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

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2022 CeZAP Infectious Diseases Symposium
(Virginia Tech, 2022-10-07)
A program for the symposium held on October 7, 2022, at The Inn at Virginia Tech.
2023 CeZAP Infectious Diseases Research Symposium
(Virginia Tech, 2023-10)
A program for the symposium held on October 6, 2023, at The Inn at Virginia Tech.
Alphavirus Particles Can Assemble with an Alternate Triangulation Number
Kaelber, Jason T.; Chmielewski, David; Chiu, Wah; Auguste, A. Jonathan (MDPI, 2022-11-27)
Alphaviruses are spherical, enveloped RNA viruses primarily transmitted by mosquitoes, and cause significant arthritogenic and neurotropic disease in humans and livestock. Previous reports have shown that—in contrast to prototypical icosahedral viruses—alphaviruses incorporate frequent defects, and these may serve important functions in the viral life cycle. We confirm the genus-wide pleomorphism in live viral particles and extend our understanding of alphavirus assembly through the discovery of an alternate architecture of Eastern equine encephalitis virus (EEEV) particles. The alternate T = 3 icosahedral architecture differs in triangulation number from the classic T = 4 icosahedral organization that typifies alphaviruses, but the alternate architecture maintains the quasi-equivalence relationship of asymmetric units. The fusion spike glycoproteins are more loosely apposed in the T = 3 form with corresponding changes in the underlying capsid protein lattice. This alternate architecture could potentially be exploited in engineering alphavirus-based particles for delivery of alphaviral or other RNA.
Auranofin exerts antibacterial activity against Neisseria gonorrhoeae in a female mouse model of genital tract infection
Elhassanny, Ahmed E. M.; Abutaleb, Nader S.; Seleem, Mohamed N. (PLOS, 2022-04-21)
Neisseria gonorrhoeae has been classified by the U.S. Centers for Disease Control and Prevention as an urgent threat due to the rapid development of antibiotic resistance to currently available antibiotics. Therefore, there is an urgent need to find new antibiotics to treat gonococcal infections. In our previous study, the gold-containing drug auranofin demonstrated potent in vitro activity against clinical isolates of N. gonorrhoeae, including multidrug-resistant strains. Therefore, the aim of this study was to investigate the in vivo activity of auranofin against N. gonorrhoeae using a murine model of vaginal infection. A significant reduction in N. gonorrhoeae recovered from the vagina was observed for infected mice treated with auranofin compared to the vehicle over the course of treatment. Relative to the vehicle, after three and five days of treatment with auranofin, a 1.04 (91%) and 1.40 (96%) average log(10)-reduction of recovered N. gonorrhoeae was observed. In conclusion, auranofin has the potential to be further investigated as a novel, safe anti-gonococcal agent to help meet the urgent need for new antimicrobial agents for N. gonorrhoeae infection.
Climate change and infectious disease: a review of evidence and research trends
Van de Vuurst, Paige; Escobar, Luis E. (2023-05-16)
Background Climate change presents an imminent threat to almost all biological systems across the globe. In recent years there have been a series of studies showing how changes in climate can impact infectious disease transmission. Many of these publications focus on simulations based on in silico data, shadowing empirical research based on field and laboratory data. A synthesis work of empirical climate change and infectious disease research is still lacking. Methods We conducted a systemic review of research from 2015 to 2020 period on climate change and infectious diseases to identify major trends and current gaps of research. Literature was sourced from Web of Science and PubMed literary repositories using a key word search, and was reviewed using a delineated inclusion criteria by a team of reviewers. Results Our review revealed that both taxonomic and geographic biases are present in climate and infectious disease research, specifically with regard to types of disease transmission and localities studied. Empirical investigations on vector-borne diseases associated with mosquitoes comprised the majority of research on the climate change and infectious disease literature. Furthermore, demographic trends in the institutions and individuals published revealed research bias towards research conducted across temperate, high-income countries. We also identified key trends in funding sources for most resent literature and a discrepancy in the gender identities of publishing authors which may reflect current systemic inequities in the scientific field. Conclusions Future research lines on climate change and infectious diseases should considered diseases of direct transmission (non-vector-borne) and more research effort in the tropics. Inclusion of local research in low- and middle-income countries was generally neglected. Research on climate change and infectious disease has failed to be socially inclusive, geographically balanced, and broad in terms of the disease systems studied, limiting our capacities to better understand the actual effects of climate change on health.
Climate change linked to vampire bat expansion and rabies virus spillover
Van de Vuurst, Paige; Qiao, Huijie; Soler-Tovar, Diego; Escobar, Luis E. (Wiley, 2023-10)
Bat-borne pathogens are a threat to global health and in recent history have had major impacts on human morbidity and mortality. Examples include diseases such as rabies, Nipah virus encephalitis, and severe acute respiratory syndrome (SARS). Climate change may exacerbate the emergence of bat-borne pathogens by affecting the ecology of bats in tropical ecosystems. Here, we report the impacts of climate change on the distributional ecology of the common vampire bat Desmodus rotundus across the last century. Our retrospective analysis revealed a positive relationship between changes in climate and the northern expansion of the distribution of D. rotundus in North America. Furthermore, we also found a reduction in the standard deviation of temperatures at D. rotundus capture locations during the last century, expressed as more consistent, less-seasonal climate in recent years. These results elucidate an association between D. rotundus range expansion and a continental-level rise in rabies virus spillover transmission from D. rotundus to cattle in the last 50 years of the 120-year study period. This correlative study, based on field observations, offers empirical evidence supporting previous statistical and mathematical simulation-based studies reporting a likely increase of bat-borne diseases in response to climate change. We conclude that the D. rotundus rabies system exemplifies the consequences of climate change augmentation at the wildlife–livestock–human interface, demonstrating how global change acts upon these complex and interconnected systems to drive increased disease emergence.
A comparative analysis exposes an amplification delay distinctive to SARS-CoV-2 Omicron variants of clinical and public health relevance
Brown, Katherine L.; Ceci, Alessandro; Roby, Clinton; Briggs, Russell B.; Ziolo, D.; Korba, R.; Mejia, R.; Kelly, S. T.; Toney, D.; Friedlander, Michael J.; Finkielstein, Carla V. (Taylor & Francis, 2023)
Mutations in the SARS-CoV-2 genome may negatively impact a diagnostic test, have no effect, or turn into an opportunity for rapid molecular screening of variants. Using an in-house Emergency Use Authorized RT-qPCR-based COVID-19 diagnostic assay, we combined sequence surveillance of viral variants and computed PCR efficiencies for mismatched templates. We found no significant mismatches for the N, E, and S set of assay primers until the Omicron variant emerged in late November 2021. We found a single mismatch between the Omicron sequence and one of our assay's primers caused a > 4 cycle delay during amplification without impacting overall assay performance. Starting in December 2021, clinical specimens received for COVID-19 diagnostic testing that generated a Cq delay greater than 4 cycles were sequenced and confirmed as Omicron. Clinical samples without a Cq delay were largely confirmed as the Delta variant. The primer-template mismatch was then used as a rapid surrogate marker for Omicron. Primers that correctly identified Omicron were designed and tested, which prepared us for the emergence of future variants with novel mismatches to our diagnostic assay's primers. Our experience demonstrates the importance of monitoring sequences, the need for predicting the impact of mismatches, their value as a surrogate marker, and the relevance of adapting one's molecular diagnostic test for evolving pathogens.
Complete Genome Sequence of Providencia stuartii CMC-4104, Isolated from a Human Splenic Abscess, Containing Multiple Copies of NDM-1 and PER-1 Carbapenem Resistance Genes
Rao, Jayasimha; Stornelli, Nicholas K.; Everson, Nathan A.; McDaniel, Lauren F.; Gomez De La Espriella, Mariana; Faulhaber, Jason R.; Todd, S. Michelle; Lahmers, Kevin K.; Jensen, Roderick V. (American Society for Microbiology, 2022-08-04)
We report the complete genome sequence of a clinical isolate of Providencia stuartii strain CMC-4104, isolated from a splenic abscess. Oxford Nanopore Technologies (ONT) and Illumina sequencing reads were assembled using Geneious to generate a 4,504,925-bp circular chromosome containing multiple copies of the NDM-1 and PER-1 genes in a genomic resistance island.
Complete Genome Sequence of Pseudomonas aeruginosa CMC-097, Isolated from a Ventilator-Associated Pneumonia Patient, Containing a Novel Carbapenem Resistance Class 1 Integron
Rao, Jayasimha; Adenikinju, Adenike; Kerkering, Thomas M.; Garner, Dorothy C.; Jensen, Roderick, V (2021-09)
We report the complete genome of a clinical strain of Pseudomonas aeruginosa CMC-097, which was isolated from a ventilator-associated pneumonia patient with a chronic infection. Illumina sequence reads were assembled using Geneious to yield a 7,044,064-bp circular chromosome containing a carbapenem resistance integron, In2020.
A database of common vampire bat reports
van de Vuurst, Paige; Diaz, M. Monica; Rodriguez-San Pedro, Annia; Allendes, Juan Luis; Brown, Natalie; Gutierrez, Juan David; Zarza, Heliot; de Oliveira, Stefan V.; Cardenas-Canales, Elsa; Barquez, Ruben M.; Escobar, Luis E. (Nature Portfolio, 2022-02-16)
The common vampire bat (Desmodus rotundus) is a sanguivorous (i.e., blood-eating) bat species distributed in the Americas from northern Mexico southwards to central Chile and Argentina. Desmodus rotundus is one of only three mammal species known to feed exclusively on blood, mainly from domestic mammals, although large wildlife and occasionally humans can also serve as a food source. Blood feeding makes D. rotundus an effective transmissor of pathogens to its prey. Consequently, this species is a common target of culling efforts by various individuals and organizations. Nevertheless, little is known about the historical distribution of D. rotundus. Detailed occurrence data are critical for the accurate assessment of past and current distributions of D. rotundus as part of ecological, biogeographical, and epidemiological research. This article presents a dataset of D. rotundus historical occurrence reports, including >39,000 locality reports across the Americas to facilitate the development of spatiotemporal studies of the species. Data are available at https://doi.org/10.6084/ m9.figshare.15025296.
A database of global coastal conditions
Castaneda-Guzman, Mariana; Mantilla-Saltos, Gabriel; Murray, Kris A.; Settlage, Robert; Escobar, Luis E. (2021-11-26)
Remote sensing satellite imagery has the potential to monitor and understand dynamic environmental phenomena by retrieving information about Earth's surface. Marine ecosystems, however, have been studied with less intensity than terrestrial ecosystems due, in part, to data limitations. Data on sea surface temperature (SST) and Chlorophyll-a (Chlo-a) can provide quantitative information of environmental conditions in coastal regions at a high spatial and temporal resolutions. Using the exclusive economic zone of coastal regions as the study area, we compiled monthly and annual statistics of SST and Chlo-a globally for 2003 to 2020. This ready-to-use dataset aims to reduce the computational time and costs for local-, regional-, continental-, and global-level studies of coastal areas. Data may be of interest to researchers in the areas of ecology, oceanography, biogeography, fisheries, and global change. Target applications of the database include environmental monitoring of biodiversity and marine microorganisms, and environmental anomalies.
Discovery of Two Inhibitors of the Type IV Pilus Assembly ATPase PilB as Potential Antivirulence Compounds
Dye, Keane J.; Vogelaar, Nancy J.; O'Hara, Megan; Sobrado, Pablo; Santos, Webster; Carlier, Paul R.; Yang, Zhaomin (American Society for Microbiology, 2022-12)
Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. With the pressing antibiotic resistance pandemic, antivirulence has been increasingly explored as an alternative strategy against bacterial infections. The bacterial type IV pilus (T4P) is a well-documented virulence factor and an attractive target for small molecules for antivirulence purposes. The PilB ATPase is essential for T4P biogenesis because it catalyzes the assembly of monomeric pilins into the polymeric pilus filament. Here, we describe the identification of two PilB inhibitors by a high-throughput screen (HTS) in vitro and their validation as effective inhibitors of T4P assembly in vivo. We used Chloracidobacterium thermophilum PilB as a model enzyme to optimize an ATPase assay for the HTS. From a library of 2,320 compounds, benserazide and levodopa, two approved drugs for Parkinson's disease, were identified and confirmed biochemically to be PilB inhibitors. We demonstrate that both compounds inhibited the T4P-dependent motility of the bacteria Myxoccocus xanthus and Acinetobacter nosocomialis. Additionally, benserazide and levodopa were shown to inhibit A. nosocomialis biofilm formation, a T4P-dependent process. Using M. xanthus as a model, we showed that both compounds inhibited T4P assembly in a dose-dependent manner. These results suggest that these two compounds are effective against the PilB protein in vivo. The potency of benserazide and levodopa as PilB inhibitors both in vitro and in vivo demonstrate potentials of the HTS and its two hits here for the development of anti-T4P chemotherapeutics.IMPORTANCE Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. Here, we report the development and implementation of a method to identify anti-T4P chemicals from compound libraries by high-throughput screen. This led to the identification and validation of two T4P inhibitors both in the test tubes and in bacteria. The discovery and validation pipeline reported here as well as the confirmation of two anti-T4P inhibitors provide new venues and leads for the development of chemotherapeutics against antibiotic-resistant infections.
The Distribution, Seasonal Abundance, and Environmental Factors Contributing to the Presence of the Asian Longhorned Tick (Haemaphysalis longicornis, Acari: Ixodidae) in Central Appalachian Virginia
Cumbie, Alexandra N.; Whitlow, Amanda M.; Arneson, Alicia; Du, Zhiyuan; Eastwood, Gillian (Oxford University Press, 2022-05-30)
Over the past decade, Haemaphysalis longicornis, the Asian longhorned tick, has undergone a geographic range expansion in the United States, from its historical range in east Asia. This tick has been characterized by its frequent parasitism of livestock, an ability to reproduce through parthenogenesis, and its ability to transmit a variety of vector-borne pathogens to livestock, wildlife, and human hosts in its native geographic range. Thus far in the United States, 17 states have reported H. longicornis populations, including 38 counties in Virginia. These numbers come from presence-absence reports provided to the U.S. Department of Agriculture, but little has been reported about this ticks' seasonality in Virginia or its habitat preferences. Our current study detected H. longicornis populations in seven of the nine surveyed counties in Virginia. Haemaphysalis longicornis were observed in multiple habitat types including mixed hardwood forests and pastures, with abundant H. longicornis populations detected at one particular pasture site in Wythe County. This study also attempted to investigate environmental conditions that may be of importance in predicting tick presence likelihood. While sample size limited the scope of these efforts, habitat type and climatic metrics were found to be important indicators of H. longicornis collection success and abundance for both the nymphal and larval life stages. This current study reports useful surveillance data for monitoring these tick populations as they become established in the western half of Virginia and provides insight into their current distribution and maintenance over a large study region.
Dithiocarbamates effectively inhibit the alpha-carbonic anhydrase from Neisseria gonorrhoeae
Giovannuzzi, Simone; Abutaleb, Nader S.; Hewitt, Chad S.; Carta, Fabrizio; Nocentini, Alessio; Seleem, Mohamed N.; Flaherty, Daniel P.; Supuran, Claudiu T. (Taylor & Francis, 2022-01-01)
Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the alpha-class carbonic anhydrase (CA, EC 4.2.1.1) from Neisseria gonorrhoeae, NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. K(I)s ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against N. gonorrhoeae, and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 mu g/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.
Diversity and genomics of giant viruses in the North Pacific Subtropical Gyre
Farzad, Roxanna; Ha, Anh D.; Aylward, Frank O. (Frontiers, 2022-11)
Large double-stranded DNA viruses of the phylum Nucleocytoviricota, often referred to as "giant viruses," are ubiquitous members of marine ecosystems that are important agents of mortality for eukaryotic plankton. Although giant viruses are known to be prevalent in marine systems, their activities in oligotrophic ocean waters remain unclear. Oligotrophic gyres constitute the majority of the ocean and assessing viral activities in these regions is therefore critical for understanding overall marine microbial processes. In this study, we generated 11 metagenome-assembled genomes (MAGs) of giant viruses from samples previously collected from Station ALOHA in the North Pacific Subtropical Gyre. Phylogenetic analyses revealed that they belong to the orders Imitervirales (n =6), Algavirales (n =4), and Pimascovirales (n =1). Genome sizes ranged from similar to 119-574 kbp, and several of the genomes encoded predicted TCA cycle components, cytoskeletal proteins, collagen, rhodopsins, and proteins potentially involved in other cellular processes. Comparison with other marine metagenomes revealed that several have broad distribution across ocean basins and represent abundant viral constituents of pelagic surface waters. Our work sheds light on the diversity of giant viruses present in oligotrophic ocean waters across the globe.
Drugs and Biodiversity Loss: Narcotraffic-Linked Landscape Change in Guatemala
Winter, Steven N.; Eastwood, Gillian; Barrios-Izás, Manuel A. (IntechOpen, 2022-10-13)
Characteristic of the Anthropocene, human impacts have resulted in worldwide losses in forested land cover, which can directly and indirectly drive biodiversity loss. The global illicit drug trade is one source of deforestation directly implicated with habitat loss in Central America, typically for drug trafficking and livestock production for money laundering. Given reports of deforestation in Central America linked to narcotraffic, we explored vegetation changes within Guatemala’s highly biodiverse Maya Biosphere Reserve by examining trends suggestive of deforestation in a protected area. As such, we collected satellite-derived data in the form of enhanced vegetation index (EVI), as well as history of burned areas, published human-“footprint” data, official population density, and artificial light activity in Laguna del Tigre National Park from 2002 to 2020 for descriptive analysis. We found consistent reductions in EVI and trends of anomalous losses of vegetation despite a baseline accounting for variation within the park. Analyses revealed weak correlations (R2 ≤ 0.26) between EVI losses and official sources of anthropogenic data, which may be attributable to the data’s limited spatial and temporal resolution. Alarmingly, simple analyses identified vegetation losses within a protected area, thus emphasizing the need for additional monitoring and science-based, but interdisciplinary policies to protect this biodiversity hotspot.
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.
Editorial: Disease Ecology and Biogeography
Escobar, Luis E.; Morand, Serge (Frontiers, 2021-10-29)
EGR1 Upregulation during Encephalitic Viral Infections Contributes to Inflammation and Cell Death
Lehman, Caitlin W.; Smith, Amy; Kelly, Jamie; Jacobs, Jonathan L.; Dinman, Jonathan D.; Kehn-Hall, Kylene (MDPI, 2022-06-02)
Early growth response 1 (EGR1) is an immediate early gene and transcription factor previously found to be significantly upregulated in human astrocytoma cells infected with Venezuelan equine encephalitis virus (VEEV). The loss of EGR1 resulted in decreased cell death but had no significant impact on viral replication. Here, we extend these studies to determine the impacts of EGR1 on gene expression following viral infection. Inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2 were upregulated in VEEV-infected cells, which was partially dependent on EGR1. Additionally, transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, KLF4, EGR2, and EGR4 were found to be partially transcriptionally dependent on EGR1. We also examined the role of EGR1 and the changes in gene expression in response to infection with other alphaviruses, including eastern equine encephalitis virus (EEEV), Sindbis virus (SINV), and chikungunya virus (CHIKV), as well as Zika virus (ZIKV) and Rift Valley fever virus (RVFV), members of the Flaviviridae and Phenuiviridae families, respectively. EGR1 was significantly upregulated to varying degrees in EEEV-, CHIKV-, RVFV-, SINV-, and ZIKV-infected astrocytoma cells. Genes that were identified as being partially transcriptionally dependent on EGR1 in infected cells included ATF3 (EEEV, CHIKV, ZIKV), JUN (EEEV), KLF4 (SINV, ZIKV, RVFV), CXCL3 (EEEV, CHIKV, ZIKV), CXCL8 (EEEV, CHIKV, ZIKV, RVFV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV, RVFV), and PTGS2 (EEEV, CHIKV, ZIKV). Additionally, inhibition of the inflammatory gene PTGS2 with Celecoxib, a small molecule inhibitor, rescued astrocytoma cells from VEEV-induced cell death but had no impact on viral titers. Collectively, these results suggest that EGR1 induction following viral infection stimulates multiple inflammatory mediators. Managing inflammation and cell death in response to viral infection is of utmost importance, especially during VEEV infection where survivors are at-risk for neurological sequalae.
Endogenous giant viruses contribute to intraspecies genomic variability in the model green alga Chlamydomonas reinhardtii
Moniruzzaman, Mohammad; Erazo-Garcia, Maria P.; Aylward, Frank O. (Oxford University Press, 2022-11)
Chlamydomonas reinhardtii is a unicellular eukaryotic alga that has been studied as a model organism for decades. Despite an extensive history as a model system, phylogenetic and genetic characteristics of viruses infecting this alga have remained elusive. We analyzed high-throughput genome sequence data of C. reinhardtii field isolates, and in six we discovered sequences belonging to endogenous giant viruses that reach up to several 100 kb in length. In addition, we have also discovered the entire genome of a closely related giant virus that is endogenized within the genome of Chlamydomonas incerta, the closest sequenced relative of C. reinhardtii. Endogenous giant viruses add hundreds of new gene families to the host strains, highlighting their contribution to the pangenome dynamics and interstrain genomic variability of C. reinhardtii. Our findings suggest that the endogenization of giant viruses may have important implications for structuring the population dynamics and ecology of protists in the environment.

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