With research expertise in 10 different thematic areas, the CeZAP affiliated faculty tackle comprehensive and complex problems in infectious diseases through interdisciplinary team approaches including engineering, social, biomedical, veterinary, medical, and plant sciences.
The CeZAP faculty conducts basic and mechanistic research in infectious diseases, and strives to translate into tangible results such as vaccines, antimicrobial drugs, intelligent infrastructure, and diagnostics that benefit the global society.
Through pilot grant programs, CeZAP promotes cross-disciplinary and new scientific collaborations to position Virginia Tech to become more competitive in acquiring large federally-funded center, program, and training grants.
The Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP) at Virginia Tech requests pilot grant applications to build interdisciplinary research teams in the broad area of infectious diseases, leading to collaborative extramural grant submissions. These pilot grants are supported financially by Fralin Life Sciences Institute and Agency 229. Priority will be given to proposals seeking to advance CeZAP’s mission to promote and foster interdisciplinary and transdisciplinary research collaborations across different colleges.
Brandon Jutras (PI, CALS), Coy Allen (Co-PI, VMCVM); Pablo Sobrado, (Co-I, CALS); Rich Helm (Co-I, CALS)
Title: Reprogramming the peptidoglycan cell-wall of Borrelia burgdorferi to understand, treat, and cure chronic Lyme disease
Summary: Late stage manifestations of Lyme disease, such as Lyme arthritis, are complex and poorly understood. We have discovered that unique fragments of peptidoglycan (PG)—an essential component of the bacterial cell wall— are released by Borrelia burgdorferi, the Lyme disease agent, during growth. Virtually all bacteria have PG but, as it turns out, the chemical composition of B. burgdorferi PG is unique and unlike any previously described. B. burgdorferi PG is capable of both persisting in Lyme arthritis patients’ months after infection and causing arthritis in a mouse model. Here, we propose to alter the chemistry of B. burgdorferi PG and determine the impacts on infection, persistence, and pathogenesis.
Mohamed Seleem (PI, VMCVM), Paul R. Carlier (Co-PI, COS)
Title: Optimization of salicylamide analogs for combating multidrug-resistant Neisseria Gonorrhoeae
Summary: Studies proposed in this grant application build upon advances made in collaborative efforts between the Seleem and Carlier laboratories (College of Veterinary Medicine and College of Science, respectively) over the past few months to optimize the repurposed FDA-approved drug, salicylamide (1a) against Neisseria gonorrhoeae. The Carlier lab will carry out analog design and synthesis while the Seleem lab will perform the antibacterial study with the goal to increase potency and efficacy of salicylamide.
Juhong Chen (PI, CALS/COE), Clay Wright (Co-PI, CALS/COE); Lijuan Yuan (Co-PI, VMCVM); Matthew Moore (Co-PI, University of Massachusetts Amherst)
Title: Development of engineered yeasts to concentrate and purify foodborne viruses for easier detection
Summary: Viruses pose grave threats to public health and the global economy because of their low infectious dose and difficulty of detection. Many analytical methods exist for detection of environmentally present viruses, but upstream concentration is required. However, current viral concentration techniques are not ideal, limiting the ability to detect most viruses routinely. We aim to engineer yeast displaying specific virus-binding peptides on their surface proteins to facilitate concentration and purification of viruses for easier detection.
Michael Schulz (PI, COS), Lijuan Yuan (Co-PI, VMCVM)
Title: Developing Antiviral Polymers to Inhibit Norovirus Infection
Summary: Noroviruses (NoVs) are the most prevalent cause of nonbacterial acute gastroenteritis, but no FDA-approved vaccines or anti-viral drugs currently exist for NoV infection. Antiviral polymers can prevent viral infections but have never been investigated for NoV treatment. We will synthesize the first anti-NoV materials and evaluate them in the gnotobiotic (Gn) pig model. This state-of-the-art animal model will enable us to draw strong translational conclusions about the potential clinical efficacy of these novel antiviral materials.
Song Li (PI, CALS), Juhong Chen (Co-PI, COE/CALS); Boris Vinatzer (Co-PI, CALS)
Title: RACING: Developing a Rapid Assay using CRISPR, artificial Intelligence, and Nanopore meta-Genome sequencing for emerging pathogen detection
Summary: Developing diagnostic assays for emerging pathogens is typically time consuming and cannot meet the need to stop rapidly spreading diseases. Herein, we plan to develop an approach that substantially simplifies the pipeline for diagnostic assay development. Our approach includes: (1) Improve our cutting-edge machine learning algorithms to identify signature nucleotide sequences for pathogens from culture-free metagenomic sequencing data; and (2) optimize a CRISPR-based biosensing system to detect pathogen DNA using these signatures.
Luis Escobar (PI, CNRE), Gill Eastwood (Co-PI, CALS); Mark Ford (Co-PI, CNRE)
Title: Relationship between Lyme disease and land-form variables
Summary: Our goal is to better elucidate the relationship between Lyme disease and other tick-borne diseases and landscape configuration, accounting for microclimate, tick ecology, and other environmental factors. This project is inspired by the research question: Is tick-borne disease transmission predictable in space and time based on quantifiable environmental correlates? The project hypothesis is that predictability of tick occurrence will vary according to the scale studied. We will model the distribution and abundance of ticks responsible of Lyme disease across diverse environmental conditions.
Jonathan Auguste (PI, CALS), Rana Ashkar (Co-PI, COS); Coy Allen (Co-I, VMCVM); Jesse Erasmus (Co-I, HDT Bio Corp)
Title: Evaluating the safety and efficacy of a novel vaccine strategy for Cache Valley virus
Summary: Cache Valley virus (CVV) is an important zoonotic arthropod-borne virus in North America. CVV can potentially emerge and become a major pathogen of humans, ovine, caprine, bovine, equid, and poultry species, resulting in potentially devastating consequences on our economy, food availability, human and animal health. To circumvent this threat, we will develop an RNA vaccine that demonstrates exceptional immunogenicity and outstanding safety in murine models, and completely protects against all aspects of CVV disease.
Nisha Duggal (PI, VMCVM), Linsey Marr (Co-PI, COE); Stanca Ciupe (Co-PI, COS)
Title: Aerosol transmission potential of SARS-CoV-2 in exhaled breath
Summary: SARS-CoV-2 is a respiratory virus, with transmission occurring via droplets released during coughing and sneezing. SARS-CoV-2 is also detected in air, and asymptomatic individuals may transmit SARS-CoV-2 in aerosols within exhaled breath. Using a hamster model of SARS-CoV-2 transmission, we will measure infectious SARS-CoV-2 in aerosols collected from exhaled breath and quantify the airborne transmission potential of SARS-CoV-2. This work will improve our understanding of SARS-CoV-2 transmission and lead to future work developing interventions.
Clément Vinauger (PI, CALS), Lauren Childs (Co-PI, COS); James Weger-Lucarelli (Co-I, VMCVM)
Title: Effects of altered larval growing conditions on the vectorial capacity of Aedes aegypti mosquitoes
Summary: The environmental growing conditions of mosquito larvae affect their development and, eventually, alter the body size and host-seeking behavior of adult females. Here, we propose a collaborative and multidisciplinary approach to 1) determine the sensory basis of this phenomenon, 2) define its impact on mosquitoes’ ability to transmit viruses, and 3) integrate this new knowledge in a mathematical model linking environmental effects on mosquito traits with their consequences on population dynamics and vectorial capacity.
Gillian Eastwood (PI, CALS), Luis Escobar (Co-PI, CNRE)
Title: The Effect of Forest Degradation on Mosquito Arboviruses
Summary: Landscape changes can influence biodiversity composition and the emergence of outbreaks, triggering spillover flow of pathogenic agents to incidental hosts. We focus on vector-borne disease, and determine vectors of arboviral pathogens in a previously unexplored region of Guatemala which is experiencing habitat destruction of intact pristine forest. By investigating both altered mosquito vector diversity and infection prevalence of mosquitoes in this system, we can define the impact of a deforestation gradient upon disease risk.
West Nile virus (WNV), St. Louis encephalitis virus (SLEV), and Usutu virus (USUV) are closely-related zoonotic arboviruses that cause severe neuroinvasive disease in humans, for which there are no vaccines or therapeutics available. WNV, SLEV, and USUV are maintained in mosquito-bird transmission cycles, with overlapping Culex vectors and passerine hosts. WNV emerged in the Americas in 1999, where it is now the most common mosquito-borne disease in the continental U.S. SLEV, which was first documented in the U.S. in 1933, recently re-emerged in the U.S. in 2015. USUV is currently emerging in Europe, where it has been introduced from Africa at least 3 times in the past two decades. To understand previous flavivirus disease emergence and to predict the continued global emergence of flavivirus disease, there is a critical need to identify the areas at risk for the establishment of their transmission cycles. We hypothesize that the novel SLEV genotype and USUV have established or have the potential to establish transmission cycles in North America due to the competence of local birds and mosquitoes and the evasion of WNV immunity in birds, thus leading to an increased risk of neuroinvasive disease in humans. This project will address this hypothesis by identifying competent hosts and vectors for USUV in North America and assessing the impact of WNV immunity in birds on subsequent SLEV infection. The findings from this study will inform surveillance strategies and provide parameters for modeling the risk of USUV and SLEV global spread.
The ability of mosquitoes to detect, process, and respond to olfactory information emitted by their hosts can affect disease transmission. The magnitude of their responses to odors varies drastically throughout the day, but, despite their clear epidemiological relevance, the neural and molecular mechanisms acting at the circuit levels to control mosquito behavior remain to be determined. The proposed research will employ an interdisciplinary approach combining behavioral assays, electrophysiological recordings, transcriptomic analysis, and CRISPR/Cas9 gene editing, to characterize rhythms in odorant detection, perception, and olfactory behavior, thereby identifying the genetic basis of the temporal plasticity in mosquito-host interactions.
NIH 1R21AI159382-01 "A chromosome-level genome assembly for the major African malaria vector Anopheles gambiae" $435,912 PI Igor Sharakhov
An important requirement for the success of genome-based strategies to malaria vector control is the availability of high-quality assemblies of mosquito genomes, which will enable researchers to identify gene targets that could be manipulated. Toward this goal, the proposed project will produce a chromosome-level genome assembly for Anopheles gambiae using Oxford Nanopore and Illumina sequencing, Hi-C scaffolding, and physical mapping.
NIH 1R01GM140361-01 "Regulation of spore peptidoglycan modification" $1.6 million with $250,000 to the Popham Lab PI Aimee Shen, TUSM, Co-Investigators Sylvie Doublie, UVM and David Popham, VT
The bacterial pathogen, Clostridioides difficile, has been designated an urgent threat to the US healthcare system by the Centers for Disease Control. In order for C. difficile to initiate infection, its infectious spore form must germinate in the gut of susceptible individuals. Since spore germination depends on the spore cell wall undergoing specific modifications, determining how this process occurs in C. difficile could inform the development of strategies for preventing C. difficile disease transmission and recurrence.
NIH 1R01GM138630-01 "Studies of Bacterial Endospore Germination" $1.22 million PI David Popham
Bacterial endospores are agents of infection and contamination leading to serious human disease, including colitis, anthrax, botulism, tetanus, and food poisoning. These spores are highly dormant and thus long-lived and very resistant to normal decontamination procedures, yet are able to germinate and initiate growth rapidly in a conducive environment. Studies in this project will reveal spore structural elements that are important for dormancy, resistance, and germination, and that can be targeted for new decontamination procedures.
NIH 1R21AI159800-01 "Detecting released peptidoglycan fragments as a biomarker for direct diagnosis of acute and chronic Lyme Disease PI Brandon Jutras, Co-PI: Coy Allen and Rich Helm
Lyme disease is a pervasive epidemic in the United States. Despite the continual increase in cases over the past 25 years, we do not have an effective way to diagnosis patients. Instead of detecting the bacterium, or a bacterial product, we rely on an indirect proxy— detecting the human immune response. There are several flaws with this practice. First, an indirect method tells physicians if the patient was exposed, not if they are currently infected. Mounting an antibody response can take weeks to detect, instead of having an immediate answer. What’s worse, these test results can be inaccurate. We have discovered that the bacterium that causes Lyme disease sheds large amounts of its’ cell-wall into its environment as it grows. Also, the cell-wall of the Lyme disease agent is unique and unlike virtually all other bacteria. We have developed a highly sensitive method to detect this cell- wall material. Using experimental mouse models, along with human patient samples, we will critically test the sensitivity and specificity of our method. Our findings may change the way we diagnose Lyme disease.
NIH 2R01AI099250-05A1 "Molecular mechanism of juveline hormone action in mosquito reproduction" 2 Million PI: Jinsong Zhu
Juvenile hormone plays a critical role in mosquito egg maturation; its synthetic mimics have shown promise to effectively sterilize adult female mosquitoes. The goal of this project is to elucidate the molecular actions of juvenile hormone and its mimics in mosquitoes and to identify new potential target sites in the juvenile hormone signaling pathway for pesticide development.
NIH R21 AI149177-01A1 "The role of the Type IV pili ATPase PilT as a surface sensor in regulating cell division" $409,449 PI: Stephen Melville
Bacterial pathogens are able to sense when they contact a surface and turn on virulence genes in response. One of the major phenotypes seen in rod-shaped bacteria is to increase the length of the cell, which enables them to adhere better and absorb more nutrients from the host. The anaerobic pathogen Clostridium perfringens has evolved a sensing mechanism that ties the activity of type IV pili, which are needed for surface attachment, to the cell division machinery. The main player in this sensing is the PilT retraction ATPase, which we hypothesize interacts differentially with pilus proteins in liquid but shifts to inactivating cell division proteins on surfaces, thereby leading to increased cell length.
The following CeZAP Affiliated Faculty have been awarded grants through the Virginia Tech College of Science Lay Nam Chang Dean’s Discovery Fund
- PI Birgit Scharf "Mechanisms of Salmonella enterica Infection by Bacteriophage Chi and Identification of Targets for Phage Therapy"
- PI Zhaomin Yang, Co-PI Anne Brown "Experimentally and Computationally Establishing C. diff PilB for Antivirulence Drug Discovery
The following CeZAP Affiliated Faculty have been awarded grants through the Virginia Tech Intellectual Properties with Link + License + Launch Proof-of-Concept Program
- Paul Carlier - New Therapeutics to Prevent Malaria Resurgence Approximately half of the world’s population remain at risk of malaria infection each year and current vaccines are only 50 percent effective. This reality necessitates drug therapy for those infected and as emerging parasites show increasing resistance to currently available drugs. This project is directed to early drug development activities for a therapeutic drug that offers a unique set of attributes to prevent malaria resurgence and potentially offer a cure for malaria itself.
- William Ducker - Antimicrobial Coating The funding will support early commercialization activities for antimicrobial coatings that can be applied to common-use surfaces, such as knobs, hand grips, service trays or a wide range of other articles. This technology offers numerous benefits over continuously disinfecting common surfaces manually using sprays, UV light, or other mechanisms. Subsequently, Ducker has formed a startup to pursue commercialization of this technology.
Nisha Duggal, Bryan Hsu and Clay Wright have won seed funding from ICTAS for innovative new projects
- SARS-CoV-2 transmission in airborne particles. Nisha Duggal, an assistant professor of molecular and cellular biology, with Linsey Marr, Charles P. Lunsford Professor of civil and environmental engineering. SARS-CoV-2 can be transmitted from one host to another in respiratory particles emitted by someone infected with the virus. Coughing, talking, and exhaling all produce these particles in various sizes that behave in different ways and may carry different amounts of infectious virus. This project will fill in missing information about the relationships between particle size, kinetics, and infectivity. Understanding those dynamics in more detail will help elucidate transmission mechanisms for the virus, insights that can inform the development of more effective mitigation strategies.
- Treatment and mitigation of foodborne illness using a genetic-based anti-virulence strategy. Bryan Hsu, an assistant professor of biological sciences, with Monica Ponder, a professor of food science and technology. Engineered phages have the potential to reprogram pathogenic bacteria in the gut by neutralizing bacterial infectivity while minimizing the risk of cultivating resistance (a critical flaw of antibiotics), by disarming pathogens so they can be shed naturally without causing disease instead of killing them. Hsu and his colleagues will investigate whether this strategy can reduce the virulence of Salmonella, a major global cause of foodborne illness and death.
- Playing the evolutionary arms race between plants and pathogens in fast-forward. Clay Wright, an assistant professor of biological systems engineering, with John McDowell, a professor in the School of Plant and Environmental Sciences. A crucial component of sustainably ramping up agricultural productivity is stemming crop losses from disease-causing microbes, which are refining their attack mechanisms as quickly as the plants can evolve new defenses against them. The research team will utilize a synthetic biology system that recreates these dynamic plant-pathogen interactions in yeast, focusing on a protein hub that’s critical to the plant immune system but can be attacked by microbes with devastating results. Iteratively manipulating individual plant genes in this automated experimental system will help pinpoint genes that can form the basis of new resistance strategies and offer new insights into plant-pathogen interactions.
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