Scholarly Works, Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP)

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Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure
VanderGiessen, Morgen; de Jager, Caroline; Leighton, Julia; Xie, Hehuang; Theus, Michelle; Johnson, Erik; Kehn-Hall, Kylene (Frontiers, 2024-12-13)
Encephalitic alphaviruses (EEVs), Traumatic Brain Injuries (TBI), and organophosphorus nerve agents (NAs) are three diverse biological, physical, and chemical injuries that can lead to long-term neurological deficits in humans. EEVs include Venezuelan, eastern, and western equine encephalitis viruses. This review describes the current understanding of neurological pathology during these three conditions, provides a comparative review of case studies vs. animal models, and summarizes current therapeutics. While epidemiological data on clinical and pathological manifestations of these conditions are known in humans, much of our current mechanistic understanding relies upon animal models. Here we review the animal models findings for EEVs, TBIs, and NAs and compare these with what is known from human case studies. Additionally, research on NAs and EEVs is limited due to their classification as high-risk pathogens (BSL-3) and/or select agents; therefore, we leverage commonalities with TBI to develop a further understanding of the mechanisms of neurological damage. Furthermore, we discuss overlapping neurological damage mechanisms between TBI, NAs, and EEVs that highlight novel medical countermeasure opportunities. We describe current treatment methods for reducing neurological damage induced by individual conditions and general neuroprotective treatment options. Finally, we discuss perspectives on the future of neuroprotective drug development against long-term neurological sequelae of EEVs, TBIs, and NAs.
Hantavirus in rodents in the United States: Temporal and spatial trends and report of new hosts
Astorga, Francisca; Alkishe, Abdelghafar; Paansri, Paanwaris; Mantilla, Gabriel; Escobar, Luis E. (Wiley, 2025-03-16)
In North America, the rodent-borne hantavirus pulmonary syndrome ispredominantly caused by the Sin Nombre virus, typically associated with the deer mouse Peromyscus maniculatus. Utilizing data from the National Ecological Observatory Network (NEON) hantavirus program, we assessed factors that may influence the spatial and temporal distribution of hantavirus inrodent populations across the United States. Between 2014 and 2019, the NEON hantavirus program conducted 104,379 small mammal captures and collected 14,004 blood samples from 49 species at 45 field sites. Our study identified 296 seropositive samples across 15 rodent species, including 8 Peromyscusspecies. We describe six new species with hantavirus seropositive samples not previously reported as hantavirus hosts. The highest number of seropositivesamples was obtained from Pe. maniculatus (n = 116; 2.9% seroprevalence),followed by Peromyscus leucopus (n = 96; 2.8%) and Microtus pennsylvanicus(n = 33; 4.2%). Hantavirus seroprevalence showed an uneven spatial distribution, with the highest seroprevalence found in Virginia (7.8%, 99 seropositivesamples), Colorado (5.7%, n = 37), and Texas (4.8%, n = 19). Hantavirus sero-positive samples were obtained from 32 sites, 10 of which presented seropositive samples in species other than Pe. maniculatus or Pe. leucopus. Seroprevalence was inconsistent across years but showed intra-annual bimodal trends, and in Pe. maniculatus and Pe. leucopus, the number of captures correlated with sero-prevalence in the following months. Seroprevalence was higher in adult males, with only one seropositive sample obtained from a juvenile Peromyscus truei. Higher body mass, presence of scrotal testes, and nonpregnant status were associated with higher seropositivity. The NEON dataset, derived from a multiyear and structured surveillance system, revealed the extensive distribution of hantavirus across broad taxonomic and environmental ranges. Future research should consider winter season surveillance and continued analyses of stored samples for a comprehensive spatiotemporal study of hantavirus circulation in wildlife. Global changes are expected to affect the dynamics of rodent populations by affecting their availability of resources and demography and, consequently, may modify transmission rates of rodent-borne zoonotic pathogens such as hantavi-rus. This study can be considered a baseline to assess hantavirus patterns across host taxa, geographies, and seasons in the United States.
Evolution at Spike protein position 519 in SARS-CoV-2 facilitated adaptation to humans
Cereghino, C.; Michalak, K.; DiGiuseppe, S.; Yu, D.; Faraji, A.; Sharp, A.K.; Brown, Anne M.; Kang, L.; Weger-Lucarelli, James; Michalak, P. (Springer Nature, 2024)
As the COVID-19 pandemic enters its fourth year, the pursuit of identifying a progenitor virus to SARSCoV- 2 and understanding the mechanism of its emergence persists, albeit against the backdrop of intensified efforts to monitor the ongoing evolution of the virus and the influx of new mutations. Surprisingly, few residues hypothesized to be essential forSARS-CoV-2 emergence and adaptation to humans have been validated experimentally, despite the importance that these mutations could contribute to the development of effective antivirals. To remedy this,we searched for genomic regions in the SARS-CoV-2 genome that show evidence of past selection around residues unique to SARSCoV- 2 compared with closely related coronaviruses. In doing so, we identified a residue at position 519 in Spike within the receptor binding domain that holds a static histidine in human-derived SARSCoV- 2 sequences but an asparagine in SARS-related coronaviruses from bats and pangolins. In experimental validation, the SARS-CoV-2 Spike protein mutant carrying the putatively ancestral H519N substitution showed reduced replication in human lung cells, suggesting that the histidine residue contributes to viral fitness in the human host. Structural analyses revealed a potential role of Spike residue 519 in mediating conformational transitions necessary for Spike prior to binding with ACE2. Pseudotyped viruses bearing the putatively ancestral N519 also demonstrated significantly reduced infectivity in cells expressing the human ACE2 receptor compared to H519. ELISA data corroborated that H519 enhances Spike binding affinity to the human ACE2 receptor compared to the putatively ancestral N519. Collectively, these findings suggest that the evolutionary transition at position 519 of the Spike protein played a critical role inSARS-CoV-2 emergence and adaptation to the human host. Additionally, this residue presents as a potential drug target for designing small molecule inhibitors tailored to this site.
Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection
Woodson, Caitlin M.; Carney, Shannon K.; Kehn-Hall, Kylene (MDPI, 2025-02-14)
Encephalitic alphaviruses, including eastern, Venezuelan, and western equine encephalitis virus (EEEV, VEEV, and WEEV, respectively) are New World alphaviruses primarily transmitted by mosquitos that cause debilitating and lethal central nervous system (CNS) disease in both humans and horses. Despite over one hundred years of research on these viruses, the underpinnings of the molecular mechanisms driving virally induced damage to the CNS remain unresolved. Moreover, virally induced encephalitis following exposure to these viruses causes catastrophic damage to the CNS, and survivors of infection often suffer from permanent neurological sequelae as a result of sustained neuroinflammation and neurological insults encountered. Animal models are undoubtedly invaluable tools in biomedical research, where physiologically relevant models are required to study pathogenesis and host–pathogen interactions. Here, we review the literature to examine nonhuman primate (NHP) and mouse models of infection for EEEV, VEEV, and WEEV. We provide a brief overview of relevant background information for each virus, including geography, epidemiology, and clinical disease. The primary focus of this review is to describe neuropathological features associated with CNS disease in NHP and mouse models of infection and compare CNS invasion and neuropathogenesis for aerosol, intranasal, and subcutaneous routes of exposure to EEEV, VEEV, and WEEV.
Increased risks of mosquito-borne disease emergence in temperate regions of South America
Estallo, Elizabet L.; Lopez, Maria Soledad; Luduena-Almeida, Francisco; Madelon, Magali I.; Layun, Federico; Robert, Michael A. (Elsevier, 2024-11-14)
Identification of Potential Vectors and Detection of Rift Valley Fever Virus in Mosquitoes Collected Before and During the 2022 Outbreak in Rwanda
Nsengimana, Isidore; Hakizimana, Emmanuel; Mupfasoni, Jackie; Hakizimana, Jean Nepomuscene; Chengula, Augustino A.; Kasanga, Christopher J.; Eastwood, Gillian (MDPI, 2025-01-08)
Rift Valley fever virus (RVFV) is an emerging mosquito-borne arbovirus of One Health importance that caused two large outbreaks in Rwanda in 2018 and 2022. Information on vector species with a role in RVFV eco-epidemiology in Rwanda is scarce. Here we sought to identify potential mosquito vectors of RVFV in Rwanda, their distribution and abundance, as well as their infection status. Since an outbreak of RVF occurred during the study period, data were obtained both during an interepidemic period and during the 2022 Rwanda RVF outbreak. Five districts of the eastern province of Rwanda were prospected using a combination of unbaited light traps and Biogents (BG Sentinel and Pro) traps baited with an artificial human scent during three periods, namely mid-August to mid-September 2021, December 2021, and April to May 2022. Trapped mosquitoes were morphologically identified and tested for viral evidence using both RT-PCR and virus isolation methods on a Vero cell line. A total of 14,815 adult mosquitoes belonging to five genera and at least 17 species were collected and tested as 765 monospecific pools. Culex quinquefasciatus was the most predominant species representing 72.7% of total counts. Of 527 mosquito pools collected before the 2022 outbreak, a single pool of Cx. quinquefasciatus showed evidence of RVFV RNA. Of 238 pools collected during the outbreak, RVFV was detected molecularly from five pools (two pools of Cx. quinquefasciatus, two pools of Anopheles ziemanni, and one pool of Anopheles gambiae sensu lato), and RVFV was isolated from the two pools of Cx. quinquefasciatus, from Kayonza and Rwamagana districts, respectively. Minimum infection rates (per 1000 mosquitoes) of 0.4 before the outbreak and 0.6–7 during the outbreak were noted. Maximum-likelihood phylogenetic analysis indicates that RVFV detected in these mosquitoes is closely related to viral strains that circulated in livestock in Rwanda and in Burundi during the same RVF outbreak in 2022. The findings reveal initial evidence for the incrimination of several mosquito species in the transmission of RVFV in Rwanda and highlight the need for more studies to understand the role of each species in supporting the spread and persistence of RVFV in the country.
A Phage-Based Approach to Identify Antivirulence Inhibitors of Bacterial Type IV Pili
Shimozono, Tori M.; Vogelaar, Nancy J.; O'Hara, Megan T.; Yang, Zhaomin (Wiley, 2025-01-17)
The increasing threat of antibiotic resistance underscores the urgent need for innovative strategies to combat infectious diseases, including the development of antivirulants. Microbial pathogens rely on their virulence factors to initiate and sustain infections. Antivirulants are small molecules designed to target virulence factors, thereby attenuating the virulence of infectious microbes. The bacterial type IV pilus (T4P), an extracellular protein filament that depends on the T4P machinery (T4PM) for its biogenesis, dynamics and function, is a key virulence factor in many significant bacterial pathogens. While the T4PM presents a promising antivirulence target, the systematic identification of inhibitors for its multiple protein constituents remains a considerable challenge. Here we report a novel high-throughput screening (HTS) approach for discovering T4P inhibitors. It uses Pseudomonas aeruginosa, a high-priority pathogen, in combination with its T4P-targeting phage, φKMV. Screening of a library of 2168 compounds using an optimised protocol led to the identification of tuspetinib, based on its deterrence of the lysis of P. aeruginosa by φKMV. Our findings show that tuspetinib also inhibits two additional T4P-targeting phages, while having no effect on a phage that recognises lipopolysaccharides as its receptor. Additionally, tuspetinib impedes T4P-mediated motility in P. aeruginosa and Acinetobacter species without impacting growth or flagellar motility. This bacterium-phage pairing approach is applicable to a broad range of virulence factors that are required for phage infection, paving ways for the development of advanced chemotherapeutics against antibiotic-resistant infections.
Identification of small molecule inhibitors of the Chloracidobacterium thermophilum type IV pilus protein PilB by ensemble virtual screening
McDonald-Ramos, Jay S.; Hicklin, Ian K.; Yang, Zhaomin; Brown, Anne M. (Elsevier, 2024-08-16)
Antivirulence strategy has been explored as an alternative to traditional antibiotic development. The bacterial type IV pilus is a virulence factor involved in host invasion and colonization in many antibiotic resistant pathogens. The PilB ATPase hydrolyzes ATP to drive the assembly of the pilus filament from pilin subunits. We evaluated Chloracidobacterium thermophilum PilB (CtPilB) as a model for structure-based virtual screening by molecular docking and molecular dynamics (MD) simulations. A hexameric structure of CtPilB was generated through homology modeling based on an existing crystal structure of a PilB from Geobacter metallireducens. Four representative structures were obtained from molecular dynamics simulations to examine the conformational plasticity of PilB and improve docking analyses by ensemble docking. Structural analyses after 1 μs of simulation revealed conformational changes in individual PilB subunits are dependent on ligand presence. Further, ensemble virtual screening of a library of 4234 compounds retrieved from the ZINC15 database identified five promising PilB inhibitors. Molecular docking and binding analyses using the four representative structures from MD simulations revealed that top-ranked compounds interact with multiple Walker A residues, one Asp-box residue, and one arginine finger, indicating these are key residues in inhibitor binding within the ATP binding pocket. The use of multiple conformations in molecular screening can provide greater insight into compound flexibility within receptor sites and better inform future drug development for therapeutics targeting the type IV pilus assembly ATPase.
Analysis of the core bacterial community associated with consumer-ready Eastern oysters (Crassostrea virginica)
Hines, Ian S.; Markov Madanick, Justin; Smith, Stephen A.; Kuhn, David D.; Stevens, Ann M. (Public Library of Science, 2023-02-22)
Shellfish, such as the Eastern oyster (Crassostrea virginica), are an important agricultural commodity. Previous research has demonstrated the importance of the native microbiome of oysters against exogenous challenges by non-native pathogens. However, the taxonomic makeup of the oyster microbiome and the impact of environmental factors on it are understudied. Research was conducted quarterly over a calendar year (February 2020 through February 2021) to analyze the taxonomic diversity of bacteria present within the microbiome of consumer-ready-to-eat live Eastern oysters. It was hypothesized that a core group of bacterial species would be present in the microbiome regardless of external factors such as the water temperature at the time of harvest or post-harvesting processing. At each time point, 18 Chesapeake Bay (eastern United States) watershed aquacultured oysters were acquired from a local grocery store, genomic DNA was extracted from the homogenized whole oyster tissues, and the bacterial 16S rRNA gene hypervariable V4 region was PCR-amplified using barcoded primers prior to sequencing via Illumina MiSeq and bioinformatic analysis of the data. A core group of bacteria were identified to be consistently associated with the Eastern oyster, including members of the phyla Firmicutes and Spirochaetota, represented by the families Mycoplasmataceae and Spirochaetaceae, respectively. The phyla Cyanobacterota and Campliobacterota became more predominant in relation to warmer or colder water column temperature, respectively, at the time of oyster harvest.
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.
Evidence of horizontal gene transfer and environmental selection impacting antibiotic resistance evolution in soil-dwelling Listeria
Goh, Ying-Xian; Anupoju, Sai Manohar Balu; Nguyen, Anthony; Zhang, Hailong; Ponder, Monica A.; Krometis, Leigh-Anne H.; Pruden, Amy; Liao, Jingqiu (Nature Research, 2024-11-19)
Soil is an important reservoir of antibiotic resistance genes (ARGs) and understanding how corresponding environmental changes influence their emergence, evolution, and spread is crucial. The soil-dwelling bacterial genus Listeria, including L. monocytogenes, the causative agent of listeriosis, serves as a keymodel for establishing this understanding. Here, we characterize ARGs in 594 genomes representing 19 Listeria species that we previously isolated from soils in natural environments across the United States. Among the five putatively functional ARGs identified, lin,which confers resistance to lincomycin, is the most prevalent, followed by mprF, sul, fosX, and norB. ARGs are predominantly found in Listeria sensu stricto species, with those more closely related to L. monocytogenes tending to harbor more ARGs. Notably, phylogenetic and recombination analyses provide evidence of recent horizontal gene transfer (HGT) in all five ARGs within and/or across species, likelymediated by transformation rather than conjugation and transduction. In addition, the richness and genetic divergence of ARGs are associated with environmental conditions, particularly soil properties (e.g., aluminum and magnesium) and surrounding land use patterns (e.g., forest coverage). Collectively, our data suggest that recent HGT and environmental selection play a vital role in the acquisition and diversification of bacterial ARGs in natural environments.
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.
Genomic Epidemiology of Rift Valley Fever Virus Involved in the 2018 and 2022 Outbreaks in Livestock in Rwanda
Nsengimana, Isidore; Juma, John; Roesel, Kristina; Gasana, Methode N.; Ndayisenga, Fabrice; Muvunyi, Claude M.; Hakizimana, Emmanuel; Hakizimana, Jean N.; Eastwood, Gillian; Chengula, Augustino A.; Bett, Bernard; Kasanga, Christopher J.; Oyola, Samuel O. (MDPI, 2024-07-17)
Rift Valley fever (RVF), a mosquito-borne transboundary zoonosis, was first confirmed in Rwanda’s livestock in 2012 and since then sporadic cases have been reported almost every year. In 2018, the country experienced its first large outbreak, which was followed by a second one in 2022. To determine the circulating virus lineages and their ancestral origin, two genome sequences from the 2018 outbreak, and thirty-six, forty-one, and thirty-eight sequences of small (S), medium (M), and large (L) genome segments, respectively, from the 2022 outbreak were generated. All of the samples from the 2022 outbreak were collected from slaughterhouses. Both maximum likelihood and Bayesian-based phylogenetic analyses were performed. The findings showed that RVF viruses belonging to a single lineage, C, were circulating during the two outbreaks, and shared a recent common ancestor with RVF viruses isolated in Uganda between 2016 and 2019, and were also linked to the 2006/2007 largest East Africa RVF outbreak reported in Kenya, Tanzania, and Somalia. Alongside the wild-type viruses, genetic evidence of the RVFV Clone 13 vaccine strain was found in slaughterhouse animals, demonstrating a possible occupational risk of exposure with unknown outcome for people working in meat-related industry. These results provide additional evidence of the ongoing wide spread of RVFV lineage C in Africa and emphasize the need for an effective national and international One Health-based collaborative approach in responding to RVF emergencies.
Hybridization between Aedes aegypti and Aedes mascarensis mosquitoes leads to disruption of male sex determination
Liang, Jiangtao; Kang, Lin; Michalak, Pawel; Sharakhov, Igor V. (Springer Nature, 2024-07-22)
Understanding the sex determination pathway and its disruptions in mosquitoes is critical for the effective control of disease vectors through genetic manipulations based on sex separation. When male hybrids of Aedes aegypti females and Ae. mascarensis males are backcrossed to Ae. aegypti females, a portion of the backcross progeny manifests as males with abnormal sexual differentiation. We discovered a significant correlation between pupal abnormalities and the feminization of subsequent adults exemplified by the relative abundance of ovarian and testicular tissues. All intersex individuals were genetic males as they expressed a male determining factor, Nix. Further, our analysis of the sex-specific splicing of doublesex and fruitless transcripts demonstrated the presence of both male and female splice variants indicating that sex determination is disrupted. A comparative transcriptomic analysis revealed similar expression levels of most female-associated genes in reproductive organs and carcasses between intersexual males and normal females. Moreover, intersexes had largely normal gene expression in testes but significant gene downregulation in male accessory glands when compared with normal males. We conclude that evolving hybrid incompatibilities between Ae. aegypti and Ae. mascarensis involve disruption of sex determination and are accompanied by changes in gene expression associated with sexual differentiation.
Ecology and geography of Cache Valley virus assessed using ecological niche modeling
Muller, John A.; López, Krisangel; Escobar, Luis E.; Auguste, A. Jonathan (2024-06-26)
Background: Cache Valley virus (CVV) is an understudied Orthobunyavirus with a high spillover transmission potential due to its wide geographical distribution and large number of associated hosts and vectors. Although CVV is known to be widely distributed throughout North America, no studies have explored its geography or employed computational methods to explore the mammal and mosquito species likely participating in the CVV sylvatic cycle. Methods: We used a literature review and online databases to compile locality data for CVV and its potential vectors and hosts. We linked location data points with climatic data via ecological niche modeling to estimate the geographical range of CVV and hotspots of transmission risk. We used background similarity tests to identify likely CVV mosquito vectors and mammal hosts to detect ecological signals from CVV sylvatic transmission. Results: CVV distribution maps revealed a widespread potential viral occurrence throughout North America. Ecological niche models identified areas with climate, vectors, and hosts suitable to maintain CVV transmission. Our background similarity tests identified Aedes vexans, Culiseta inornata, and Culex tarsalis as the most likely vectors and Odocoileus virginianus (white-tailed deer) as the most likely host sustaining sylvatic transmission. Conclusions: CVV has a continental-level, widespread transmission potential. Large areas of North America have suitable climate, vectors, and hosts for CVV emergence, establishment, and spread. We identified geographical hotspots that have no confirmed CVV reports to date and, in view of CVV misdiagnosis or underreporting, can guide future surveillance to specific localities and species.
Widespread Circulation of Tick-Borne Viruses in Virginia—Evidence of Exposure to Heartland, Bourbon, and Powassan Viruses in Wildlife and Livestock
Garba, Ahmed; Riley, Jennifer; Lahmers, Kevin K.; Eastwood, Gillian (MDPI, 2024-04-30)
Emerging tick-borne viruses such as Powassan virus (POWV), Bourbon virus (BRBV), and Heartland virus (HRTV), whilst rare, can cause severe health problems in humans. While limited clinical cases have been reported thus far in Virginia, the presence of tick-borne viruses poses a serious health threat, and the extent of their prevalence in Virginia is unknown. Here, we sought evidence of POWV, BRBV, and HRTV exposure in Virginia via a serological assessment of wildlife and livestock. Wildlife in Virginia were found to be seropositive against POWV (18%), BRBV (8%), and HRTV (5%), with western and northern regions of the state having a higher prevalence. Multiple wildlife species were shown to have been exposed to each virus examined. To a lesser extent, cattle also showed exposure to tick-borne viruses, with seroprevalences of 1%, 1.2%, and 8% detected in cattle against POWV, BRBV, and HRTV, respectively. Cross-reactivity against other known circulating mosquito-borne flaviviruses was ruled out. In conclusion, there is widespread exposure to tick-borne viruses in western and northern Virginia, with exposure to a diverse range of animal populations. Our study provides the first confirmation that HRTV is circulating in the Commonwealth. These findings strengthen the existing evidence of emerging tick-borne viruses in Virginia and highlight the need for public health vigilance to avoid tick bites.
Peptidoglycan in osteoarthritis synovial tissue is associated with joint inflammation
Holub, Meaghan N.; Wahhab, Amanda; Rouse, Joseph R.; Danner, Rebecca; Hackner, Lauren G.; Duris, Christine B.; McClune, Mecaila E.; Dressler, Jules M.; Strle, Klemen; Jutras, Brandon L.; Edelstein, Adam I.; Lochhead, Robert B. (2024-03-27)
Objectives: Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine if PG is present in synovial tissue of osteoarthritis patients at the time of primary total knee arthroplasty (TKA), and if its presence is associated with inflammation and patient reported outcomes. Methods: Intraoperative synovial tissue and synovial fluid samples were obtained from 56 patients undergoing primary TKA, none of whom had history of infection. PG in synovial tissue was detected by immunohistochemistry (IHC) and immunofluorescence microscopy (IFM). Synovial tissue inflammation and fibrosis were assessed by histopathology and synovial fluid cytokine quantification. Primary human fibroblasts isolated from arthritis synovial tissue were stimulated with PG to determine inflammatory cytokine response. Results: A total of 33/56 (59%) of primary TKA synovial tissue samples were positive for PG by IHC, and PG staining colocalized with markers of synovial macrophages and fibroblasts by IFM. Synovial tissue inflammation and elevated IL-6 in synovial fluid positively correlated with PG positivity. Primary human fibroblasts stimulated with PG secreted high levels of IL-6, consistent with ex vivo findings. Interestingly, we observed a significant inverse correlation between PG and age at time of TKA, indicating younger age at time of TKA was associated with higher PG levels. Conclusion: Peptidoglycan is commonly found in synovial tissue from patients undergoing TKA. Our data indicate that PG may play an important role in inflammatory synovitis, particularly in patients who undergo TKA at a relatively younger age.
Expanding the Biosynthetic Toolbox: The Potential and Challenges of In Vitro Type II Polyketide Synthase Research
Rivers, Max A. J.; Lowell, Andrew N. (MDPI, 2024-03-07)
Type II polyketide synthase (PKS) systems are a rich source of structurally diverse polycyclic aromatic compounds with clinically relevant antibiotic and chemotherapeutic properties. The enzymes responsible for synthesizing the polyketide core, known collectively as the minimal cassette, hold potential for applications in synthetic biology. The minimal cassette provides polyketides of different chain lengths, which interact with other enzymes that are responsible for the varied cyclization patterns. Additionally, the type II PKS enzyme clusters offer a wide repertoire of tailoring enzymes for oxidations, glycosylations, cyclizations, and rearrangements. This review begins with the variety of chemical space accessible with type II PKS systems including the recently discovered highly reducing variants that produce polyalkenes instead of the archetypical polyketide motif. The main discussion analyzes the previous approaches with an emphasis on further research that is needed to characterize the minimal cassette enzymes in vitro. Finally, the potential type II PKS systems hold the potential to offer new tools in biocatalysis and synthetic biology, particularly in the production of novel antibiotics and biofuels.
SARS-CoV-2 Specific Nanobodies Neutralize Different Variants of Concern and Reduce Virus Load in the Brain of h-ACE2 Transgenic Mice
Pavan, María Florencia; Bok, Marina; Betanzos San Juan, Rafael; Malito, Juan Pablo; Marcoppido, Gisela Ariana; Franco, Diego Rafael; Militelo, Daniela Ayelen; Schammas, Juan Manuel; Bari, Sara Elizabeth; Stone, William; López, Krisangel; Porier, Danielle LaBrie; Muller, John Anthony; Auguste, A. Jonathan; Yuan, Lijuan; Wigdorovitz, Andrés; Parreño, Viviana Gladys; Ibañez, Lorena Itat (MDPI, 2024-01-25)
Since the beginning of the COVID-19 pandemic, there has been a significant need to develop antivirals and vaccines to combat the disease. In this work, we developed llama-derived nanobodies (Nbs) directed against the receptor binding domain (RBD) and other domains of the Spike (S) protein of SARS-CoV-2. Most of the Nbs with neutralizing properties were directed to RBD and were able to block S-2P/ACE2 interaction. Three neutralizing Nbs recognized the N-terminal domain (NTD) of the S-2P protein. Intranasal administration of Nbs induced protection ranging from 40% to 80% after challenge with the WA1/2020 strain in k18-hACE2 transgenic mice. Interestingly, protection was associated with a significant reduction in virus replication in nasal turbinates and a reduction in virus load in the brain. Employing pseudovirus neutralization assays, we identified Nbs with neutralizing capacity against the Alpha, Beta, Delta, and Omicron variants, including a Nb capable of neutralizing all variants tested. Furthermore, cocktails of different Nbs performed better than individual Nbs at neutralizing two Omicron variants (B.1.529 and BA.2). Altogether, the data suggest the potential of SARS-CoV-2 specific Nbs for intranasal treatment of COVID-19 encephalitis.

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