Scholarly Works, Biomedical Sciences and Pathobiology

Permanent URI for this collection

https://hdl.handle.net/10919/24342

Research articles, presentations, and other scholarship

Browse

Now showing 1 - 20 of 646

Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases
Betancourt, Jovany J.; Ding, Minna; Yoder, J. Marina; Mutyaba, Issa; Atkins, Hannah M.; De la Cruz, Gabriela; Meya, David B.; Nielsen, Kirsten (American Society for Microbiology, 2025-01-14)
Cryptococcus neoformans is a fungal pathogen that can cause lethal disease in immunocompromised patients. Immunocompetent host immune responses, such as formation of pulmonary granulomas, control the infection and prevent disseminated disease. Little is known about the immunological conditions establishing the latent infection granuloma in the lungs. To investigate this, we performed an analysis of pulmonary immune cell populations, cytokine changes, and granuloma formation during infection with a latent disease-causing clinical isolate in C3HeB/FeJ mice over 360 days. We found that latently infected mice progress through three phases of granuloma formation where different immune profiles dominate: an early phase characterized by eosinophilia, high IL-4/IL-13, and C. neoformans proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1α/IFNγ, granuloma expansion, and increased blood antigen levels; and a late phase characterized by a significant expansion of T cells, granuloma condensation, and decreases in lung fungal burden and blood antigen levels. These findings highlight a complex series of immune changes that occur during the establishment of granulomas that control C. neoformans in the lungs and lay the foundation for studies to identify critical beneficial immune responses to Cryptococcus infections.
Potential of Stem-Cell-Induced Peripheral Nerve Regeneration: From Animal Models to Clinical Trials
Wynne, Taylor M.; Fritz, Virginia Grey; Simmons, Zachary T.; Zahed, Malek; Seth, Ananya; Abbasi, Tamir; Reymundi, Michael J.; Roballo, Kelly C. S. (MDPI, 2024-11-23)
Peripheral nerve injury has become an increasingly prevalent clinical concern, causing great morbidity in the community. Although there have been significant advancements in the treatment of peripheral nerve damage in recent years, the issue of long-term nerve regeneration remains. Furthermore, Wallerian degeneration has created an obstacle to long-term nerve regeneration. For this reason, there has been extensive research on the use of exogenous and endogenous stem cells as an adjunct or even primary treatment option for peripheral nerve injury. The plasticity and inducibility of stem cells make them an enticing option for initiating neuronal cell regrowth and optimal sensory and functional nerve regeneration. Peripheral nerve injury has a broad range of causative factors and etiologies. As such, unique stem cell-induced peripheral nerve treatments are being investigated to ameliorate the damage incited by all causes, including trauma, neuropathy, and systemic neurodegenerative diseases. This review is oriented to outline the potential role of stem cell therapies in peripheral nerve injury versus the current standards of care, compare the benefits and drawbacks of specific stem cell lines under investigation, and highlight the current models of stem cell therapy in the peripheral nervous system, with the ultimate goal of narrowing down and optimizing the role and scope of stem cell therapy in peripheral nerve injury.
Predicting patients with septic shock and sepsis through analyzing whole-blood expression of NK cell-related hub genes using an advanced machine learning framework
Du, Chao; Tan, Stephanie C.; Bu, Heng-Fu; Subramanian, Saravanan; Geng, Hua; Wang, Xiao; Xie, Hehuang; Wu, Xiaowei; Zhou, Tingfa; Liu, Ruijin; Xu, Zhen; Liu, Bing; Tan, Xiao-Di (Frontiers, 2024-11-28)
Background: Sepsis is a life-threatening condition that causes millions of deaths globally each year. The need for biomarkers to predict the progression of sepsis to septic shock remains critical, with rapid, reliable methods still lacking. Transcriptomics data has recently emerged as a valuable resource for disease phenotyping and endotyping, making it a promising tool for predicting disease stages. Therefore, we aimed to establish an advanced machine learning framework to predict sepsis and septic shock using transcriptomics datasets with rapid turnaround methods. Methods: We retrieved four NCBI GEO transcriptomics datasets previously generated from peripheral blood samples of healthy individuals and patients with sepsis and septic shock. The datasets were processed for bioinformatic analysis and supplemented with a series of bench experiments, leading to the identification of a hub gene panel relevant to sepsis and septic shock. The hub gene panel was used to establish a novel prediction model to distinguish sepsis from septic shock through a multistage machine learning pipeline, incorporating linear discriminant analysis, risk score analysis, and ensemble method combined with Least Absolute Shrinkage and Selection Operator analysis. Finally, we validated the prediction model with the hub gene dataset generated by RT-qPCR using peripheral blood samples from newly recruited patients. Results: Our analysis led to identify six hub genes (GZMB, PRF1, KLRD1, SH2D1A, LCK, and CD247) which are related to NK cell cytotoxicity and septic shock, collectively termed 6-HubGss. Using this panel, we created SepxFindeR, a machine learning model that demonstrated high accuracy in predicting sepsis and septic shock and distinguishing septic shock from sepsis in a cross-database context. Remarkably, the SepxFindeR model proved compatible with RT-qPCR datasets based on the 6-HubGss panel, facilitating the identification of newly recruited patients with sepsis and septic shock. Conclusions: Our bioinformatic approach led to the discovery of the 6-HubGss biomarker panel and the development of the SepxFindeR machine learning model, enabling accurate prediction of septic shock and distinction from sepsis with rapid processing capabilities.
An in vitro evaluation of intravenous lipid emulsion on three common canine toxicants
Jones, Emery; Walton, Stuart A.; Davis, Jennifer; Council-Troche, McAlister (Frontiers, 2024-09-25)
Objective: To determine whether intravenous lipid emulsion (ILE) therapy significantly reduces the concentration of baclofen, ibuprofen, and/or bromethalin in canine whole blood over time. Animals: Seven 500 mL bags of canine DEA 1.1 negative blood were divided into aliquots of 125 mL and randomly assigned to one of three treatment groups (baclofen, ibuprofen, bromethalin) or four control groups (a positive control for each treatment group and a negative control group). Procedures: Injectable ibuprofen (200 mg/kg), baclofen (8 mg/kg), or bromethalin (3 mg/kg) was apportioned into 125 mL aliquots of canine whole blood and incubated for 30 min at 38.5°C. ILE (12.4 mL, Intralipid®) was added to each sample and the solution vortexed [215 rpm for 15 min at 37°C (98.6°F)]. Samples were obtained at designated time points (0, 15, 30, 60, 180, 360 min), centrifuged, and separated into serum and RBC fractions. Serum samples were ultracentrifuged (22,000 g for 10 min at 37°C) to separate lipid rich and poor fractions. Samples were stored at −80°C prior to analysis. Results: A significant decrease in total drug concentration was established for bromethalin and its metabolite desmethylbromethalin compared to positive controls. ILE significantly reduced desmethylbromethalin at the 30-and 360-min time points. The remainder of the desmethylbromethalin time points did not reach significance. Bromethalin concentration was significantly reduced at all time points compared to positive controls. Neither baclofen nor ibuprofen had significant changes in concentration. Conclusion: ILE therapy was effective at reducing the total drug concentration of bromethalin and its metabolite desmethylbromethalin supporting the lipid sink theory. As a single compartment in vitro study, this study does not evaluate other proposed mechanisms of action of ILE therapy. ILE therapy may have other means of significantly decreasing lipophilic drug concentration in cases of toxicosis.
Case report: Placental chorioadenoma in a primiparous pug dog
Balogh, Orsolya; Diab, Santiago; Parker, Acadia; de Sousa, Gabriela C.; Cecere, Julie T.; McCarter, Samantha J.; Sponenberg, Dan Phillip (Frontiers, 2024-11-27)
A single 1.7 cm × 1.2 cm × 1 cm focal, raised, smooth, round, pink to flesh-colored mass protruding from the chorioallantois of the zonary placenta was found during Cesarean section in a primiparous pug bitch. Microscopically, the non-encapsulated, non-infiltrative, exophytic mass originated from the chorioallantoic stroma overlying the labyrinth and was composed of many arborizing fronds generally lined by 1 to 2 layers of cuboidal, columnar and occasionally polygonal, large trophoblastic cells, but frequently by a larger number of cells that occasionally piled up to form small nests or nodules. The gross and microscopic characteristics of this mass were compatible with a benign neoplastic process arising in the chorioallantois and involving placental trophoblasts, hence the diagnosis of a placental chorioadenoma. Five of the six newborn puppies were viable and of normal birthweight, while one puppy, which had lower birthweight than the others, could not be resuscitated and was humanely euthanized. Although placental tumors in dogs are very rare, this case is compelling evidence in the argument for routine inspection of canine placentas to identify potentially deleterious macro- or microscopic conditions that may be linked to negative fetal outcomes.
Phosphorylation of Ser711 Residue in the Hypervariable Region of Zoonotic Genotype 3 Hepatitis E Virus is Important for Virus Replication
Wang, Bo; Subramaniam, Sakthivel; Tian, Debin; Mahsoub, Hassan M.; Heffron, C. Lynn; Meng, Xiang-Jin (American Society for Microbiology, 2024-10-08)
Hepatitis E virus (HEV) is distinct from other hepatotropic viruses because it is zoonotic. HEV-1 and HEV-2 exclusively infect humans, whereas HEV-3 and HEV-4 are zoonotic. However, the viral and/or host factors responsible for cross-species HEV transmission remain elusive. The hypervariable region (HVR) in HEV is extremely heterogenetic and is implicated in HEV adaptation. Here, we investigated the potential role of Serine phosphorylation in the HVR in HEV replication. We first analyzed HVR sequences across different HEV genotypes and identified a unique region at the N-terminus of the HVR, which is variable in the human-exclusive HEV genotypes but relatively conserved in zoonotic HEV genotypes. Using predictive tools, we identified four potential phosphorylation sites that are highly conserved in zoonotic HEV-3 and HEV-4 genomes but absent in human-exclusive HEV-1 strains. To explore the functional significance of these putative phosphorylation sites, we introduced mutations into the HEV-3 infectious clone and indicator replicon, replacing each Serine residue individually with alanine or aspartic acid, and assessed the impact of these substitutions on HEV-3 replication. We found that the phospho-blatant S711A mutant significantly reduced virus replication, whereas the phospho-mimetic S711D mutant modestly reduced virus replication. Conversely, mutations in the other three Serine residues did not significantly affect HEV-3 replication. Furthermore, we demonstrated that Ser711 phosphorylation did not alter host cell tropism of zoonotic HEV-3. In conclusion, our results showed that potential phosphorylation of the Ser711 residue significantly affects HEV-3 replication in vitro, providing new insights into the potential mechanisms of zoonotic HEV transmission.
The role of gut microbiota in different murine models of systemic lupus erythematosus
Lu, Ran; Luo, Xin M. (Taylor & Francis, 2024-07-16)
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings.
TCDD and CH223191 alter T cell balance but fail to induce anti-inflammatory response in adult lupus mice
Gutierrez, Fernando; Murphy, Quiyana M.; Swartwout, Brianna K.; Read, Kaitlin A.; Edwards, Michael R.; Abdelhamid, Leila; Cabana-Puig, Xavier; Testerman, James C.; Xu, Tian; Lu, Ran; Amin, Pavly; Cecere, Thomas E.; Reilly, Christopher M.; Oestreich, Kenneth J.; Ciupe, Stanca M.; Luo, Xin M. (The American Association of Immunologists, 2024-02-14)
Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.
Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans
Jackson, Katrina M.; Kono, Thomas; Betancourt, Jovany J.; Wang, Yina; Kabbale, Kisakye D.; Ding, Minna; Kezh, Perry; Ha, Grace; Yoder, J. Marina; Fulton, Sophie R.; Mukaremera, Liliane; Tiffin, Peter; Gusa, Asiya; Meya, David B.; Billmyre, R. Blake; Xue, Chaoyang; Nielsen, Kirsten (Nature Research, 2024-12-02)
Studies across various pathogens highlight the importance of pathogen genetic differences in disease manifestation. In the human fungal pathogen Cryptococcus neoformans, sequence type (ST) associates with patient outcome. We performed a meta-analysis of four genomic studies and identified overlapping gene regions associated with virulence, suggesting the importance of these gene regions in cryptococcal disease in diverse clinical isolates. We explored the relationship between virulence and strain genetic differences using the cryptococcosis mouse model and a closely related library of ST93 clinical isolates. We identified four in vivo virulence phenotypes: hypervirulence, typical virulence with CNS disease, typical virulence with non-CNS disease, and latent disease. Hypervirulent isolates were clade specific and associated with an interferon gamma (IFNγ) dominated immune response. Using a genome wide association study (GWAS), we identified nine genes with polymorphisms associated with IFNγ production, including the inositol sensor ITR4. The itr4Δ mutant recapitulated the hypervirulence phenotype and ITR4 affects expression of two IFNγ associated genes. Finally, we showed that IFNγ production is associated with SNPs that downregulate ITR4 and with SNP accumulation in other IFNγ associated genes. These data highlight the complex role of pathogen genetics in virulence and identify genes associated with hypervirulence and IFNγ in Cryptococcus neoformans.
Effects of subclinical Theileria orientalis Ikeda genotype infection on average daily gain ratios and a satisfactory rating in the breeding soundness exam in bull test stations in Virginia
Guynn, Sierra R.; Currin, John F.; Todd, S. Michelle; Greiner, Scott P.; Lahmers, Kevin K. (Texas A&M University Libraries, 2023-07-17)
Theileria orientalis Ikeda genotype is a tick borne hemoprotozoan that typically causes economic losses in dairy and beef cattle in Australia, New Zealand and Japan. Acute clinical infections from T. orientalis Ikeda include anemia, icterus, ill-thrift and death. The acute phase of the infection has been associated with decreased libido in dairy bulls, decreased live weight gain in beef bulls and increased mortality in naïve adults and calves. A sequela to acute infections within a herd is persistent subclinical infections, which have been associated with decreased mean daily gain in suckling beef calves. In late 2017, T. orientalis Ikeda was detected in beef cattle from multiple counties in Virginia and was associated with anemia, weakness, late term abortions and death. As of 2022, T. orientalis Ikeda has been identified in beef cattle in 31 of 95 Virginia counties. Beef production, typically in naturally bred cow-calf operations, is the second largest agricultural commodity in Virginia. Central bull testing programs for performance evaluation and marketing of beef bulls has existed for over 60 years in Virginia. T. orientalis Ikeda was first detected at the Southwest bull test station in 2020 when screened at conclusion of the test. The objective of this study was to determine if subclinical infection with T. orientalis Ikeda affected the average daily gain (ADG) ratios of all bulls on test and the achievement of a satisfactory rating of the breeding soundness exam (BSE) for senior bulls.
Theileria orientalis Ikeda infection does not negatively impact growth performance or breeding soundness exam results in young beef bulls at bull test stations
Guynn, Sierra R.; Greiner, Scott P.; Currin, John F.; Todd, S. Michelle; Assenga, Alphonce; Hungerford, Laura L.; Lahmers, Kevin K. (Frontiers, 2024-07-18)
Introduction: Theileria orientalis Ikeda genotype is an emerging cattle disease in the US. Since 2017, when T. orientalis Ikeda was discovered in beef cattle in two counties in Virginia, cattle infections have risen to include ~67% of Virginia counties and 14 states. Consistent with New Zealand studies, many infected herds in Virginia were >90% positive upon initial testing without overt evidence of infection. Central bull tests present a unique opportunity to study the effects of T. orientalis Ikeda infections, as bulls from multiple source herds are consolidated. The objective of this study was to determine if infection with T. orientalis Ikeda affected the average daily gain (ADG), adjusted yearling weight (AYW) and breeding soundness of bulls at two test stations in Virginia over a period of years. Materials and methods: The bulls were fed and housed similarly to compare their growth performance and breeding soundness. For T. orientalis Ikeda testing, DNA was extracted from whole blood for quantitative polymerase chain reaction. Results: The number of bulls infected with T. orientalis Ikeda at initial delivery to the stations increased significantly over the years studied. Multivariable linear regression models, using Angus bulls from Virginia test stations, indicated no significant effect on ADG or AYW in bulls that became test positive during the test or were positive for the duration, compared to Angus bulls that were negative for the duration. At LOC A, the odds of passing a breeding soundness exam (BSE) were not significantly different for bulls that turned positive during the test or were positive for the duration, compared to bulls that were negative for the duration of the test. At LOC B, bulls that became positive during the test were 2.4 times more likely (95% CI: 1.165–4.995, p = 0.016) to pass their BSE compared to bulls that remained negative throughout the test. Discussion: We do not suppose that an obscured infection of T. orientalis Ikeda is protective for bulls to pass a BSE. However, this study demonstrates an obscured infection of T. orientalis Ikeda does not negatively affect weight gain or achievement of a satisfactory BSE rating at the central bull test stations in Virginia.
NS2B-D55E and NS2B-E65D Variations Are Responsible for Differences in NS2B-NS3 Protease Activities Between Japanese Encephalitis Virus Genotype I and III in Fluorogenic Peptide Model
Wahaab, Abdul; Zhang, Yan; Liu, Ke; Rasgon, Jason L.; Kang, Lei; Hameed, Muddassar; Li, Chenxi; Anwar, Muhammad Naveed; Zhang, Yanbing; Shoaib, Anam; Li, Beibei; Qiu, Yafeng; Wei, Jianchao; Ma, Zhiyong (MDPI, 2024-11-26)
Japanese encephalitis virus (JEV) NS2B-NS3 is a protein complex composed of NS3 proteases and an NS2B co-factor. The N-terminal protease domain (180 residues) of NS3 (NS3(pro)) interacts directly with a central 40-amino acid hydrophilic domain of NS2B (NS2B(H)) to form an active serine protease. In this study, the recombinant NS2B(H)-NS3(pro) proteases were prepared in E. coli and used to compare the enzymatic activity between genotype I (GI) and III (GIII) NS2B-NS3 proteases. The GI NS2B(H)-NS3(pro) was able to cleave the sites at the internal C, NS2A/NS2B, NS2B/NS3, and NS3/NS4A junctions that were identical to the sites proteolytically processed by GIII NS2B(H)-NS3(pro). Analysis of the enzymatic activity of recombinant NS2B(H)-NS3(pro) proteases using a model of fluorogenic peptide substrate revealed that the proteolytical processing activity of GIII NS2B(H)-NS3(pro) was significantly higher than that of GI NS2B(H)-NS3(pro). There were eight amino acid variations between GI and GIII NS2B(H)-NS3(pro), which may be responsible for the difference in enzymatic activities between GI and GIII proteases. Therefore, recombinant mutants were generated by exchanging the NS2B(H) and NS3(pro) domains between GI and GIII NS2B(H)-NS3(pro) and subjected to protease activity analysis. Substitution of NS2B(H) significantly altered the protease activities, as compared to the parental NS2B(H)-NS3(pro), suggesting that NS2B(H) played an essential role in the regulation of NS3(pro) protease activity. To further identify the amino acids responsible for the difference in protease activities, multiple substitution mutants including the individual and combined mutations at the variant residues 55 and 65 of NS2B(H) were generated and subjected to protease activity analysis. Replacement of NS2B-55 and NS2B-65 of GI to GIII significantly increased the enzymatic activity of GI NS2B(H)-NS3(pro) protease, whereas mutation of NS2B-55 and NS2B-65 of GIII to GI remarkably reduced the enzymatic activity of GIII NS2B(H)-NS3(pro) protease. Overall, these data demonstrated that NS2B-55 and NS2B-65 variations in the hydrophilic domain of NS2B co-contributed to the difference in NS2B(H)-NS3(pro) protease activities between GI and GIII. However, it will be crucial to explore these mutations in other in vivo and/or in vitro models. Collectively, these observations will be useful for understanding the replication of JEV GI and GIII viruses.
Spatial Transcriptomics and Single-Nucleus Multi-Omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development
Xu, Xiguang; Lin, Yu; Yin, Liduo; Serpa, Priscila da Silva; Conacher, Benjamin; Pacholec, Christina; Carvallo, Francisco; Hrubec, Terry; Farris, Shannon; Zimmerman, Kurt; Wang, Xiaobin; Xie, Hehuang (MDPI, 2024-11-07)
Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.
State of the Field: Cytotoxic Immune Cell Responses in C. neoformans and C. deneoformans Infection
Okafor, Elizabeth C.; Nielsen, Kirsten (MDPI, 2024-10-12)
Cryptococcus neoformans is an environmental pathogen that causes life-threatening disease in immunocompromised persons. The majority of immunological studies have centered on CD4⁺ T-cell dysfunction and associated cytokine signaling pathways, optimization of phagocytic cell function against fungal cells, and identification of robust antigens for vaccine development. However, a growing body of literature exists regarding cytotoxic cells, specifically CD8⁺ T-cells, Natural Killer cells, gamma/delta T-cells, NK T-cells, and Cytotoxic CD4⁺ T-cells, and their role in the innate and adaptive immune response during C. neoformans and C. deneoformans infection. In this review, we (1) provide a comprehensive report of data gathered from mouse and human studies on cytotoxic cell function and phenotype, (2) discuss harmonious and conflicting results on cellular responses in mice models and human infection, (3) identify gaps of knowledge in the field ripe for exploration, and (4) highlight how innovative immunological tools could enhance the study of cytotoxic cells and their potential immunomodulation during cryptococcosis.
Virus Shedding and Diarrhea: A Review of Human Norovirus Genogroup II Infection in Gnotobiotic Pigs
Nyblade, Charlotte; Yuan, Lijuan (MDPI, 2024-09-07)
For nearly twenty years, gnotobiotic (Gn) pigs have been used as a model of human norovirus (HuNoV) infection and disease. Unique in their ability to develop diarrhea and shed virus post oral challenge, Gn pigs have since been used to evaluate the infectivity of several genogroup II HuNoV strains. Nearly all major pandemic GII.4 variants have been tested in Gn pigs, with varying rates of infectivity. Some induce an asymptomatic state despite being shed in large quantities in stool, and others induce high incidence of both diarrhea and virus shedding. Non-GII.4 strains, including GII.12 and GII.6, have also been evaluated in Gn pigs. Again, rates of diarrhea and virus shedding tend to vary between studies. Several factors may influence these findings, including age, dosage, biological host factors, or bacterial presence. The impact of these factors is nuanced and requires further evaluation to elucidate the exact mechanisms behind increases or decreases in infection rates. Regardless, the value of Gn pig models in HuNoV research cannot be understated, and the model will surely continue to contribute to the field in years to come.
Investigation of High Frequency Irreversible Electroporation for Canine Spontaneous Primary Lung Tumor Ablation
Hay, Alayna N.; Aycock, Kenneth N.; Lorenzo, Melvin F.; David, Kailee; Coutermarsh-Ott, Sheryl; Salameh, Zaid; Campelo, Sabrina N.; Arroyo, Julio P.; Ciepluch, Brittany; Daniel, Gregory; Davalos, Rafael V.; Tuohy, Joanne (MDPI, 2024-09-07)
In this study, the feasibility of treating canine primary lung tumors with high-frequency irreversible electroporation (H-FIRE) was investigated as a novel lung cancer treatment option. H-FIRE is a minimally invasive tissue ablation modality that delivers bipolar pulsed electric fields to targeted cells, generating nanopores in cell membranes and rendering targeted cells nonviable. In the current study, canine patients (n = 5) with primary lung tumors underwent H-FIRE treatment with an applied voltage of 2250 V using a 2-5-2 µs H-FIRE waveform to achieve partial tumor ablation prior to the surgical resection of the primary tumor. Surgically resected tumor samples were evaluated histologically for tumor ablation, and with immunohistochemical (IHC) staining to identify cell death (activated caspase-3) and macrophages (IBA-1, CD206, and iNOS). Changes in immunity and inflammatory gene signatures were also evaluated in tumor samples. H-FIRE ablation was evident by the microscopic observation of discrete foci of acute hemorrhage and necrosis, and in a subset of tumors (n = 2), we observed a greater intensity of cleaved caspase-3 staining in tumor cells within treated tumor regions compared to adjacent untreated tumor tissue. At the study evaluation timepoint of 2 h post H-FIRE, we observed differential gene expression changes in the genes IDO1, IL6, TNF, CD209, and FOXP3 in treated tumor regions relative to paired untreated tumor regions. Additionally, we preliminarily evaluated the technical feasibility of delivering H-FIRE percutaneously under CT guidance to canine lung tumor patients (n = 2). Overall, H-FIRE treatment was well tolerated with no adverse clinical events, and our results suggest H-FIRE potentially altered the tumor immune microenvironment.
SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia
Joyce, Jonathan D.; Moore, Greyson A.; Goswami, Poorna; Harrell, Telvin L.; Taylor, Tina M.; Hawks, Seth A.; Green, Jillian C.; Jia, Mo; Irwin, Matthew D.; Leslie, Emma; Duggal, Nisha K.; Thompson, Christopher K.; Bertke, Andrea S. (MDPI, 2024-07-28)
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.
Widespread exposure to SARS-CoV-2 in wildlife communities
Goldberg, Amanda R.; Langwig, Kate E.; Brown, Katherine L.; Marano, Jeffrey M.; Rai, Pallavi; King, Kelsie M.; Sharp, Amanda K.; Ceci, Alessandro; Kailing, Christopher D.; Kailing, Macy J.; Briggs, Russell; Urbano, Matthew G.; Roby, Clinton; Brown, Anne M.; Weger-Lucarelli, James; Finkielstein, Carla V.; Hoyt, Joseph R. (Springer, 2024-07-29)
Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.
Retrospective Single Nucleotide Polymorphism Analysis of Host Resistance and Susceptibility to Ovine Johne’s Disease Using Restored FFPE DNA
Kravitz, Amanda; Liao, Mingsi; Morota, Gota; Tyler, Ron; Cockrum, Rebecca; Manohar, B. Murali; Ronald, B. Samuel Masilamoni; Collins, Michael T.; Sriranganathan, Nammalwar (MDPI, 2024-07-15)
Johne’s disease (JD), also known as paratuberculosis, is a chronic, untreatable gastroenteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. Evidence for host genetic resistance to disease progression exists, although it is limited due to the extended incubation period (years) and diagnostic challenges. To overcome this, previously restored formalin-fixed paraffin embedded tissue (FFPE) DNA from archived FFPE tissue cassettes was utilized for a novel retrospective case-control genome-wide association study (GWAS) on ovine JD. Samples from known MAP-infected flocks with ante- and postmortem diagnostic data were used. Cases (N = 9) had evidence of tissue infection, compared to controls (N = 25) without evidence of tissue infection despite positive antemortem diagnostics. A genome-wide efficient mixed model analysis (GEMMA) to conduct a GWAS using restored FFPE DNA SNP results from the Illumina Ovine SNP50 Bead Chip, identified 10 SNPs reaching genome-wide significance of p < 1 × 10⁻⁶ on chromosomes 1, 3, 4, 24, and 26. Pathway analysis using PANTHER and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was completed on 45 genes found within 1 Mb of significant SNPs. Our work provides a framework for the novel use of archived FFPE tissues for animal genetic studies in complex diseases and further evidence for a genetic association in JD.
mSphere of Influence: MmuPV1-a dual tropic papillomavirus, red herring, or novel insight into HPV pathogenesis
Romero-Masters, James (American Society for Microbiology, 2024-06-26)
James Romero-Masters works in the field of tumor virology, focusing on the role of the human papillomavirus oncogenes in pathogenesis. In this mSphere of Influence article, they reflect on how the article "Mouse papillomavirus infection persists in mucosal tissues of an immunocompetent mouse strain and progresses to cancer" impacted them, informing their research strategies, and what it means for the mouse papillomavirus model.

Browse

Recent Submissions