The major research focus of our lab is a vector-borne zoonosis called Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes scapularis ticks. Once transmitted to susceptible animals or humans, the pathogen establishes a resilient infection that can debilitate multiple organs, causing arthritis, carditis, or a variety of neurological disorders. Antibiotic treatment is not always effective; a fraction of patients continues to experience chronic or relapsing symptoms that are non-responsive to antimicrobial therapy. Furthermore, a human vaccine against Lyme disease is currently unavailable, making this a critical public health concern. Despite increased public awareness, the incidence of Lyme disease is still on the rise, with approximately 300,000 cases reported annually in the United States alone.
Considering all of these factors, our lab continues to highly prioritize a deeper understanding of the biology of the microbe and its vector, the molecular basis of the infection, and the complex interactions between the pathogen, the vector, and mammalian hosts. We aim to apply such information towards the development of effective interventions against Lyme disease.
Read on for a detailed scientific overview of our lab studies.
MOLECULAR PATHOGENESIS OF LYME DISEASE
An estimated 1,400 species of diverse pathogens can infect humans, but only a small fraction of these (including B. burgdorferi) are capable of establishing a persistent infection. We discovered a new paradigm for Borrelia infection by showing that a surface antigen (BBA57) supports spirochete survival in the critical early phase of mammalian infection, and triggers inflammation in the disseminated phase of borrelial infection. We found that BBA57 is an unorthodox regulator of multiple other virulence determinants, as it orchestrates a unique host immune evasion strategy by suppressing host complement-mediated killing and neutrophil-derived microbicidal responses. These studies highlight the evolution of remarkable plasticity in the immune evasion strategies of an atypical pathogen such as B. burgdorferi, which is exceptionally adapted to persist in multiple hosts and on a long-term basis without complete host clearance. We are exploring the cellular and molecular events behind the genesis of inflammatory responses, like arthritis, that are associated with the pathogen. Findings from these studies will have far-reaching therapeutic implications for the control of Lyme borreliosis.
NOVEL IMMUNE SIGNALING PATHWAYS
Ongoing studies from our laboratory have characterized how specific tick molecular components can control the persistence of invading pathogens like B. burgdorferi. We recently made the remarkable discovery of a novel cross-species signaling cascade: an interferon-like defense system that is operative in Ixodes ticks and reduces Borrelia proliferation in the vector. These pioneering studies imply the existence of a conserved interspecies communication pathway that bridges bactericidal immune responses between ticks and mammals. Our continued efforts, which are focused on a basic understanding of tick immunobiology, are now supported by a program project grant through NIH. These studies will define the molecular mechanisms behind cross-species IFNγ signaling, particularly how it boosts tick borreliacidal activity.
MICROBIAL BIOLOGY AND VIRULENCE
Given their notable evolutionary distance from other bacterial species, spirochetes - including B. burgdorferi - possess unique cellular, genetic, and antigenic structures. A key goal of our research is to characterize the unique borrelial antigens that are critical for pathogen survival and virulence, as well as host-pathogen interactions, as they represent potential preventive or therapeutic targets. Our lab and others have shown that these virulence determinants can support various aspects of microbial biology and infectivity, such as tick-to-mammal transmission, establishment of murine infection, evasion of innate and adaptive immunity, vascular dissemination and invasion of distant organs, and colonization of tissues, sometimes in a tissue-specific manner.
MULTIFACETED HOST-PATHOGEN AND PROTEIN-PROTEIN INTERACTIONS
Our lab has discovered that some borrelial virulence determinants interact with host molecules or other spirochete proteins, and that these biomolecular interaction events are essential to infection. We continue to study how protein-protein interaction (PPI) events constitute valid drug targets. Drawing from our active collaborations and the rich infrastructure at the National Center for Advancing Translational Sciences (NCATS), we are: 1) defining the structure of these antigens at atomic resolutions to learn more about their biological significance, and 2) exploring the potential for novel Lyme disease therapeutics by blocking antigen functions or PPI events via small molecule therapeutics.
NOVEL DIAGNOSTIC ANTIGENS, VACCINES, AND IMMUNIZATION PLATFORMS
To support the development of new strategies against Lyme disease, our efforts have focused on novel diagnostic tests, vaccines, and immunization platforms. Vaccine studies involving several virulence determinants, as highlighted above, identified a set of borrelial antigens (such as BBA52, BB0405, and BBI39) that can evoke protective host immunity and therefore may serve as next-generation vaccine candidates against Lyme disease, as recently funded by a collaborative NIH grant. Some tick antigens that are involved in pathogen interaction, or that support tick feeding on hosts, could possibly be used to develop “anti-tick vaccines”. Portions of these vaccination studies are currently funded by a contract from Merck Inc. and previous sub-contracts from USDA.
NOVEL CONCEPTS AND TOOLS TO STUDY DISEASE RESISTANCE AND PATHOGENESIS OF TICK-BORNE INFECTIONS
We have assembled numerous key protocols into a textbook, which is helpful to any laboratory that studies organisms with difficult genetics. Our lab also contributed to the development of gene manipulation technologies, the characterization of many novel B. burgdorferi proteins, and the advancement of several key experimental techniques, such as mutant analysis in vivo, RNA interference, and other genomic or proteomic tools to study Borrelia persistence and host interactions. In our ongoing work, we are pioneering novel transgenic models and genome-editing tools via sperm-mediated gene transfer and in-ovo manipulation, including the use of CRISPR/Cas9 technologies for genome editing in non-model organisms. These efforts will enrich our toolbox, deepen our knowledge of tick-borne infections, and contribute to the development of novel interventions.