Infectious Disease Faculty at Virginia Tech
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Program Summary: Mosquito-borne viruses are a global problem, with hundreds of millions of infections per year and more than a billion people at risk. The 1999 introduction of West Nile virus into North America has reminded our culture of how frightening mosquito-borne diseases can be. In 2003, there were 9,858 reported cases of West Nile, including 262 deaths. This contrasts with an estimated 50-100 million cases of dengue fever (DF), and as many as 500,000 cases of dengue hemorrhagic fever (DHF) per year worldwide, resulting in 5,000-10,000 deaths. Currently, viruses such as West Nile virus, LaCrosse virus, and eastern equine encephalitis virus circulate in the state of Virginia, threatening the health and safety of its citizens. Mosquito species which are able of transmitting dengue viruses or yellow fever virus are present in Virginia and in other parts of the U.S. Thus, there is the continual risk of a reintroduction of these deadly viruses into the U.S.. My research program is comprised of both basic and applied aspects. The basic research component focuses on both the viruses and the mosquitoes. I seek to understand, at the molecular and genetic level, how these viruses infect, replicate, and are transmitted by mosquitoes to humans. I also seek to understand the mosquito immune response to these viruses, as unlike people, mosquitoes do not become ill when infected with these deadly viruses. Only by understanding genetic changes in the mosquito, genetic changes in the virus, as well as the effects of different environmental situations can we truly hope to anticipate and prevent mosquito-borne viral outbreaks. The applied component of my research focuses on using this information to design and implement new methods of controlling or preventing mosquito-borne viral disease outbreaks. This includes using genetics to block the mosquito’s ability to transmit viruses, and the development of new diagnostic tools to identify mosquitoes which are more likely to participate in an outbreak.
Program Summary: Chronic inflammation is found at the core of the most devastating and costly diseases afflicting people in the Commonwealth of Virginia, the U.S. and the world. Common inflammatory features in obesity, diabetes, cardiovascular disease, hypertension and cancer include the abnormal recruitment and activation of immune cells. For example, obese and diabetic individuals have higher amounts of immune cells in fat than leaner subjects, whereas patients with cardiovascular disease accumulate immune cells in their blood vessels. Low-grade chronic inflammation significantly contributes to increased severity, more rapid disease progression, and higher mortality rates. We have found that inflammatory processes in general, and obesity-related inflammation in particular, can be attenuated nutritionally through anti-inflammatory receptors found in the nucleus of cells. Interestingly, immune cells are highly responsive to regulation through a nuclear receptor named peroxisome proliferator-activated receptor ☐ (PPAR ☐). The long-term goal of my laboratory is to identify novel, naturally occurring, orally active compounds that bind to this receptor and elicit anti-inflammatory actions. I received funding from the Institute for Biomedical and Public Health Sciences to further characterize the mechanisms by which one of the newly identified botanical compounds, abscisic acid, ameliorates insulin resistance and obesity-related inflammation. This funding has recently been leveraged with support from the National Institutes of Health. Our findings in this area could be used as a proof-of-concept for supporting the development of a botanical center at Virginia Tech aimed at the high-scale identification of new botanicals with anti-inflammatory properties.
Program Summary: Many of the newly emerging diseases in humans, such as West Nile Virus, Hantavirus and Lyme disease, are transmitted between animals and humans. In addition, many human parasitic diseases use insect vectors or require intermediate hosts to survive. Understanding how pathogens and parasites persist in nature and what ecological and environmental factors contribute to disease emergence can assist with control efforts. The current focus of my research is on understanding how biodiversity influences parasites and pathogens in natural systems. Within this realm, I am examining two very different systems. The first system is a host-parasite system involving amphibian and snail hosts and a trematode parasite. I am experimentally examining how changes in the species composition of ponds can influence infection in tadpoles, as well as exploring how features of the landscape influence transmission of the parasite. The second system involves the normal bacterial community that lives on the skin of amphibians. I am examining whether beneficial bacteria can actually prevent infection of the skin with pathogens and whether environmental stressors can alter the outcome of these species interactions. Ecological interactions between species and ongoing environmental changes likely play key roles in the emergence of many diseases in both wildlife and human populations. My research will provide insight into these processes in natural systems.
Program Summary: My research area is toxicology and neuroscience, specifically in the area of insecticides, since most act as nerve poisons. New and safer chemicals are urgently needed for use in human disease control and agriculture. My research program includes studies on both mammals and insects to design chemicals with good selectivity and which are focused on the interactions of small organic molecules with protein receptors found on cell membranes. These organic molecules can be drugs, peptides, neurotransmitters, or insecticides. Most of my research is focused on the mechanisms of how these compounds are toxic to the nervous system, along with investigation into the mechanisms of insecticide resistance. My research approach is multidisciplinary and includes studies of whole animal toxicity, effects on the nervous system, and actions on proteins at the biochemical level.
Dr. Stephen M. Boyle
Professor of Microbiology, Virginia-Maryland Regional College of Veterinary Medicine
Program Summary: The immune system of animals and humans is a complex collection of cells that allow the clearance of disease-producing microorganisms (pathogens) that have crossed the physical barrier presented by the skin or mucous membranes. The immune system produces antibodies and other cells that interact with the pathogens and causes them to be destroyed. When an animal is injected with a vaccine (derived from the pathogen), it causes the immune system to produce antibodies and cells that prevent the pathogen from causing disease. Our laboratory is working to improve a vaccine (Brucella abortus RB51), created at VA Tech and approved by the United States Department of Agriculture in 1996, to prevent the disease called brucellosis that occurs in animals and humans. The vaccine improvement is aimed at other animal diseases by using the original vaccine as a platform to stimulate the immune system to protect against not only brucellosis but other diseases as well (e.g., anthrax). The impact of such a potent vaccine will reduce the cost of producing healthy livestock and health care by preventing the spread of diseases from animals to humans.
Program Summary: La Crosse (LAC) virus is the leading cause of pediatric encephalitis in the United States. Within the past decade, there has been a rapid emergence of the virus and its primary mosquito vector in several southeastern states, including Virginia. This has corresponded to an increase in numbers of human cases of LAC encephalitis in the U.S. and it has become necessary to determine the extent of LAC virus activity in Virginia. This effort, however, is complicated by the possible involvement of two non-native species of mosquitoes that have recently become established in areas where the LAC virus is currently found. It has also been complicated by our inability, because of time, effort, and costs, to directly assess mosquito populations over large areas. As such, two hypotheses are being tested to address these problems. We hypothesize that non-native mosquito vectors are contributing to the increased incidence of LAC virus and that the presence of LAC virus antibody in canine blood can be used as a practical indicator of LAC virus transmission rates to vertebrates, making it possible to use dogs as sentinel animals for LAC virus activity and transmission risk to humans. We are testing this hypothesis in area-wide studies in three regions in southwest Virginia using a combination of field surveys, and analytical, molecular, and geospatial techniques. One of the regions (far southwestern Virginia) has reported human cases of LAC encephalitis and LAC-positive mosquitoes, the second region has LAC-positive mosquitoes but no human cases (New River Valley), and the third region has had neither human cases nor LAC-positive mosquitoes (Shenandoah Valley).
Program Summary: Medicine in the 20th century was transformed by the contribution of organic chemists who prepared dozens of life-saving pharmaceuticals. Even in the present genomic era, new drugs will undoubtedly be responsible for huge improvements in human health. Our research has resulted in the development of new drug candidates for clinical depression and Alzheimer's memory loss, several of which have been granted U.S. patents. Currently, our main focus includes prevention of the brain damage associated with Alzheimer's disease and the development of new agents to limit the spread of malaria by the Anopheles mosquito.
Program Summary: The three processes required to sustain life on earth include respiration, photosynthesis, and nitrogen fixation. All three of these involve oxidation and reduction reactions. For example, during respiration (breathing) food sources are oxidized to form carbon dioxide in a process that provides energy; during photosynthesis, plants use energy from the sun to reduce carbon dioxide to form sugars (food). These oxidation and reduction reactions occur at iron atoms that are found in complexes called iron-sulfur clusters. The biological formation of iron-sulfur clusters is different for different organisms. For this reason, and because formation of iron-sulfur clusters is required for an organism to survive, disruption of this process in pathogenic organisms provides an ideal target for the development of therapeutic agents. Furthermore, because photosynthesis and formation of nitrogenous fertilizers can be limited by the availability of iron-sulfur clusters, any improvement in iron-sulfur cluster formation by using genetic manipulation provides an avenue for increased food production and development of disease resistant crops.
Dr. Stephen Eubank
Deputy Director, Network Dynamics and Simulation Science Lab (NDSSL), Virginia Bioinformatics Institute
Adjunct Professor, Department of Physics
Program Summary: The NDSSL is pursuing an advanced research and development program for interaction-based modeling, simulation, and associated analysis, experimental design, and decision support tools for understanding large biological, information, social, and technological systems. Extremely detailed, multi-scale computer simulations allow formal and experimental investigation of these systems. The need for such simulations is derived from questions posed by scientists, policy makers, and planners involved with very large complex systems. The simulation applications are underwritten by a theoretical program in discrete mathematics and theoretical computer science that is sustained by more than a decade of experience with the interplay of research and application.
I am the PI for a research group in the NIH Modeling Infectious Disease Agent Study (MIDAS) network. Our project models the spread of disease transmitted from person to person in urban areas, allowing for the assessment of prevention, intervention, and response strategies by simulating the daily movements of synthetic individuals within an urban region. Our models allow the user to specify the effects in detail of a pathogen on a specific person, and to assign different effects to various people based on demographic characteristics. Through MIDAS, we have influenced national policy on preparing for an influenza pandemic; through related work for DoD we are supporting the development of mitigation strategies for military populations in a pandemic. In conjunction with population mobility models it can represent behavioral reactions to an outbreak, including official interventions. As part of an NSF Human Social Dynamics grant, NDSSL is using this model to study the co-evolution of social networks and disease transmission networks.
In addition, I am co-PI for a CDC Center of Excellence in Public Health Informatics led by Matt Samore at the University of Utah. This project seeks to understand how public health decision makers can use epidemiological models. Other projects at NDSSL relevant to infectious disease include creating spatial models of vector-borne disease epidemiology and applying them to malaria in sub-Saharan Africa, and modeling the human immune system in detail to study the dynamics of HIV recombination within an individual.
Dr. Joseph O. Falkinham, III
Professor, Department of Biological Sciences
Program Summary: New antibiotics are needed for treating emerging pathogens (e.g., Mycobacterium), antibiotic-resistant pathogens (e.g., Enterococcus, Staphylococcus aureus, and Methicillin-resistant S.aureus, MRSA), and fungal pathogens (e.g., Candida spp.). In the U.S., MRSA infections in hospitalized patients are estimated to increase theaverage hospitalization by 10 days and cost over $900M. New affordable antimicrobials are also needed to help persons in the epidemic-prone Third World. Further, new antibacterial and antifungal agents are needed owing to the loss in potency and efficacy of current drugs. Our preliminary data indicate that several members of a novel class of drugs caused an inhibition of growth at microgram concentrations against such pathogens as S.aureus, MRSA, and C. albicans. These new antibiotics could potentially prevent and treat topical infections, such as vaginitis (C. albicans), and prevent nasal colonization and transmission of S.aureus and MRSA. Moreover, as data accumulate concerning the efficacies of these antibiotics, our investigations may be extended to include designing antibiotics for treating more serious systemic infections. Finally, discovering the mechanism of antimicrobial action of these novel antibiotics will lead to the identification of new drug targets in pathogenic bacteria, mycobacteria, and fungi.
Program Summary: Viral Mothers: Modernity, Risk, and Maternal Embodiment
The medical community has known since the late 1980s that HIV is passed through breast milk from infected mothers to their babies. In the United States and other highly industrialized countries, HIV-positive mothers receive medical advice not to breastfeed their babies. Because formula (or replacement) feeding is considered normal in the U.S. and other similar nations, this public health protocol receives little attention.
In the global south, the AIDS epidemic threatens to disrupt breastfeeding’s traditional contribution to infant health and survival, particularly in Sub-Saharan Africa where the seroprevalence among women of childbearing age is high. Attention to the dangers of breastfeeding in the context of maternal HIV infection has changed international public health guidelines concerning infant feeding, creating dissention in public health efforts and confusing mothers who have long been taught the benefits of breast milk. Most public debates about infant feeding, while attending to issues of health and well being, are also fueled by social anxieties about mothers’ bodies and maternal roles in the modern era. Understanding how cultural perceptions of mothers influence public health debates is crucial to making sure that the advice, support, and treatment offered to HIV-positive mothers is appropriate and will contribute to overall health and well being.
My analysis involves historical, cultural, and discourse-based interpretive methods, primarily addressing figurations of mothers in public health debates, medical advice genres, and the mass media. This methodology is similar to what I used in writing Mother’s Milk: Breastfeeding Controversies in American Culture (Routledge 2003).
My preliminary findings in Viral Mothers suggest that the transmission of HIV through breastfeeding evokes other contemporary concerns about bodies, germs, and the environment that affect all of us, especially as we struggle with the significance of health, risk, and embodiment in the modern period. Our fears about mothers who are infectious, or whose bodies contain toxic chemicals that can be transferred to infants, are related to more generalized fears of contamination and contagion that seem to characterize our era.
This is not a book that will show us how to separate real concerns from imagined ones. Rather, it is a series of arguments that reveal how very real concerns are nevertheless imagined and experienced through ideological constructions of maternity. Identifying these does not dissolve them, but demonstrates everyone’s subjection to meaning systems that are connected to powerful institutions and cultural values. I include biomedicine among these powerful institutions, whose values seemingly permeate most daily behaviors in modern societies.
Program Summary: Pathogens are colonizing novel hosts with increasing frequency due to global agricultural traffic and habitat alteration. Managing and mitigating these emerging disease threats to humans and wildlife requires a detailed understanding of why populations vary in susceptibility to diseases over space and time. My research program investigates the ecological and evolutionary mechanisms that underlie pathogen susceptibility, from single host individuals to multi-host communities. I currently study disease dynamics in the context of two broad frameworks: 1) genetic and species-level diversity, and 2) environmental and social stressors. I approach disease ecology from a multi-disciplinary perspective in order to understand how stress, genetics, social behavior, community composition, and environmental context interact dynamically to influence host disease susceptibility and pathogen transmission. Ultimately, these studies will improve our understanding of the processes that underlie disease emergence and spread in wild animal, domestic animal, and human populations.
Dr. Thomas J Inzana
Professor Veterinary Medicine
Interim Associate Vice-President for Research and Tyler J and Francis F. Young Professor of Bacteriology
Project Summary: Francisella tularensis is a Category A bacterial pathogen and the etiologic of tularemia. Currently there is no approved vaccine for tularemia, and no approved rapid, non-culture diagnostic test. Due to the threat of bioterrorism, improved vaccines, diagnostic tests, and therapeutics are a high priority for F. tularensis and other select agents. F. tularensis is reported to be encapsulated, which may be an important component for virulence and a target for diagnostic test, but a capsule has never been isolated or characterized from this bacterium. Our laboratory has isolated a novel glycolipid from F. tularensis that is antigenic, and is upregulated under stress conditions. We are currently conjugating this glycolipid to a protein to evaluate it as a subunit vaccine against tularemia in mice. Furthermore, we have identified the putative capsule DNA locus and have made a mutant that may be unable to export this glycolipid. Antibodies to this glycolipid are being raised for use in diagnostic tests.
Histophilus somni is responsible for a wide variety of systemic diseases in cattle, including meningitis, myocarditis, pneumonia, and septicemia. H. somni possesses a wide variety of virulence factors, some of which our laboratory has characterized over the past 20 years. Unlike most obligate mucosal pathogens and members of the Pasteurellaceae, H. somni produces an exopolysaccharide and an excellent biofilm. We have recently determined that H. somni forms this biofilm in vivo, in heart tissue and in the lungs. Our current work is focused on biofilm formation in the natural bovine host, and the use of this system as a model for biofilm infections in humans.
Program Summary: Natural products have made a major contribution to drug discovery and especially to cancer chemotherapy, with Taxol being the best-selling anticancer drug in history. Research in our group is centered on the chemistry of biologically active natural products related to cancer, with major areas being the chemistry and mechanism of action of the anti-cancer agent Taxol, the discovery of new anticancer agents from plants, and biodiversity conservation and drug discovery in tropical rain forests. Taxol works by binding to microtubules, and we are studying this binding in collaboration with colleagues at State University of New York Binghamton, Emory University, and Washington University. The aim of our work is to help in the design and synthesis of potent and readily accessible Taxol analogs. We are also collaborating with scientists from CytImmune Inc. in designing a nanoparticle-based drug delivery system and with a colleague at the National Institutes of Health in the design of a new method for the treatment of prostate cancer. In the natural products area, we are involved in a search for novel anti-cancer agents from Nature in a major collaborative project that combines drug discovery from the rain forests and oceans of Madagascar with biodiversity conservation and economic development for the Malagasy people. We are also starting a new approach to the discovery of novel antimalarial drugs in collaboration with a colleague at Georgetown University.
Program Summary: Malaria is responsible for the death of 1-2 million people annually. Most of malaria’s victims are children under the age of five living in tropical areas of the world. The emergence, over the past couple of decades, of parasites that are resistant to available drugs has limited our treatment options. There is, therefore, an urgent need for the development of new anti-malarial drugs. The malaria parasite, a single-cell organism, causes disease as it reproduces within human red blood cells. As it grows, the parasite consumes its host cell from the inside, devouring most of the red blood cell’s oxygen-carrying protein, hemoglobin. My research aims to understand how the malaria parasite is able to pull off this massive catabolic feat. We focus our attention on enzymes called peptidases, which chop hemoglobin into small pieces, and ultimately, into its amino acid building blocks. By understanding how these peptidases work, we hope to discover chinks in the parasite’s armor that could be exploited for the development of peptidase inhibitors that have anti-malarial activity.
Program Summary: The emergence of infectious diseases is driven by social, cultural, economic, political, and environmental processes. For example, urbanization, civil conflict, and climate variability and change have all been linked to the spread of infectious diseases and/or the range of disease vectors. These processes act at different scales and across scales to either contribute to or prevent disease emergence. At the global scale, travelers can carry disease agents around the world, while vectors can also be transferred through similar means. Climate variability and change impact the range of vectors, with areas expanding or contracting based on temperature and precipitation patterns at regional scales. Lastly, at fine scales, individual behaviors and local environmental characteristics can result in the creation of vector habitat in a community and around a home. Geospatial technologies, such as remote sensing and geographic information systems (GIS), provide an effective way to evaluate the relationship between disease emergence and the underlying human or environmental factors that play a role in that emergence. Human and physical variables can be combined within a GIS to illuminate the ways in which processes act, and interact, across spatial scales to result in disease emergence.
Program Summary: Many pathogenic bacteria encounter different environments during their infectious cycle and their ability to adapt to these changes is mediated by global regulatory networks. In particular, recent research has shown that bacterial virulence is often regulated by networks involved in the process of “quorum-sensing” – the regulation of gene expression as a function of cell density. My research focuses on the integration of computational analysis and collaboration with experiments to discover novel components and achieve a more fundamental understanding of quorum-sensing networks in bacteria. In the process, we have computationally discovered and experimentally verified novel genes called small RNAs which play a critical role in the quorum-sensing pathway and in regulating virulence. Considerable research suggests that many virulent bacteria can be rendered nonvirulent by the inhibition of their quorum-sensing pathways. Therefore, research into quorum sensing may provide a novel means of treating many common and damaging bacterial infections without the use of antibiotics. Furthermore, biotechnological approaches designed to exploit beneficial quorum-sensing processes may prove useful in improving industrial-scale production of natural or engineered bacterial products. Thus, the study of quorum-sensing is important from a basic science perspective as well as for its applications to medicine and biotechnology.
Program Summary: Tryptophan is an essential amino acid, serving as a building block in protein synthesis. Tryptophan from food is oxidized to kynurenine and then to 3-hydroxykynurenine (3-HK) in mammals. 3-HK is easily oxidized under physiological conditions, leading to the production of reactive oxygen species. Reactive oxygen species are implicated in inflammation and disease. Marked neuron death was noticed in cultures treated with 3-HK at a concentration as low as 1 micromolar. 3-HK can be hydrolyzed by an enzyme (kynureninase) to alanine and 3-hydroxyanthranilic acid and eventually completely oxidized to carbon dioxide and water through a complicated biochemical pathway. In mosquitoes, tryptophan is oxidized to 3-HK, but, unlike in mammals and in some other species, mosquitoes do not produce a kynureninase, thus blocking the hydrolysis of 3-HK, an essential step in the complete degradation of 3-HK to carbon dioxide and water. Consequently, mosquitoes must dispose of 3-HK in a different manner than mammals. To prevent 3-HK from accumulating, a highly efficient enzyme (a transaminase) transforms the chemically reactive 3-HK to the chemically stable xanthurenic acid. This pathway evolved specifically in mosquitoes and serves as an essential mechanism for 3-HK detoxification. The objective of our research is to understand the structure/function relationship of the specific transaminase involved in mosquito 3-HK detoxification. Because the 3-HK transaminase is essential for mosquito survival, understanding its structural basis of catalysis may provide insight for future mosquito control strategy.
Program Summary: Our research group is studying the molecular and cellular mechanism controlling human innate immunity and inflammation. Human innate immunity serves as a radar surveillance system capable of sensing danger and abnormal signals from the environment as well as signals from within the human body. Proper activation of innate immunity is essential for host defense against invading pathogens, wound healing following injury, as well as eradication of dead or malignant cancer cells. However, excessive or abnormal innate immunity and inflammation leads to serious inflammatory diseases such as cardiovascular disease, diabetes, asthma, rheumatoid arthritis, as well as neurological inflammatory diseases. It is no surprise that the National Institutes of Health have recently put together a major roadmap entitled “Inflammation is the common cause for human disease”. Despite the significance of innate immunity and inflammation, the molecular and cellular mechanism underlying this process is not clearly understood. Many cell surface receptors and associated intracellular signaling molecules are critically involved in the proper regulation of human innate immunity network. Our group has unraveled the function of several key intracellular proteins essential for mediating the human innate immunity process. By employing techniques in experimental molecular biology, targeted disruption of select genes in transgenic mice models, and gathering genetic information from human patients, we are defining potential molecular targets for future intervention of chronic human inflammatory diseases.
Dr. David S. Lindsay
Professor of Parasitology, Department of Biomedical Sciences and Pathobiology
Program Summary: My laboratory focus on intracellular zoonotic parasites including Toxoplasma gondii, Encephalitozoon cuniculi, Cryptosporidium parvum, Trypanosoma cruzi, and Leishmania infantum. We examine aspects of the epidemiology, pathogenesis, immune response, transmission, and treatment of these zoonotic protozoan parasites. Toxoplasma gondii has long been known as a cause of congenital disease in humans and about 91% of the female population in the US of childbearing age are at risk of developing infection with this parasite. Maternally infected children often suffer from mental retardation, blindness, and vision and hearing problems. One aspect of my research is examining the efficacy of new anti-protozoals in vitro and in vivo. My group is also interested in the biology of the tissue cyst stage. We were the first to demonstrate that all stages of the complex T. gondii life cycle could produce tissue cysts in cell culture and that all isolates had the ability to form tissue cysts in cell culture. These findings ruled out the influence of the host immune system on the induction of tissue cyst formation. We are currently developing an in vitro system to examine the effects of various chemotherapeutic agents on tissue cysts. Tissue cysts are dormant stages and not susceptible to drugs that kill other stages of the parasite. Stage conversion from tissue cyst containing slowly growing bradyzoites to rapidly multiplying destructive tachyzoites is responsible for encephalitis in AIDS patients and in toxoplasmosis seen in organ transplantation patients. We are collaborating with others on developing a vaccine against toxoplasmosis with the knowledge that a vaccine that prevents clinical disease but allows for the production of tissue cysts is of limited value. Toxoplasma gondii infection has recently been associated with schizophrenia in humans and behavioral changes in rodents. Our future work will be to examine the effect of chronic infection with T. gondii on the levels of neurotransmitters in the brains of mice.
Another area of focus of my research group is Encephalitozoon cuniculi. It is a microsporidian parasite usually associated with disease in rabbits but fatal disease also occurs in dogs and immunocompromised humans. We have developed new diagnostic tests for E. cuniculi and demonstrated the activity of several disinfectants against the spores of this parasite. There are 3 strains of E. cuniculi and dogs have strain III. Interestingly, most E. cuniculi infections in humans in the US have been from strain III associated with dogs. Several outbreaks of fatal encephalitozoonosis have occurred in endangered monkey species in Zoos and they are also caused by E. cuniculi strain III. We are currently examining the prevalence of this parasite in dogs in the US and other regions of the world.
Program Summary: Bacterial pathogens are able to cause disease in humans because they can colonize different parts of the body and, for some pathogens, secrete powerful toxins that damage cells and tissues. The bacterial pathogen Clostridium perfringens, which causes gas gangrene and food poisoning, is efficient at both of these aspects of the disease process. It colonizes the human colon very efficiently and we are studying the mechanism it uses to attach itself to host cells. We believe these bacteria use a type of pili, hair-like structures that stick out of the surface of the bacterium, to attach to host cell surfaces. They not only use the pili for attachment, but they can also use them to move along the surface of human cells with a gliding motion. Our research centers on the mechanism of pili assembly and function, with the hope that we can use the results to develop strategies to limit the ability of the bacterium to colonize human tissues. C. perfringens also secretes large quantities of powerful toxins that kill host cells. The other main area of research in our lab is to understand how the bacterium regulates the synthesis of these toxins since they are the major mediator of disease. If we can develop strategies that prevent the bacterium from making or secreting toxins, this would be a very useful approach to cure the diseases caused by C. perfringens, which often do not respond to antibiotics alone.
Dr. X.J. Meng, M.D., Ph.D.
Professor of Molecular Virology,
Viginia-Maryland Regional College of Veterinary Medicine
Program Summary: Dr. Meng’s research focuses on the development of vaccines against emerging, re-emerging, and zoonotic viral diseases of public health and/or economic importance. His laboratory studies multiple virus systems including the hepatitis E virus (the causative agent of human hepatitis E, which is an important human pathogen), Type 2 porcine circovirus (which is an emerging and economically important swine pathogen), and porcine reproductive and respiratory syndrome virus (another economically important swine pathogen). This research has recently led to the development and licensure of the first United State Department of Agriculture fully-licensed vaccine, “Suvaxyan® PCV2 One Dose”, against a deadly global swine disease. This vaccine will save the global swine industry millions of dollars each year from loss caused by the disease.
Co-PI: Endang Purwantini, Senior Research Associate, Virginia Bioinformatics Institute
Program Summary: The emergence of multi- and extensively-drug-resistant tuberculosis (MDR and XDR TB) as a major threat to the world population calls for rapid development of new TB drugs; the last effective drug, which was specifically developed for treating TB, was introduced in 1966. The goal of our research is to identify new cellular targets in Mycobacterium tuberculosis, the causative agent of TB, for the development of new therapeutics for TB. We have taken two approaches: one involves laboratory-based microbial genetics, molecular biology and biochemistry investigations, and the other is a site-based study. For the first approach we have focused on the physiological role of coenzyme F420 in the mycobacteria and the structure-function relationships in GTP-dependent phosphoenolpyruvate carboxykinase (GTP-PEPCK). Coenzyme F420 is a deazaflavin derivative. It is structurally similar to flavins but functionally acts as a hydride transfer-restricted coenzyme similar to the nicotinamides. F420 is present in all known methanogenic archaea, but it is rare in the bacterial domain, where it is primarily found in Actinobacteria such as mycobacteria. All mycobacteria examined thus far contain F420, and these bacteria express an F420-specific glucose-6-phosphate dehydrogenase (Fgd). The use of Fgd-generated reduced F420 (F420H2) in the mycobacteria is unknown. Our on-going investigation indicates that F420H2 helps to protect mycobacterial cells from oxidative and nitrosative damages similar to those induced by the macrophages. We are currently characterizing the components of this defense system. We have identified an F420-dependent enzyme that oxygenates mycolic acids, which are critical components of the mycobacterial cell envelope. The complex architecture of the cell envelope helps to protect M. tuberculosis from the bactericidal effects of human immune cells and most synthetic antibacterial agents. GTP-PEPCK is a key enzyme for gluconeogenesis in M. tuberculosis and therefore is essential for the survival of M. tuberculosis within the granuloma in a dormant or latent stage. The latent form of M. tuberculosis is not sensitive to most of the currently used TB drugs. As a result, the treatment of TB requires a rather lengthy drug therapy, which has been the reason for patient non-compliance and consequent development of drug-resistant strains of M. tuberculosis. Our research on GTP-PEPCK is focused on determining the differences between the structure-function relationships of the mycobacterial and human enzyme and thereby identifying the avenues for developing inhibitors for the M. tuberculosis GTP-PEPCK that will not affect the human enzyme. The site-based study utilizes clinical strains of M. tuberculosis isolated at the Rotinsulu Pulmonary Hospital (Bandung, Indonesia); this work represents collaboration between the Virginia Bioinformatics Institute (our group and the laboratory of Dr. Stephen Eubank), Institut Teknologi Bandung and Rotinsulu Pulmonary Hospital. The project goal is to determine the genetic and biochemical basis for the development of more virulent and MDR or XDR strains of M. tuberculosis. The project is based on the hypothesis that population lifestyles (economic status, mobility, environment) and treatment methodologies determine the immune system of a patient and chemical environment within the infected immune cells and promote changes in the genome of the pathogen which lead to increased virulence and drug resistance in TB.
The bacteria Staphylococus aureus is a leading cause of community acquired infections, surgical site infections, bovine mastitis and human skin infections. The increased occurrence of multi-drug resistant strains necessitates the identification of new mechanisms for controlling this pathogen. S. aureus causes disease in the human by producing toxins and by invading epithelial cells (EC). EC are implicated in the production of coagulatory proteins to maintain hemostasis. Unfortunately, S. aureus can alter host inflammatory and coagulatory responses by production of numerous virulence factors. We believe that intracellular invasion and persistence within host cells enables S. aureus to manipulate the host immune response to its advantage, causing abscess formation and chronic infections. One of our goals is to understand the basic immune and coagulatory responses of EC during infection with S. aureus.
We believe that within both bovine and human population, certain individuals are susceptible and others are resistant to S. aureus infection. The bovine population, like humans, is naturally exposed to S. aureus. However, unlike a human model, our animal model provides a detailed history of infection status and a catalogued collection of the S. aureus strains that caused these infections. Using the bovine population we hope to identify antigens that stimulate immune memory and are candidates for vaccine development.
Program Summary: Mosquito-borne virus infections are a tremendous worldwide public health burden. Mosquito-borne pathogens are maintained in nature through complex transmission cycles that involve vertebrate hosts and mosquito vectors. While infection of the vertebrate host is acute and often associated with disease, a hallmark of arthropod-borne virus (arbovirus) infections in the mosquito is a general lack of pathology. Mosquito-borne viruses would not survive in nature if they adversely affected the mosquito host, as they are dependent on this disease vector for transmission. Therefore, a glaring deficiency in our understanding of arboviral disease transmission has long been the paucity of information on how mosquito cells are able to resist the pathogenic potential of arboviruses. Thus, the focus of my research program is on understanding the interactions occurring between the virus and vector that result in the establishment and persistence of non-pathogenic infections in the mosquito host. The information obtained from these studies will improve our ability to predict and prevent arboviral disease epidemics. In addition, a strategy that would replace natural populations of mosquitoes with genetically modified mosquitoes is currently being investigated for controlling these important pathogens. Understanding the genetic components controlling the pathogenic potential of arboviruses may be useful in such a strategy. For example, it may be possible to create mosquitoes that would be rapidly killed when infected with an arbovirus. Thus, in the future, a more complete understanding of how persistent arbovirus infections are established in the vector host may provide a basis for human intervention of arboviral disease transmission.
Program Summary: Each year in the United States, 5.2 million illnesses are attributed to food-borne bacteria. Two common bacterial food-borne pathogens, Salmonella enterica and Escherichia coli O157:H7 are responsible for an estimated 1.4 million and 79 thousand illnesses each year, respectively according to the Centers for Control and Prevention. Fourteen percent of all food-borne illness outbreaks reported in North America could be linked directly to minimally processed fruit and vegetables.
Even though produce may be contaminated during growth, harvest, processing, distribution or final preparation, these outbreaks have raised concerns about the pre-harvest colonization by human pathogens including S. enterica and E.coli O157:H7. However, little is known about the ecology and mechanisms used by human pathogens to survive the stressful conditions in environment (soil, water, surface of the plant). The ability of a human pathogen to colonize a plant is influenced not only by environmental stresses such as temperature, exposure to UV radiation and dehydration, but also by the interaction with the native species of plant microbiota. By identifying antagonistic or permissive members of the produce microbiota we may develop control strategies that make use of such beneficial bacteria to control growth and survival of enteric pathogens on produce allowing for design of effective packaging and control procedures post-harvest.
Recent outbreaks associated with ready to eat, bagged spinach indicate that human pathogens survive the modified atmosphere conditions designed to prolong shelf life. The relatively small populations of S. enterica serotypes on plants and low infectious dose of Salmonella (as few as 100) in produce linked outbreaks (1) suggests that physiological adaptation to plant associated factors may increase survival on both a plant and human host. The expression of environmental survival and virulence genes on the plant surface may adapt some bacteria to survive in harsh stomach and intestinal fluids and attach to human cells, increasing the severity of illness. We will compare the ability of produce outbreaks associated serovars of S. enterica and E.coli O157:H7 to adhere and invade human Caco-2 cells when grown in association with plants and other food matrices. It is unlikely that all human pathogens respond identically so it will be necessary to characterize survival and genetic response of several strains of S. enterica and E.coli O157:H7 isolated from the environment, animal and clinical sources. These differences in survival, host specificity, or expression of virulence genes likely lie within specific regions of the genome, necessitating a combination of molecular subtyping methodologies and comparative molecular techniques. By identifying genes responsible for survival and virulence we will enhance our ability to develop intervention strategies and interpret subtyping data used to trace food-borne outbreaks.
Identifying the mechanisms by which microbes survive is vital both for disease control and the extension of basic science. Additional research on the survival and response to environmental and minimal processing conditions may reveal uncharacterized mechanisms of pathogenesis, will improve our understanding of the spectrum of Salmonella diseases, and will enhance our ability to develop intervention strategies.
Program Summary: Bacteria are major agents causing illness and death in humans and other animals. We study two aspects of bacterial growth and survival that have great effects on the ability of bacteria to cause disease: the formation of their peptidoglycan cell wall and the formation of dormant spores. Synthesis of the bacterial cell wall has traditionally been the best target for antibiotic development. It is the target of penicillin, vancomycin, and other widely used drugs. Cell wall synthesis is still considered an outstanding target since it is highly conserved across virtually all bacterial species. Our studies on the precise roles of a variety of proteins in cell wall synthesis will contribute to the rational design of new classes of antibiotics. Formation of spores allows certain bacteria to survive in and invade habitats unavailable to other species and, thus, to affect human health. The spores of Bacillus anthracis are the infectious agent for anthrax, and the sporulation by Clostridium perfringens is required for this species to cause both food poisoning and gangrene. We study spore structure in both of these species, specifically the unique spore peptidoglycan wall, in order to determine how this structure contributes to the ability of spores to survive high heat and other treatments that normally kill all other cell types and how this structure is degraded when the spores are ready to germinate and cause disease. Our studies will contribute to the development of better methods for cleaning spore-contaminated sites and preventing disease.
Dr. P. Christopher Roberts
Associate Professor of Virology,
Center for Molecular Medicine and Infectious Diseases
Virginia-Maryland Regional College of Veterinary Medicine
Program Summary: Influenza virus and other respiratory pathogens continue to cause widespread disease affecting not only humans but also numerous animal species. At particular risk are the elderly. With the emergence of the “Bird Flu”, there is an increased risk of disease which could culminate in broad economic disturbances throughout the U.S. and globally. Vaccination still represents the most viable option for controlling viral diseases, including influenza. A major focus of our program is to develop newer, more protective vaccines that provide long-lasting protection to humans and animals against emerging viral pathogens, particularly influenza. One target group that we are focusing on is the elderly. The rising elderly population in the U.S. will increase medical care costs that are already overstretched. By developing vaccines targeting the elderly, we hope to significantly reduce health care costs associated with respiratory viruses. Ideally, enhanced protective vaccines should result in less hospital/physician visits, less absences from work, and reduced health care costs overall. Finally, our program is seeking new ways to utilize naturally occurring viruses as a means to selectively target cancer cells within the body and destroy them. This represents a new and exciting area of research that offers enormous potential in treating advanced cancer.
Program Summary: We are interested in using chemistry to understand biological processes. Central to our theme is organic chemistry as a tool that intersects with molecular life sciences, such as molecular and cell biology. Our primary focus is the development of chemical toolboxes to address problems in biology. Currently, our work is aimed at discovering and developing novel molecular entities that can be used as probes or as therapeutics for disease states (Parkinson’s and Alzheimer’s disease) that are not efficiently addressed using conventional small molecule drugs. We are also interested in the search for new strategies in combating infectious diseases such as malaria and influenza. In organic chemistry, we are employing a chemical biology approach in evolving nucleic acid polymers such as RNA to discover molecular scaffolds that can catalyze chemical reactions that are environmentally friendly. One of our goals is to use modular RNA to perform the total synthesis of natural products, where one product can arise from a complex pool of starting materials.
Project Summary: The bacterium Pseudomonas aeruginosa is an opportunistic pathogen that causes a number of life threatening infections in predisposed individuals. For instance, chronic lung infections by P.aeruginosa are the major cause of mortality in cystic fibrosis patients. Generally, P.aeruginosa infections can follow two distinct paths: acute and chronic infections. Acute infections are characterized by a rapid and severe disease progression. The hallmark of this infection path is the type III secretion system, a syringe-like channel, employed by P.aeruginosa to export a number of virulence factors that suppress the host immune response. Chronic infections, on the other hand, follow a different, but no less destructive path. The characteristic feature of chronic infections is the formation of protective biofilms that shield the bacterial colonies. Biofilms constitute a formidable physical barrier that not only protect P.aeruginosa from the host immune system but also impart dramatically increased antibiotic resistance to the bacterium. We study the regulatory mechanisms that control both the type III secretion system and biofilm formation. We use an integrated approach for our work that combines structural biology, biochemical studies, and microbiology. Our long term goal is to aid the development of new therapeutic options against P.aeruginosa through discovery of novel anti-microbial agents.
Program Summary: More than one million human lives are lost each year by malaria, a disease transmitted exclusively by the Anopheles mosquito. Some of the most effective public-health measures against vector-borne diseases throughout history have been those targeted at the vector. However, because of growing insecticide resistance, the available strategies for alleviating the impact of malaria are now insufficient. In fact, partially because of global warming, increased air transportation, and the ability of mosquitoes to quickly adapt to new habitats, the public-health burden of malaria is increasing and expanding. There is an urgent need to explore novel strategies for vector-based disease control. Ecological adaptations of vectors can significantly increase malaria transmission. For example, mosquitoes that are adapted to an arid climate can occupy larger geographic regions and human dwellings. Ecological, behavioral, and physiological adaptations related to malaria transmission are often associated with genome rearrangements. My research aims to understand the role of genome rearrangements in mosquito evolution, adaptation, and ability to transmit malaria parasites. The ultimate goal of this research is to develop a novel genomics-based approach for vector control.
Dr. Nammalwar Sriranganathan
Professor of Microbiology, Department of Biomedical Sciences and Pathobiology
Faculty-In-Charge, BSL-3 Laboratory
Project Summary: My laboratory is developing and testing vaccines against intracellular pathogens. We are using a current USDA approved cattle vaccine, B. abortus RB51, developed at the Center for Molecular Medicine and Infectious Diseases at Virginia Tech, as a vector to express protective antigens against other infectious agents. We are developing and testing RB51-Neospora caninum (RB51-NC) recombinant candidate vaccines in both a lethal and a pregnant mouse model. Three candidate RB51-NC recombinant vaccines have shown promise in one, or both, of these models. Flagellin, a filament protein that forms bacterial flagellum, appears to function as an excellent adjuvant for the intranasal route of vaccine delivery and induces high levels of antibodies against F1. It has been found to provide protection against an aerosol challenge of Yersinia pestis, the causative agent of bubonic plague, at 150 times the lethal dose. Similar studies are being conducted using the V antigen as the initiator and we are in the process of analyzing the results. Some of the F1/V constructs, with flagellin as the adjuvant, appear to provide protection. We are also studying the effect of aging on the immune response against the intracellular pathogen B. abortus and we have seen some interesting observations that are now being pursued. Recently, we have also initiated efforts to develop targeted drug delivery against intracellular pathogens.
Program Summary: The Stevens lab works in the general field of molecular microbiology with an emphasis on bacterial environmental sensing and gene regulation. The majority of the research projects focus on the phenomenon of bacterial quorum sensing, a mechanism whereby bacterial cells communicate with one another through the use of small molecules called autoinducers. By understanding this mode of bacterial gene regulation, methods to manipulate it in ways beneficial to society may be discovered. Our group currently studies the quorum sensing systems of three different bacteria, one that establishes symbiotic/beneficial relationships with animals, one that is an important plant/corn pathogen and one that is free-living in the environment. In a separate project, we are exploring the development of antibiotic resistance in environmental bacteria that are exposed to stress from common chemical contaminants.
Dr. Elankumaran Subbiah
Assistant Professor of Virology,
Virginia-Maryland Regional College of Veterinary Medicine
Program Summary: According to the World Health Organization, cancer accounts for 7.1 million deaths annually (12.5% of the global total). Approximately 20 million people suffer from cancer; a figure projected to rise to 30 million in the next 20 years. The current options for treating most cancers include radiation and chemotherapy, with their associated issues of efficacy and quality of life. Cancer therapy using viruses is gaining importance and may be able to circumvent some of these issues. Our program is directed towards genetically modifying a natural tumor selective virus of chickens to treat human and animal cancer. Newcastle disease virus is a major pathogen of chickens and other birds throughout the world. It causes only mild conjunctivitis in humans. With reverse genetic technology we are attempting to create tumor-specific variants of Newcastle disease virus so that it can have a high therapeutic index for various types of cancer. For example, our recently funded project from the U.S. Department of Defense seeks to develop a prostate-specific antigen targeted to Newcastle disease virus to treat prostate cancer. Similarly, we are in the process of creating tailor-made viruses for various types of human and animal cancer. We believe we will be able to address many of the difficulties in current cancer treatment with this approach.
Program Summary: Mosquito transmitted diseases, such as malaria, dengue fever, and encephalitis, claim millions of lives worldwide each year. My laboratory is using modern genomics and bioinformatics tools to study the basic genetics and physiology of mosquitoes with the long-term goal of reducing the burden of vector-borne infectious diseases. My research program covers three areas. The first is mosquito transposable elements (TEs), which are mobile genetic elements that have the ability to replicate and spread in the genome. Our objectives are to understand the fundamental biology of TEs and their genomic and evolutionary impacts as well as to explore the applications of TEs as molecular tools to manipulate mosquito genomes for the purpose of interrupting transmission of pathogens. Second, we are conducting comparative genomics on a range of mosquitoes to provide high-resolution identification of regulatory elements, uncover gene expansions/loss/rearrangements, and reveal correlations between these genetic changes and biological adaptations which are being tested experimentally. Finally, we have recently identified a number of mosquito-specific microRNAs (miRNAs), which are a novel class of gene modulating molecules. miRNAs are ~22 nucleotide long non-coding RNAs that modulate the expression of cellular genes by binding to cognate mRNAs for cleavage or translational repression. miRNAs are widely distributed in metazoans and plants. Many miRNAs exhibit finely controlled spatio-temporal expression profiles. Several of these have been shown to be key regulatory molecules during embryonic development, stem cell division, neurogenesis, heart development, haematopoietic cell differentiation, and cell death. miRNAs are also implicated in cancer and control of viral infection. The level of several miRNAs changed 2-3 fold in mosquitoes after a blood meal, according to our preliminary miRNA array analyses using whole body samples. We are testing the hypothesis that a small number of miRNAs are among the key factors regulating tissue and temporal specific response to blood feeding during the mosquito gonotrophic cycle and other miRNAs may be involved in mosquito-pathogen interactions.
Program Summary: The cell division cycle (CDC) is the sequence of events whereby a growing cell makes new copies of all its parts and divides them, more-or-less, evenly between two daughter cells so that each daughter contains all the information and machinery necessary to repeat the process. The CDC is a fundamental process of life, underlying all biological growth, development, and reproduction. Mistakes and problems in cell growth and division underlie many human health problems, including cancer, tissue regeneration, and infectious diseases. In the same way that an engineer must understand the mechanical and/or electrical components of a machine and how they interact in order to fix it when it’s broken, a life scientist must understand the molecular components of the cellular control system and how they interact in order to develop new drugs and therapies for the infirmities that stem from faulty controls. Molecular biologists have identified many of these components (genes and proteins) and interactions (biochemical reactions) for the basic processes of life, including the CDC. My world-leading research group builds mathematical models of these control systems in order to better understand the complex molecular interactions within living cells and how they are perturbed in diseased states.
Dr. Boris A Vinatzer
Assistant Professor, Department Plant Pathology, Physiology, and Weed Science
Program Summary: Pathogens of humans, animals, and plants are dynamic entities that continuously evolve to overcome their hosts’ immune system or to become resistant to new drugs. Even new pathogen variants with new life styles can arise. For example, the detrimental bubonic plaque pathogen, Yersinia pestis, which is transmitted by flea bites, is believed to have evolved from a mild pathogen, which was unable to be transmitted by fleas, only approximately 10,000 years ago. Plant pathogenic bacteria use the same basic evolutionary mechanisms as human pathogens. We found evidence that with the introduction of agriculture, some plant pathogens changed their life style from being mild pathogens of many different plants (which made them competitive in natural mixed – plant communities) to being highly aggressive pathogens of only one plant species (which made them competitive in agricultural fields of single crops). Studying the basic evolutionary mechanisms that plant pathogens used to become more aggressive can help us to predict the risk that certain pathogens will become more aggressive in the future and to develop agricultural and medical practices that reduce the risk of the evolution of new highly aggressive pathogens.
Program Summary: Nuclear magnetic resonance (NMR) spectroscopy is positioned today to address new frontiers of science from materials research to soil science, from anatomy to physiology, and from structural biology to proteomics. NMR provides investigators the ability to gain structural information on the atomic level in systems that do not contain long range order and to obtain dynamic information on a timescale that is unavailable by other techniques. Our laboratory focuses on the development and application of modern state-of-the-art solid-state NMR techniques to investigate the diverse problems in biological science and modern materials. Our particular interests are the structures of proteins/peptides that are hard to solubilize or crystallize—as is often the case for membrane proteins, amyloid fibrils, and protein/peptide aggregates. These are impossible to approach by NMR in solution-state or X-ray crystallography. Present research activities include: 1) determining the structures and dynamics of membrane-bound antimicrobial peptides; 2) determining the structure and dynamics of HIV-1 Tat peptides binding to liposomes and Jurkat cells to understand the intracellular delivery mechanism of proteins and small colloidal particles into the cytoplasm across cell membranes; and 3) determining the conformational and interfacial structures of protein-protein, protein-ligand, and protein-DNA complexes that are hard to be crystallized.
Program Summary: Awareness and proper responses to changes in the environment is critical for the survival of any biological entity. Bacteria, whether pathogenic or otherwise, are no exception. Human pathogens generally behave differently when they are within our body from when they are outside. This is partially because they sense the changes in nutrients, temperature and other things within the unfortunate host. How do organisms so small manage to sense and respond to environmental changes to either thrive in particular niches or to result in tremendous human suffering and misery? That is the main question we address using the gram-negative soil bacterium Myxococcus xanthus. That is, how does this bacterium see, smell or feel the changes in their surroundings and how do the cues they perceive lead to changes in their behavior and metabolism?
Program Summary: Rotaviruses are the leading cause of severe gastroenteritis in infants and children worldwide. Probiotics, such as Lactobacilli, have been shown to reduce the severity of rotavirus diarrhea; however the immunologic mechanisms have not been clearly defined. Colonization of the human intestine with commensal microbes is hypothesized to drive the maturation of the mucosal immune system during neonatal life, but the mechanisms are unknown. A goal of our laboratory is to define the impact of colonization of the intestine by probiotic commensal microbes on development of the mucosal immune system and innate and adaptive immune responses to enteric virus infections and to clarify the immunological mechanisms involved using gnotobiotic pigs colonized with two Lactobacillus strains used in the food industry.
Program Summary: Most female mosquitoes need to feed on vertebrate blood and use the nutrients for their own egg production. During blood feeding, mosquitoes transmit many devastating diseases, such as malaria, dengue fever, filariasis, and West Nile encephalitis. The causative pathogens have developed exquisite strategies to exploit mosquitoes to complete their own life cycles and, at the same time, to evade the mosquito immune system to ensure their own survival. We are exploring various strategies to control these emerging or resurging mosquito-borne diseases. An effective approach is to minimize the risk of infection by reducing mosquito populations. In the face of the growing pesticide resistance detected in field populations of mosquito vectors, new environmentally safe chemicals are needed to kill mosquitoes at various developmental stages. Understanding how mosquito endogenous growth regulators exert their function will facilitate discovery of chemicals that repress or block the normal growth and development of the mosquito. Another promising approach is to use genetic engineering to eliminate or decrease the vector competence of mosquitoes. Some mosquitoes are refractory to infections of pathogens in nature. Comparing gene expression of refractory and susceptible mosquitoes in response to pathogen infections will shed light on the molecular nature of mosquito-pathogen interactions and provide invaluable information on what protein factors in mosquitoes are suitable for genetic intervention to adversely affect the pathogens.