BAKALETZ LABORATORY
Our laboratory’s research focus is attempting to understand the pathogenic mechanisms operational in the polymicrobial disease, otitis media (OM) (or middle ear infection). Specifically, we are interested in elucidating how upper respiratory tract viruses predispose the middle ear to invasion by any of the three predominant bacterial pathogens of OM. We are also interested in understanding how the mammalian host responds to each of these groups of microbes, particularly at the level of innate immunity, as well as determining how the bacteria involved (primarily nontypeable Haemophilus influenzae) defend themselves against these innate immune effectors. Using multiple approaches, we then attempt to identify potential molecular targets for the design, development and pre-clinical testing of vaccine candidates using an animal model of viral-bacterial superinfection that we developed. Our long-term goal is to develop novel methods to treat or preferably, to prevent, otitis media. |
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Faculty and Staff
Principal Investigator: Lauren Opremcak Bakaletz, Ph.D.
e-mail: Lauren.Bakaletz@nationwidechildrens.org |
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Carruthers, Michael
e-mail: Michael.Carruthers@nationwidechildrens.org |
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Das, Subinoy
e-mail: Subinoy.Das@nationwidechildrens.org |
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Dickson, Amanda
e-mail: Amanda.Dickson@nationwidechildrens.org |
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Jurcisek, Joe
e-mail: Joseph.Jurcisek@nationwidechildrens.org |
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McGillivary, Glen
e-mail: Glen.McGillivary@nationwidechildrens.org |
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Neelans, Jennifer
e-mail: Jennifer.Neelans@nationwidechildrens.org |
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Novotny, Laura
e-mail: Laura.Novotny@nationwidechildrens.org |
EDWARDS LABORATORY
Neisseria gonorrhoeae is the etiological agent of the disease gonorrhea and a major co-factor in HIV-1 infection. Teenagers and young adults are at high risk for infection, which is unsettling in view of the increased risk for HIV-1 infection associated with gonorrhea. Women suffer a disproportionate burden of health complications associated with N. gonorrhoeae infection. Infection in men develops as an acute urethritis; however, infection in women typically is asymptomatic, often leading to ascending infection and chronic disease sequelae. Consistent with the different clinical presentations of gonococcal infection observed between men and women, the pathogenic mechanisms and the human receptors mediating infection also differ. The high frequency with which these bacteria alter their cell surface constituents and the varied mechanisms that they use to invade host cells has made vaccine development extremely problematic.
The presence of complement receptor type 3 (CR3) on epithelial of the female tract and engagement of this receptor leading to membrane ruffling are novel findings. Currently, there are no data defining putative effector molecules mediating ruffling triggered by CR3 engagement and few studies have examined signal transduction in (primary) epithelial cells. Our data suggest that secreted gonococcal products mediate these processes by interacting with cervical cell proteins and subverting their function. This suggests that a dynamic interplay between host and bacterial constituents in potentiating gonococcal disease. These processes are further complicated by cyclic environmental changes, which occur within the female genital tract. A major focus of our future work will be to further characterize the host and bacterial factors and responses required for successful gonococcal infection of cervical epithelia. We are interested in further delineating the signal transduction cascades initiated with cervical gonococcal infection, in analyzing the cyclic contribution of complement and of hormones to these processes, and in examining the oxidative and non-oxidative defenses potentially generated by cervical epithelia with gonococcal challenge. We are also interested in determining if the complement-gonococcus-cervical interaction is unique or if this aberrant complement-microbe interaction occurs between other mucosal surfaces (e. g. airway epithelium) and bacteria (e. g. Neisseria meningitidis type B and Bordetella pertussis). Although these queries are rooted in cellular microbiology, we use a wide variety of approaches to explore these questions. By further elucidating (at the molecular and cellular level) host and bacterial factors and responses facilitating infection, it may be possible to identify new vaccine candidates or to develop new therapeutic strategies for better disease management and improved women’s health.
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Faculty and Staff
Principal Investigator: Jennifer L. Edwards, Ph.D.
e-mail: Jennifer.Edwards@nationwidechildrens.org |
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Butler, Emily
e-mail: emily.butler@nationwidechildrens.org |
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Edwards, Trevor
e-mail: Trevor.Edwards@nationwidechildrens.org |
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Neelans, Jennifer
e-mail: Jennifer.Neelans@nationwidechildrens.org |
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Royal, Maurice
e-mail: maurice.royal@nationwidechildrens.org |
JUSTICE LABORATORY
More than 4.5 million women and children will seek treatment for a urinary tract infection (UTI), accounting for almost 2 billion dollars in medical expenditures each year. Uropathogenic Escherichia coli (UPEC) is the most common causative agent, accounting for up to 80% of all reported cases. In addition to an increase in the number of antibiotic resistant organisms that cause UTI, clinicians are frustrated by the significant recurrence that occurs within the first year of presentation with a UTI. Many women use antibiotics daily to reduce the rate of recurrence, only to succumb to infection upon discontinuing antibiotic treatment. UTIs have been classically described as self-limiting, extracellular infections that recur due to re-introduction of bacteria into the bladder. This paradigm for UTIs has been challenged due to the mounting information obtained by investigations of murine cystitis using strains of UPEC isolated from the urine of women seeking treatment for cystitis. Multiple studies have demonstrated that UPEC invades into the superficial bladder epithelial cells. While free in the epithelial cell cytoplasm, UPEC growth proceeds through a complex developmental and differentiation pathway, leading to the establishment of a chronic, quiescent infection in the bladder tissue. This chronic infection can be the source of organisms for a recurrent infection, demonstrating that current treatments need to be modified to aide in curing and/or preventing recurrent UTIs. The innate immune response is primarily responsible for the control of infectious agents in the urinary tract. UPEC has devised multiple strategies to combat these defenses to establish infection. Initially, UPEC suppress the production of cytokines produced by bladder epithelial cells to recruit infiltration of neutrophils. Secondly, residence in the intracellular environment allows for survival from innate immune-mediated killing. Lastly, during this developmental cycle, filamentous UPEC are observed in hosts with an intact immune response to lipopolysaccharide (LPS), suggesting that bacteria and host recognize and respond to each other. Real-time video microscopic evaluation of infected murine bladders revealed that filamentous UPEC may also play a role in evasion of the innate immune-mediated killing. My laboratory will focus on characterization of the bacterial and host factors required for the UPEC developmental pathway, the mechanisms of innate immune evasion, in addition to deciphering the molecular signals produced by both host and pathogen that occur at the host-pathogen interface. The ultimate goal is to use this information to rationally identify novel therapeutic regimens.
Web Site: http://justicelab.nchresearch.org
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Faculty and Staff
Principal Investigator: Sheryl Justice, Ph. D.
e-mail: Sheryl.Justice@nationwidechildrens.org |
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Bolton, Michael
e-mail: Michael.Bolton@nationwidechildrens.org |
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Casper, Travis
e-mail: Travis.Casper@nationwidechildrens.org |
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Dadoub, Shareef
e-mail: Shareef.Dadoub@nationwidechildrens.org |
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Horvath, Dennis
e-mail: Dennis.Horvath@nationwidechildrens.org |
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Li, Rollin
e-mail: Rollin.Li@nationwidechildrens.org |
KING LABORATORY
Streptococcus pneumoniae colonizes the human airway, a critical first step in S. pneumoniae disease. However, the mechanisms by which this important human pathogen adheres to epithelial surfaces and persists, despite host defenses, is poorly understood. S. pneumoniae has the ability to manipulate sugars. I hypothesize that bacterial deglycosylation of human targets may contribute to both adherence and persistence in the human airway. The long-term aims of my research are to understand how S. pneumoniae efficiently colonizes humans in order to design more efficient vaccines or therapeutics. |
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Faculty and Staff
Principal Investigator: Samantha J. King, Ph.D.
e-mail: Samantha.King@nationwidechildrens.org |
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Burnaugh, Amanda
e-mail: Amanda.Burnaugh@nationwidechildrens.org |
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Fuller, Lindsey
e-mail: Lindsey.Fuller@nationwidechildrens.org |
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Marion, Carolyn
e-mail: Carolyn.Marion@nationwidechildrens.org |
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Stewart, Jason
e-mail: Jason.Stewart@nationwidechildrens.org |
MASON LABORATORY
Studies in
my laboratory focus on understanding the complex molecular mechanisms that underlie
bacterial pathogenesis and the host response.
Nontypeable Haemophilus influenzae
(NTHi) is a common member of the host normal flora (a commensal) and yet predominates in both chronic otitis media with
effusion, acute otitis media and in other localized respiratory diseases such
as acute sinusitis, community-acquired pneumonia and has important consequences
in patients with chronic obstructive pulmonary disease and cystic fibrosis (opportunistic pathogen). We hypothesized that NTHi differentially
expresses a number of genes as the microbe transitions to an opportunistic
disease state. Our investigations provided
one of the earliest description and understanding of Haemophilus pathogenesis in
vivo. Importantly, NTHI adaptation to
the diverse host environment resulted in the up-regulation of sap (sensitivity
to antimicrobial peptides) operon gene expression,
previously shown in other microorganisms to mediate resistance to killing by
antimicrobial peptides (APs), key components of the host innate immune response. These
genes encode the Sap transporter, a member of an ABC transporter family that mediates
recognition of small peptides, cations, or iron-containing proteins, which are
then targeted for transport across the inner membrane into the bacterial
cytoplasm. We hypothesized that the
pathogenic potential of NTHI is dictated by its ability to resist
immune-mediated clearance mechanisms and specifically, killing by host APs. Using genetic tools and biophotonic imaging
of NTHi-infected chinchillas, we demonstrated that the sap genes are expressed in
vivo early in infection and mutants defective in sap gene expression are sensitive to killing by host APs, and thus,
are rapidly cleared in vivo. Our work showed that APs directly bind the
Sap transporter binding protein, supporting a model of AP transport to the
bacterial cytoplasm and subsequent proteolysis or destruction, and initiation
of a regulatory cascade that activates other resistance determinants. We further demonstrated that components of
the Sap transporter are also required for potassium uptake in NTHi, a function which
counters rapid potassium efflux from the bacterium, a hallmark of AP lethality. Current work in my laboratory continues to
define how NTHI senses and transports APs, and define a role for Sap proteins
in ATP-dependence on potassium transport, thus supporting a dual molecular
mechanism that promotes bacterial survival and establishment of disease. Further, we are interested in the role Sap
gene products play in NTHi survival on epithelial cells since mutations in the
Sap transporter alter NTHi biofilm formation, adherence properties and alter
host cell responses. Since Sap system
homologues are conserved among bacterial species, our long-range goal is to
better define a global resistance mechanism which, if targeted, could have
far-reaching implications and therapeutic value.
Web Site: http://masonlab.nchresearch.org
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Faculty and Staff
Principal Investigator: Kevin M. Mason, Ph. D.
e-mail: kevin.mason@nationwidechildrens.org |
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Leimbach, Catie
e-mail: Catherine.Leimbach@nationwidechildrens.org |
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Szelestey, Blake
e-mail: Blake.Szelestey@nationwidechildrens.org |
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Waheed, Yasmine
e-mail: Yasmine.Waheed@nationwidechildrens.org |
MUNSON LABORATORY
Nontypeable Haemophilus influenzae (NTHi) is an important cause of otitis media in children, and a major cause of lower respiratory disease in children in the developing world. The organism is also associated with exacerbations of chronic bronchitis, and pneumonia in elderly and immunocompromised patients.
Haemophilus ducreyi is the causative agent of chancroid, a sexually transmitted disease. Chancroid ulcers facilitate the transmission of HIV.
My laboratory is employing a number of genetic and immunological approaches in order to assess the role of outer membrane proteins, toxins and adhesins in the pathogenesis of Haemophilus disease. |
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Faculty and Staff
Principal Investigator: Robert S. Munson, Jr., Ph.D.
e-mail: Robert.Munson@nationwidechildrens.org |
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Baker, Beth
e-mail: Beth.Baker@nationwidechildrens.org |
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Harrison, Alistair
e-mail: Alistair.Harrison@nationwidechildrens.org |
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Song, Katherine
e-mail: songk@nationwidechildrens.org |
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Tracy, Erin
e-mail: Erin.Tracy@nationwidechildrens.org |
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Walker, Dawn
e-mail: Dawn.Walker@nationwidechildrens.org |
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Zhong, Hua
e-mail: Hua.Zhong@nationwidechildrens.org |
PARTIDA-SANCHEZ LABORATORY
My laboratory is interested in the study of immune cell recruitment induced by infection and/or inflammation. Our research projects are focused on molecular analyses of chemokine receptor-mediated G-protein-linked signaling and calcium influx in neutrophils and DCs. We are conducting experiments to study regulation of calcium influx mediated by CD38-catalyzed metabolites and the ADPR-activated calcium channel TRPM2 in inflammatory cells. We would like to assess whether CD38 inhibiting drugs, CD38-derived antagonists, and/or TRPM2 channel inhibitors, have potential therapeutic use to block undesired chronic inflammatory responses, or harmful T cell responses leading to autoimmunity. This knowledge could allow us to design new strategies for clinical intervention in several immunological disorders, as well as inflammatory and infectious diseases. |
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Faculty and Staff
Principal Investigator: Santiago Partida-Sanchez, Ph.D.
e-mail: Santiago.Partida-Sanchez@nationwidechildrens.org |
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Bhagat, Harivadan
e-mail: Harivadan.Bhagat@nationwidechildrens.org |
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Cortado, Hannah
e-mail: Hannah.Cortado@nationwidechildrens.org |
WHITE LABORATORY
The focus of our laboratory is in the area of Biomedical
Genomics, developing and using state of the art genomic technologies to
investigate and understand the mechanisms of transcriptional regulation as it
relates to human health and disease. Our approach is to utilize DNA microarray
technologies to produce genome wide expression profiles, of both mRNAs and
small RNAs, SNP analysis, array CGH, and promoter occupancy analysis. In
addition to the array based application we are also exploring the tremendous
possibilities of Next Generation Sequencing technologies. Together with the
Research Faculty here at Nationwide Children’s Hospital we are utilizing the
genomic information gained from these technologies to better understand, treat
and prevent human disease. |
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Faculty and Staff
Principal Investigator: Peter White, Ph.D.
e-mail: Peter.White@nationwidechildrens.org |
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Newsom, David
e-mail: David.Newsom@nationwidechildrens.org |
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Sowby, Whitney
e-mail: whitney.sowby@nationwidechildrens.org |
