapsulated in nanoparticles comprised of PLGA and were shown to induce expression of bacterial Cas9 in murine bone marrow derived macrophages in vitro. These results suggest that this nanoparticle-based plasmid delivery method can be effective for future in vivo applications of the CRISPR–Cas9 system.
Identifying Transcriptional Regulatory Modules Among Different Chromatin States in Mouse Neural Stem Cells
Banerjee, Sharmi; Zhu, Hongxiao; Tang, Man; Feng, Wu-chun; Wu, Xiaowei; Xie, Hehuang David (Frontiers, 2019-01-15)
Gene expression regulation is a complex process involving the interplay between transcription factors and chromatin states. Significant progress has been made toward understanding the impact of chromatin states on gene expression. Nevertheless, the mechanism of transcription factors binding combinatorially in different chromatin states to enable selective regulation of gene expression remains an interesting research area. We introduce a nonparametric Bayesian clustering method for inhomogeneous Poisson processes to detect heterogeneous binding patterns of multiple proteins including transcription factors to form regulatory modules in different chromatin states. We applied this approach on ChIP-seq data for mouse neural stem cells containing 21 proteins and observed different groups or modules of proteins clustered within different chromatin states. These chromatin-state-specific regulatory modules were found to have significant influence on gene expression. We also observed different motif preferences for certain TFs between different chromatin states. Our results reveal a degree of interdependency between chromatin states and combinatorial binding of proteins in the complex transcriptional regulatory process. The software package is available on Github at - https://github.com/BSharmi/DPM-LGCP.
The Impact of Protein Acetylation/Deacetylation on Systemic Lupus Erythematosus
Ren, Jingjing; Panther, Eric J.; Liao, Xiaofeng; Grammer, Amrie C.; Lipsky, Peter E.; Reilly, Christopher M. (MDPI, 2018-12-12)
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body’s immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been identified, it is clear that both genetics and environmental factors trigger the disease. Identical twins have a 24% chance of getting lupus disease if the other one is affected. Internal factors such as female gender and sex hormones, the major histocompatibility complex (MHC) locus and other genetic polymorphisms have been shown to affect SLE, as well as external, environmental influences such as sunlight exposure, smoking, vitamin D deficiency, and certain infections. Several studies have reported and proposed multiple associations between the alteration of the epigenome and the pathogenesis of autoimmune disease. Epigenetic factors contributing to SLE include microRNAs, DNA methylation status, and the acetylation/deacetylation of histone proteins. Additionally, the acetylation of non-histone proteins can also influence cellular function. A better understanding of non-genomic factors that regulate SLE will provide insight into the mechanisms that initiate and facilitate disease and also contribute to the development of novel therapeutics that can specifically target pathogenic molecular pathways.
Inhibition of toxoplasma gondii and plasmodium falciparum infections in vitro by nsc3852, a redox active anti proliferative and tumor cell differentiation agent
Strobl, J. S.; Seibert, C. W.; Li, Y. B.; Nagarkatti, R.; Mitchell, S. M.; Rosypal, A. C.; Rathore, D.; Lindsay, David S. (American Society of Parasitology, 2009-02)
We searched the National Cancer Institute (NCI) compound library for structures related to the antitumor quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the antiprotozoan activity for each of 13 structures. Half of these compounds inhibited Toroplastna gondii tachyzoite propagation in human fibroblasts at <= 1 mu M. The active compounds comprise a series of low-molecular-weight quinolines bearing nitrogen substituents in the ring-5 position. NSC3852 (EC(50) 80 nM) and NSC74949 (EC(50) 646 nM) were the most potent. NSC3852 also inhibited Plasmodium falciparum growth in human red blood cells (EC(50) 1.3 mu M). To investigate the mechanism for NSC3852's anti-T. gondii activity, we used chemiluminescence assays to detect reactive oxygen species (ROS) formation in freshly isolated tachyzoites and in infected host cells; the absence of ROS generation by NSC3852 in these assays indicated NSC3852 does not redox cycle in T. gondii. Inhibitors of enzyme sources of free radicals such as superoxide anion, nitric oxide (NO), and their reaction product peroxynitrite did not interfere with the anti-T. gondii activity of NSC3852. However, inhibition of T. gondii tachyzoite propagation by NSC3852 involved redox reactions because tachyzoites were protected from NSC3852 by inclusion of the cell permeant superoxide dismutase mimetic, MnTMPyP or N-acetylcysteine in the culture medium. We conclude that the Prediction of Activity Spectra for Substances (PASS) computer program is useful in finding new compounds that inhibit T. gondii tachyzoites in vitro and that NSC3852 is a potent T. gondii inhibitor that: acts by indirect generation of oxidative stress in T. gondii.
Metagonimoides oregonensis (heterophyidae: digenea) infection in pleurocerid snails and desmognathus quadramaculatus salamander larvae in southern Appalachian streams
Belden, Lisa K.; Peterman, William E.; Smith, Stephen A.; Brooks, Lauren R.; Benfield, Ernest F.; Black, Wesley P.; Yang, Zhaomin; Wojdak, Jeremy M. (American Society of Parasitology, 2012-08)
Metagonimoides oregonensis (Heterophyidae) is a little-known digenetic trematode that uses raccoons and possibly mink as definitive hosts, and stream snails and amphibians as intermediate hosts. Some variation in the life cycle and adult morphology in western and eastern populations has been previously noted. In the southern Appalachians, Pleurocera snails and stream salamanders, e.g., Desmognathus spp., are used as intermediate hosts in the life cycle. We completed a series of studies in this system examining some aspects of larval trematode morphology and first and second intermediate host use. Molecular sequencing of the 28S rDNA of cercariae in our survey placed them clearly within the heterophyid family. However, light and scanning electron microscopy revealed both lateral and dorso-ventral finfolds on the cercariae in our region, whereas original descriptions of M. oregonensis cercariae from the west coast indicate only a dorso-ventral finfold, so further work on the systematics of this group may be warranted. A survey of first intermediate host, Pleurocera proxima, from 7 streams in the region identified only M. oregonensis, virgulate-type cercariae, and cotylomicrocercous-type cercariae in the streams, with M. oregonensis having the highest prevalence, and the only type present that use amphibians as second intermediate hosts. Based on clearing and staining of 6 Desmognathus quadramaculatus salamander larvae, we found that individual salamanders could have over 600 metacercariae, which form between muscle fibers throughout the body. Histological observations suggest that the metacercariae do not cause excessive tissue damage or inflammation, and likely persist through metamorphosis, thereby transmitting potentially large numbers of worms to definitive host raccoons foraging along streams.
Molecular Phenotyping and Genomic Characterization of a Novel Neuroactive Bacterium Strain, Lactobacillus murinus HU-1
Lebovitz, Yeonwoo; Theus, Michelle H. (2019-10-04)
Natural, incidental, and engineered nanomaterials and their impacts on the Earth system
Hochella, Michael F. Jr.; Mogk, David W.; Ranville, James; Allen, Irving C.; Luther, George W.; Marr, Linsey C.; McGrail, B. Peter; Murayama, Mitsuhiro; Qafoku, Nikolla P.; Rosso, Kevin M.; Sahai, Nita; Schroeder, Paul A.; Vikesland, Peter J.; Westerhoff, Paul; Yang, Yi (2019-03-29)
Nanomaterials are critical components in the Earth system's past, present, and future characteristics and behavior. They have been present since Earth's origin in great abundance. Life, from the earliest cells to modern humans, has evolved in intimate association with naturally occurring nanomaterials. This synergy began to shift considerably with human industrialization. Particularly since the Industrial Revolution some two-and-a-half centuries ago, incidental nanomaterials (produced unintentionally by human activity) have been continuously produced and distributed worldwide. In some areas, they now rival the amount of naturally occurring nanomaterials. In the past half-century, engineered nanomaterials have been produced in very small amounts relative to the other two types of nanomaterials, but still in large enough quantities to make them a consequential component of the planet. All nanomaterials, regardless of their origin, have distinct chemical and physical properties throughout their size range, clearly setting them apart from their macroscopic equivalents and necessitating careful study. Following major advances in experimental, computational, analytical, and field approaches, it is becoming possible to better assess and understand all types and origins of nanomaterials in the Earth system. It is also now possible to frame their immediate and long-term impact on environmental and human health at local, regional, and global scales.
Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons
Yanez, Andy A.; Harrell, Telvin; Sriranganathan, Heather J.; Ives, Angela M.; Bertke, Andrea S. (MDPI, 2017-02-07)
Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.
Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2
Chuong, Christina; DuChane, Christine M.; Webb, Emily M.; Rai, Pallavi; Marano, Jeffrey M.; Bernier, Chad M.; Merola, Joseph S.; Weger-Lucarelli, James (MDPI, 2021-05-25)
SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl₂ (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.
Pathogenesis and shedding of Usutu virus in juvenile chickens
Kuchinsky, Sarah C.; Frere, Francesca; Heitzman-Breen, Nora; Golden, Jacob; Vázquez, Ana; Honaker, Christa F.; Siegel, Paul B.; Ciupe, Stanca M.; LeRoith, Tanya; Duggal, Nisha K. (Taylor & Francis, 2021-01-01)
Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus that causes severe neuroinvasive disease in humans and has been implicated in the loss of breeding bird populations in Europe. USUV is maintained in an enzootic cycle between ornithophilic mosquitos and wild birds. As a member of the Japanese encephalitis serocomplex, USUV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both neuroinvasive arboviruses endemic in wild bird populations in the United States. An avian model for USUV is essential to understanding zoonotic transmission. Here we describe the first avian models of USUV infection with the development of viremia. Juvenile commercial ISA Brown chickens were susceptible to infection by multiple USUV strains with evidence of cardiac lesions. Juvenile chickens from two chicken lines selected for high (HAS) or low (LAS) antibody production against sheep red blood cells showed markedly different responses to USUV infection. Morbidity and mortality were observed in the LAS chickens, but not HAS chickens. LAS chickens had significantly higher viral titers in blood and other tissues, as well as oral secretions, and significantly lower development of neutralizing antibody responses compared to HAS chickens. Mathematical modelling of virus-host interactions showed that the viral clearance rate is a stronger mitigating factor for USUV viremia than neutralizing antibody response in this avian model. These chicken models provide a tool for further understanding USUV pathogenesis in birds and evaluating transmission dynamics between avian hosts and mosquito vectors.

Browse

Browsing College of Science (COS) by Department "Biomedical Sciences and Pathobiology"

Results Per Page

Sort Options