Project I. Genetic analysis of Rickettsia: pathogenesis and host immunity
Rickettsia is a group of obligate intracellular Gram-negative bacterial organisms transmitted by hematophagous arthropod vectors, including ticks. With the ongoing environmental changes, the public health burden for tick-borne rickettsial diseases has increased in recent years. Fortunately, recent advances in genetic tools for Rickettsia have enabled studies to identify multiple virulence mechanisms that permit rickettsial intracellular survival and pathogenesis. In our lab, we perform random insertional kkaebi transposon mutagenesis to identify previously uncharacterized virulence genes in Rickettsia. Using kkaebi variants, our laboratory determined the biological attributes of the polysaccharide synthesis operon in lipopolysaccharide biosynthesis, surface protein assembly, spotted fever pathogenesis, and host immune modulation. In addition, we identified a conserved hemolysin that induces hemolysis in a pH-, temperature-, and host species-dependent manner. We continue to generate additional kkaebi variants in Rickettsia and aim to elucidate conserved and unique molecular mechanisms underlying pathogenesis, host immunity, and tick transmission.
Rickettsia is a group of obligate intracellular Gram-negative bacterial organisms transmitted by hematophagous arthropod vectors, including ticks. With the ongoing environmental changes, the public health burden for tick-borne rickettsial diseases has increased in recent years. Fortunately, recent advances in genetic tools for Rickettsia have enabled studies to identify multiple virulence mechanisms that permit rickettsial intracellular survival and pathogenesis. In our lab, we perform random insertional kkaebi transposon mutagenesis to identify previously uncharacterized virulence genes in Rickettsia. Using kkaebi variants, our laboratory determined the biological attributes of the polysaccharide synthesis operon in lipopolysaccharide biosynthesis, surface protein assembly, spotted fever pathogenesis, and host immune modulation. In addition, we identified a conserved hemolysin that induces hemolysis in a pH-, temperature-, and host species-dependent manner. We continue to generate additional kkaebi variants in Rickettsia and aim to elucidate conserved and unique molecular mechanisms underlying pathogenesis, host immunity, and tick transmission.
Project II. Tick survey and Rickettsia transmission
Suffolk County is endemic for many tick-borne diseases transmitted by three major tick species: Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), and Ixodes scapularis (deer tick). Through collaboration with Dr. Rochlin, our active tick survey determined a rapid and successful expansion of invasive Haemaphysalis longicornis (longhorned tick). Ongoing efforts to find associated pathogens led to the identification of Rickettsia amblyommatis in a small number of field-collected longhorned ticks. Using an artificial membrane tick feeding system, we demonstrated that H. longicornis can support transstadial transmission (from one growth stage to the next growth stage), but not transovarial transmission (from adult female to eggs) of R. amblyommatis. Currently, we aim to optimize artificial membrane feeding and in vivo transmission models to elucidate molecular mechanisms underlying tick transmission of Rickettsia. Of note, R. amblyommatis, a presumed pathogen of spotted fever, is frequently isolated from A. americanum, but its pathogenicity in humans remains unclear. Thus, we collaborate with Dr. Handel to study the prevalence of R. amblyommatis infections among participants residing in endemic areas.
Suffolk County is endemic for many tick-borne diseases transmitted by three major tick species: Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), and Ixodes scapularis (deer tick). Through collaboration with Dr. Rochlin, our active tick survey determined a rapid and successful expansion of invasive Haemaphysalis longicornis (longhorned tick). Ongoing efforts to find associated pathogens led to the identification of Rickettsia amblyommatis in a small number of field-collected longhorned ticks. Using an artificial membrane tick feeding system, we demonstrated that H. longicornis can support transstadial transmission (from one growth stage to the next growth stage), but not transovarial transmission (from adult female to eggs) of R. amblyommatis. Currently, we aim to optimize artificial membrane feeding and in vivo transmission models to elucidate molecular mechanisms underlying tick transmission of Rickettsia. Of note, R. amblyommatis, a presumed pathogen of spotted fever, is frequently isolated from A. americanum, but its pathogenicity in humans remains unclear. Thus, we collaborate with Dr. Handel to study the prevalence of R. amblyommatis infections among participants residing in endemic areas.
Project III. Neutralizing Staphylococcus aureus virulence
Staphylococcus aureus employs various virulence mechanisms to colonize the anterior nares, invade host tissues, and evade our immune systems. Furthermore, due to rising antibiotic resistance, treatment options for S. aureus infections remain limited. Our previous studies identified multiple immune evasive mechanisms and vaccine strategies to combat staphylococcal infections. Unfortunately, despite extensive effort, all clinical trials have failed to meet the endpoint, leaving no FDA-approved vaccine for S. aureus. Thus, there exists an urgent need to develop novel therapeutics and vaccines for S. aureus. Through collaboration with Drs. Bahar, Serebryany, and Tonge, we aim to develop allosteric and selective inhibitors that neutralize key virulence mechanisms of S. aureus and identify genetic requirements for resistance to allosteric inhibitors.
Staphylococcus aureus employs various virulence mechanisms to colonize the anterior nares, invade host tissues, and evade our immune systems. Furthermore, due to rising antibiotic resistance, treatment options for S. aureus infections remain limited. Our previous studies identified multiple immune evasive mechanisms and vaccine strategies to combat staphylococcal infections. Unfortunately, despite extensive effort, all clinical trials have failed to meet the endpoint, leaving no FDA-approved vaccine for S. aureus. Thus, there exists an urgent need to develop novel therapeutics and vaccines for S. aureus. Through collaboration with Drs. Bahar, Serebryany, and Tonge, we aim to develop allosteric and selective inhibitors that neutralize key virulence mechanisms of S. aureus and identify genetic requirements for resistance to allosteric inhibitors.