Internal Medicine; Infectious Disease
I am an attending physician on the Infectious Diseases service at Roswell Park Cancer Institute (RPCI). My clinical duties include inpatient and outpatient consultations at RPCI and on-call duties at Buffalo General Medical Center. In addition to providing clinical care, I teach medical students, residents and fellows in daily rounds and through formal didactic lectures. My primary research interest focuses on the epidemiology, pathogenesis, prevention and treatment of opportunistic infections in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation. In addition, I study the epidemiology, pathogenesis and transmission of colonization and infection by vancomycin resistant Enterococcus in patients with hematologic malignancies. My long-term goal is to define strategies to prevent transmission, determine virulence and decrease the mortality associated with these infections. Finally, I participate as a site principal investigator in several multicenter clinical trials.
Immunology; Infectious Disease
My patient care and teaching responsibilities are centered at the Veterans Administration hospital where I care for hospitalized patients and maintain an active outpatient clinic. I enjoy teaching medical students and residents in both lecture and small group settings. In addition, my laboratory is open to interested undergraduate, graduate and medical students and residents seeking to gain a research experience. Research interests of my laboratory focus on two key areas of the function of specialized immune cells called macrophages. Our first area of interest concentrates on the immunologic roles of mammalian macrophage gangliosides. Gangliosides are unique molecules that hold diverse regulatory roles as receptors and as mediators of cell differentiation in cells of most species. Our studies encompass ganglioside regulation of macrophage inflammatory responses, ganglioside-associated alterations of the architecture of macrophage cell membranes in HIV-infected individuals, and the function of macrophage gangliosides as receptors for bacterial pathogens and toxins. This work will lead to a better understanding of mechanisms of macrophage activation, to permit manipulation of host immune responses. Our second area of interest centers on the regulation of inflammatory responses of human alveolar macrophages by respiratory bacterial pathogens and bacterial antigens that contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Studies encompass defining the repertoire of inflammatory mediators of human alveolar and blood-derived macrophages regulated by bacterial pathogens and characterizing bacteria-regulated immunologic properties of macrophages, in patients with COPD. These investigations into fundamental mechanisms of dysfunctional immune responses of macrophages underlying the progression of COPD are providing the basis for designing novel and more effective therapies.
Eukaryotic Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Signal Transduction; Vision science
Toxoplasma gondii is an obligate intracellular parasite that has the unique ability of infecting most nucleated cells in almost all warm-blooded animals. It is one of the most widespread infections in the world: approximately 50 percent of the world‘s population is infected. Luckily, most infected people are asymptomatic; however, in AIDS patients and other immune-compromised individuals, Toxoplasma causes serious and life-threatening disease. Besides its own medical importance, we study Toxoplasma because it represents an ideal model system to study how other related pathogens cause disease. These include Plasmodium, which is the causative agent of malaria that is responsible for millions of deaths worldwide, and Cryptosporidium, which causes another important secondary infection in AIDS patients. Toxoplasma is a great model system because it can easily be grown in vitro, its genome has been sequenced and it can be genetically manipulated. My research team and I are focused on two different but related questions. First, we want to know how the parasite grows inside of its host cell. One of the important things Toxoplasma must do to grow is hijack host cell pathway and factors. We are using functional genomic assays such as microarrays and genome-wide RNA interference (RNAi) screens to identify these host factors. Identifying them is important because if the parasite cannot use these pathways, the parasite will not grow or cause disease. Thus, these pathways represent novel drug targets. As an example, we discovered that oxygen-regulated transcription factors in the host cell are necessary to support parasite growth. We are currently identifying how these transcription factors function and how the parasite adapts to the various oxygen environments it encounters during its lifecycle. Second, we want to know how Toxoplasma affects the central nervous system and how anti-Toxoplasma immune responses function in the central nervous system. These questions are important because Toxoplasma primarily causes disease in the brain and retina. Our work has revealed that when Toxoplasma actively grows in the brain (a condition known as toxoplasmic encephalitis), it causes a massive reorganization of inhibitory synapses. These changes inhibit GABAergic synaptic transmission and this inhibition is a major factor in the onset of seizures in infected individuals. A second line of research using an ocular infection model has focused on defining how immune responses in the central nervous system are generated by Toxoplasma and then resolved once the infection is under control.
Bacterial Pathogenesis; Infectious Disease; Microbial Pathogenesis; Microbiology
My research interests focus on bacterial pathogenesis, emphasizing bacterial biofilms, antimicrobial therapies and vaccine antigens. One major area of my research lab is otitis media (OM) or middle ear disease. Approximately 80 percent of children experience one episode of OM while others have recurrent infections. Chronic OM infection causes hearing impairment leading to developmental problems as these children reach school age. My laboratory has concentrated on two major causes of OM, Moraxella catarrhalis and Streptococcus pneumoniae. Our recent work suggests that M. catarrhalis colonization predisposes patients to colonization with S. pneumoniae in polymicrobial biofilms. The goals of this work are to define biofilm-associated factors and to identify signals that induce bacteria to transition from asymptomatic colonizers to pathogenic organisms leading to OM. Our second major research focus is the identification of novel antimicrobial therapies. Chronic OM is likely a biofilm-associated disease and biofilms are highly antibiotic resistant. Antibiotic resistance is a major problem worldwide and new drug development is both time consuming and extremely expensive. We have demonstrated that photodynamic therapy (PDT), an FDA-approved cancer treatment, is also bactericidal against the three major otopathogens. Thus, the goal of this research is to adapt PDT into a clinically effective treatment for chronic OM. Our third research area involves novel antimicrobial treatments for orthopedic/prosthetic infections. Infections after orthopedic intervention, including knee/hip replacements and insertion of prosthetic devices, are devastating to the patient and these infections will likely increase over the next 20 years. This is particularly relevant to the military where improvised explosive devices cause severe extremity injuries requiring amputation. Antibiotic-resistant biofilms are the primary source of these infections. In collaboration with colleagues at UB, we are testing a novel electrical stimulation method for prevention/eradication of biofilm infections on implant materials. The goals of this research are to define the optimal antimicrobial parameters that are broadly effective against multiple pathogens, including Staphylococcus aureus, Acinetobacter baumannii, Staphylococcus epidermidis and Klebsiella pneumoniae. The members of my research team typically include a combination of graduate students, lab technicians and a junior faculty member. In the summer, I usually mentor medical students or undergraduates who are interested in the fundamentals of basic science and translational research focused on microbial pathogenesis.
I provide inpatient infectious disease consultation services at both Erie County Medical Center (ECMC) and Buffalo General Medical Center (BGMC). In addition, I collaborate with the ECMC renal and pancreas transplant team to evaluate and treat infectious complications associated with solid organ transplantation. I feel honored to serve patients who receive a lifesaving organ in order to help live a normal life. Lastly, I see outpatients with various infectious disease problems at the immunodeficiency clinic at ECMC. I enjoy teaching medical students, residents and infectious diseases fellows the principles and practice of infectious diseases. The majority of my teaching is at clinical sites at ECMC and BGMC. However, I also give didactic lectures during specialty conferences and grand rounds. Although the majority of my time is centered on patient care and teaching, I am also involved with clinical research. My role is to identify and recruit patients for a variety of clinical trials designed to assess new modalities for the prevention or treatment of infectious diseases.
Allergy and Immunology; Medical Microbiology; Infectious Disease; Microbiology; Genomics and proteomics; Immunology; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Gene Expression; Signal Transduction; Protein Function and Structure; Bacterial Pathogenesis
Research efforts in my laboratory are focused in the fields of immunology and bacterial pathogenesis, two diverse fields of biomedical research for which I have two separate research groups. Projects in both fields are performed by undergraduates, doctoral and master’s degree students, postdoctoral fellows and senior research associates. One major focus of my laboratory is studying the regulation of mucosal immune responses. We investigate the cellular and molecular events by which Type II heat-labile enterotoxins (HLTs), produced by certain strains of Escherichia coli, modulate immune responses. We have demonstrated that LT-Ilia, LT-IIb and LT-IIc, when co-administered with an antigen, have the capacity to enhance antibody and cellular immune responses to that antigen. Using a variety of immunological and cellular technologies, including flow cytometry, fluorescence resonance energy transfer (FRET) detection, cytokine multiplex analysis, mutagenesis, quantitative Reverse Transcription PCR (qRT-PCR), RNA-sequencing (RNA-Seq) and a variety of transgenic mice, we are investigating the mechanisms by which these immunomodulators productively interact with various immunocompetent cells (T cells, B cells, dendritic cells, macrophages) to induce or suppress cytokine production, costimulatory ligand expression and cellular proliferation. A practical outgrowth of these experiments is the potential to engineer novel recombinant vaccines by genetically fusing antigens from different pathogens to the enterotoxins. Recent experiments have shown that these HLT are lethal for triple-negative breast cancer cells, which has opened a new area of oncological research for the lab. A second focus of my laboratory is to investigate the molecular mechanisms by which adherent-invasive Escherichia coli (AIEC) induce, exacerbate or prolong the symptoms of inflammatory bowel disease (IBD) and Crohn’s disease, two acute and chronic inflammatory diseases of the human gut. In vitro, AIEC strains invade into the cytoplasm of several epithelial cell lines. Using recombinant screening methods and RNA-Seq technologies, we are identifying the genes of AIEC that are required to attach and to invade gut cells.
Infectious Disease; Infectious Disease; Microbial Pathogenesis; Vitamins and Trace Nutrient
I care for patients who are hospitalized at Erie County Medical Center where I also serve as the hospital epidemiologist addressing infection control. I teach medical students, residents, and fellows in both hospital and classroom settings. In UB’s schools of medicine and dentistry, I teach a variety of topics including microbiology, pharmacology and toxicology, oral biology, and gastrointestinal systems, host defenses, and global health. I also conduct laboratory research on diarrhea-producing strains of E. coli bacteria. My lab focuses on enteropathogenic Escherichia coli (EPEC), Shiga-toxigenic E. coli (STEC, aka EHEC) and enterotoxigenic E. coli (ETEC). We are working on the role of intestinal host defenses such as nitric oxide and on the immune modulatory effects of adenosine. We have discovered that zinc can directly inhibit the virulence of pathogenic bacteria, and we are working on turning these laboratory findings into treatments. In our work on zinc we collaborate with Michael Duffey, PhD, in the Department of Physiology and Biophysics. Recently we have discovered that zinc can inhibit the development of resistance to antibiotics in Escherichia coli and other bacteria. Zinc does this by its ability to inhibit the SOS response, a bacterial stress response triggered by damage to the bacterial DNA. We are collaborating with Dr. Mark Sutton of Biochemistry to better determine the mechanism of zinc in this regard. I am interested in international medicine and global health and participate in an annual medical mission trip to Honduras, a trip in which student volunteers are encouraged to participate. Closer to home, I am a volunteer physician at Good Neighbors Health Center, a free clinic for the underserved on Jefferson Avenue in Buffalo. Resident physicians are encouraged to volunteer, and students may also be able to arrange clinical experiences. I am Co-Medical Director, with Dr. Ryosuke Osawa, of the Erie County TB Clinic. Learning experiences in my laboratory, in infection prevention and hospital epidemiology, or in international health, may be available for motivated students, residents, and fellows.
Autoimmunity; Bioinformatics; Genomics and proteomics; Immunology; Infectious Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology
My primary research is in the field of biomedical ontology development. An ontology is a controlled, structured vocabulary intended to represent knowledge within a particular domain. Terms in an ontology have logical relationships to each other and to terms in other ontologies, to allow for reasoning and inference across the ontology. Biomedical ontologies allow annotation and integration of scientific data within particular fields of science and medicine, and their careful curation and logical structure facilitate data analysis. My work in biomedical ontology is strongly informed by my earlier experience in laboratory research in immunology, genetics, molecular biology and virology. My research group works on ontologies for both basic and clinical applications, in collaboration with researchers both at UB and other institutions. I led efforts to revise and extend the Cell Ontology, which is intended to represent in vivo cell types from across biology. We worked extensively to bring it up to community-accepted standards in ontology development, placing particular emphasis on improving the representation of hematopoietic cells and neurons. We are developing the Cell Ontology as a metadata standard for annotation and analysis of experimental data in immunology in support of the National Institute of Allergy and Infectious Diseases (NIAID) ImmPort Immunology Database and Analysis Portal and Human Immunology Project Consortium. We have also developed ways to use the Cell Ontology in support of the analysis of gene expression data linked to cell types and have contributed to the Functional Annotation of the Mammalian Genome (FANTOM) 5 Consortium‘s work on identifying gene transcription start sites across multiple cell types and tissues. My research team is also developing the Neurological Disease Ontology to represent clinical and basic aspects of neurological diseases in order to support translational research in this area. In collaboration with clinical colleagues at UB, we are initially focusing on Alzheimer’s disease and dementia, multiple sclerosis and stroke. We have as well developed a companion ontology, the Neuropsychological Testing Ontology, to aid in the annotation and analysis of neuropsychological testing results used as part of the diagnosis of Alzheimer‘s disease and other neurological diseases. I am a long-term member of the Gene Ontology (GO) Consortium and have a particular interest in the representation of immunology and neuroscience in the GO. I am also involved in UB’s contribution to the Protein Ontology and contribute as well to the work of the Infectious Disease Ontology Consortium, Immunology Ontology Consortium and Vaccine Ontology Consortium. I teach and mentor students at the master’s and doctoral levels, and advise undergraduate, graduate, and medical students in summer research projects as well.
As an Infectious Disease specialist, I see and evaluate adult patients as part of the Infectious Disease inpatient consultation service at both Buffalo General Medical Center (BGMC) and Erie County Medical Center (ECMC). I enjoy teaching medical students, residents and fellows the principles of Infectious Disease at both ECMC and BGMC. The practice of infectious disease crosses a large variety of specialties from Surgery to Internal Medicine and I believe exposure to this field in training is very important. I appreciate the interdisciplinary aspect of Infectious Diseases and its intersection with global health, microbiology, and epidemiology. The face of the infectious processes seen in Buffalo will continue to change due to the effects of globalization and climate change and I find this especially fascinating.
Infectious Disease; Bioinformatics; Microbial Pathogenesis
My clinical interest work focuses on infectious diseases, particularly those caused by Staphylococcus aureus. I practice medicine at the VA Western New York Healthcare System, where I am Chief of the Infectious Disease Section. The service here treats veterans with a wide variety of infectious diseases, including HIV and hepatitis C. I follow both inpatients and outpatients on this clinical service. Medical students, residents, and fellows evaluate and follow infectious disease consultations with me on the inpatient service. I teach extensively in the Medical School, and serve as Vice Chair for Education in the Department of Medicine. I enjoy working with students throughout the full spectrum of medical education, from first-year medical students to senior fellows in Infectious Disease. My research interests dovetail with my clinical work. I study Staphylococcal infections, particularly complications related to S. aureus bloodstream infections. My laboratory uses advanced molecular biology techniques to identify bacterial virulence factors. In collaboration with Steve Gill at the University of Rochester, we are analyzing three years of clinical data on S. aureus bacteremia in the Buffalo area and sequencing hundreds of bacteremia isolates of S. aureus to identify the genomic architectures associated with more severe complications and those associated with poor clinical outcomes. This work makes use of bioinformatics and database design, techniques that support my ongoing collaborations with other investigators on bioinformatics problems, particularly with Moraxella catarrhalis and Haemophilus influenzae. Prior to my studies in S. aureus, I conducted research on a fascinating pathogen, H. influenzae bio group aegyptius and Brazilian Purpuric Fever. Over that 10-year period my laboratory identified a unique epitope on a surface proteins associated with the disease. We were able to create the only isogenic mutant so far described with this pathogen that is highly refractory to genetic manipulation.
Addictions; Gastroenterology; Internal Medicine; Liver (Hepatology); Infectious Disease
I care for patients with liver disease and addiction disorders, including opiate dependency, viral hepatitis, alcoholic and fatty liver disease, in an outpatient setting at Erie County Medical Center where I am the medical director of hepatology. In collaboration with the division of infectious diseases, I also evaluate and treat patients with hepatitis C virus (HCV) and HIV co-infection. I also treat veterans with opiate dependency at the Buffalo VA Medical Center, in the addiction medicine unit. My patient-care efforts include digital outreach: I co-authored an article for the inaugural issue of the patient-oriented online magazine “HCV Next.” My research involves improving hepatitis C treatments in populations disproportionately affected by HCV but with limited access to health care (including many American veterans, ethnic minority groups, injection drug users, and patients with psychological disorders) as well as developing novel modalities to deliver care. The goal of my research is to expand HCV treatment services to a wide-ranging group of patients, especially those without immediate access to care, in an effort to reduce global disease burden. This may include training primary care or other providers to treat HCV and using telemedicine and co-localization as a way to increase treatment uptake in areas such as rural primary care clinics and methadone clinics. My team is also investigating barriers to hepatitis C screening and treatment. Using the data we collect (e.g., patients’ knowledge of the disease, their perceptions regarding treatment, their willingness to be treated), we can design initiatives to improve patient-based HCV education and work toward the goal of increasing treatment uptake. This component of my research also looks at the same issues on the provider side: provider HCV knowledge and screening, referral and treatment practices. These data will help us understand what the provider-level barriers are to disease control, and we can design provider-based HCV educational initiatives to improve screening and referral for care. I am also a co-investigator on numerous clinical trials related to new therapeutic agents for hepatitis C and fatty liver disease, including a study funded by the Centers for Disease Control and Prevention (CDC) to evaluate the use of telemedicine to treat HCV in methadone maintenance clinics. I present and lecture nationally about hepatitis C with an emphasis on opiate dependence and special populations. I am a member of the New York State Hepatitis C Demonstration Project expert panel. I teach medical students in small group settings in the area of gastroenterology and hepatology. I also precept internal medicine residents and gastroenterology fellows in the outpatient clinics.
Infectious Disease; Microbiology; Molecular and Cellular Biology; Molecular genetics; DNA Replication, Recombination and Repair; Virology; Genome Integrity
The major focus of my laboratory is in understanding the molecular machines that make up the DNA replication forks of the small human DNA viruses, polyoma- and papillomaviruses. Papillomaviruses and polyomaviruses are human pathogens; human papillomavirus (HPV) results in a vast number of human cancers, and the human polyomaviruses JC and BK cause serious disease and death in immunocompromised patients. Both viral systems provide important models for the study of human DNA replication mechanisms and have allowed for vital insights into eukaryotic DNA replication. The study of polyomavirus DNA replication led to the first identification of many cellular DNA replication complexes and processes; papillomavirus has provided the best structures and models to date of replicative hexameric DNA helicases and how they function. I typically train undergraduate, master’s and doctoral students and postdoctoral scholars, assistant research professors and laboratory technicians. My laboratory focuses on two primary areas. One is elucidating the dynamic protein-protein interactions that allow the series of enzymes required to replicate DNA to act in concert and in the correct sequence required to duplicate the genome. My laboratory has been at the forefront of identifying the interactions between the one critical HPV DNA replication protein, the origin-binding DNA helicase, E1, and cellular DNA replication proteins. Understanding these interactions and the roles they play in the HPV DNA replication process has helped our understanding of, and continues to lead to information that tells us more about how both viral and eukaryotic DNA replication forks function. In addition, as we identify protein-protein interactions between HPV E1 and cellular factors that are essential for HPV DNA synthesis, we will uncover potential targets for development of broad-range HPV antivirals that could act to block HPV replication. We recently obtained a large multilaboratory NIH research grant to investigate just this possibility for the interaction between HPV E1 and the human DNA replication protein, Topoisomerase I. The second primary area of investigation is elucidating how the cellular DNA damage response (DDR) pathways inhibit DNA replication when cells are subjected to DNA damage. For many years, the DDR field focused on the effects of DDR on the cell cycle kinases as the only method by which DNA replication was arrested. In the mid- to late-2000s, researchers recognized that in mammalian cells there is also a substantial (tenfold) inhibition of elongation of DNA replication following DDR. The mechanisms for this inhibition are unknown. Using both in vitro and cell-based simian virus 40 (SV40) DNA replication systems, we have shown that SV40 DNA replication is also shut down in response to DDR kinase pathways and that this is not based on cell cycle kinase action. Therefore, SV40 provides a useful model system for determining how elongation of DNA replication is inhibited by DDR. Furthermore, we have shown that in contrast HPV DNA replication does not respond to DDR, providing us an important control DNA replication system for these studies. (The lack of DDR arrest of HPV DNA replication likely explains why HPV integrates so readily into host cell chromosomes−an important step for HPV-induced carcinogenesis). Our studies on the DDR effect on polyoma and papilloma virus DNA replication will lead to insights into the effect of DDR on cellular DNA replication as well as an understanding of how HPV integrates into host cell chromosomes causing HPV-induced cancers.
I primarily provide consultations for inpatients at Buffalo General Medical Center (BGMC) and Gates Vascular Institute (GVI). I also provide consultation services at Roswell Park Cancer Institute during on-call weekends. In my clinic at BGMC, I evaluate and treat patients with a variety of infections primarily as a follow-up from recent hospitalization. This allows for continuity of care, a service that is highly appreciated by the medical and surgical services at BGMC and GVI. I enjoy teaching medical students, residents, and fellows on inpatient consultation service at BGMC and GVI; consultations may be called by a medical or a surgical service. Medical services include general internal medicine or one of the medical specialties (cardiology, pulmonary, nephrology, oncology, etc.), neurology, family medicine and rehab medicine. Surgical services include general surgery, colorectal surgery, bariatric surgery, cardiothoracic surgery, orthopedic and hand surgery, vascular surgery, plastic surgery and urology. This spectrum of consultations allows for a broad variety of patients, which provides fellows and residents a diverse intellectual experience during their rotation. I see patients with residents and fellows and discuss cases with them. Also, I provide didactic morning reports to the internal medicine residency program. During my off-service months, I enjoy writing case reports with the medicine residents. I am also the director of the Anti-microbial Stewardship (AMS) program at BGMC and GVI. In this role, and in collaboration with the pharmacy department, I am responsible for providing an overview to the antimicrobial use at these institutions. The aim of the AMS program is to help provide to the different specialties a better understanding of appropriate use of antibiotics and to adjust or de-escalate antibiotics whenever it is deemed appropriate. Our goals are to reduce nosocomial infections like Clostridium difficile, reduce colonization/infection with multi-drug resistant organisms and decrease the length of hospital stay whenever possible.
Research in my laboratory focuses on nontypeable Haemophilus influenzae and Moraxella catarrhalis, important pathogens in otitis media and lower respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). A goal of work is to develop vaccine to prevent these infections. To that end, outer membrane proteins have been identified and are being evaluated as potential vaccine antigens. A COPD Study Clinic supported by a grant from the Department of Veteran Affairs has been running continuously since 1994. This prospective study follows adults with COPD during monthly clinic visits during which sputum and serum samples are collected. Bacterial isolates are recovered from sputum and are subjected to molecular typing. These studies are elucidating the dynamics of respiratory tract bacterial colonization. In addition, serum and sputum samples are being studied to learn about systemic and mucosal immune responses to bacterial pathogens.
My clinical expertise is in the management of infections in patients who have undergone solid organ transplant or hematopoietic stem cell transplant. These patients require a dedicated diagnostic and treatment approach, as they are severely immunocompromised due to medications they receive to prevent organ rejection and are susceptible to a large number of pathogens (bacteria, fungi, viruses) that should not cause infections in healthy individuals. I also treat infections in immunocompromised patients secondary to cancer, chemotherapy, and medications (steroids, biologics, etc). I provide consultation for inpatients in Buffalo General Medical Center (BGMC) and Roswell Park Cancer Institute, usually as a result of a referral from a primary care physician, but I also see patients referred from specialty services such as general surgery for surgical site infections, orthopedics for joint infections, cardiothoracic surgery for pacemaker infections, etc. In my clinic at BGMC, I evaluate and treat patients with a variety of infections, as follow-up from recent hospitalizations and a referral from a primary care physician. I also work at Erie County Department of Health Tuberculosis Clinic as Co-Medical Director. I enjoy teaching medical students, residents, and fellows in inpatient consultation service and lectures in BGMC and Roswell. I see patients with residents and fellows, and we discuss their cases.
Eukaryotic Pathogenesis; Gene Expression; Infectious Disease; Microbial Pathogenesis; Microbiology; RNA; Signal Transduction
There are estimated to be over one million species of fungi on the earth, yet very few of these species are capable of causing deadly systemic infections in humans. One of the major limiting factors for most fungi is their inability to grow at mammalian core body temperature. We utilize the fungal pathogen Cryptococcus neoformans var. grubii as a representative fungal pathogen to understand how these few fungi have adapted to growth at mammalian body temperature. C. neoformans is a worthy pathogen, as it is estimated to cause over 500,000 deaths from meningoencephalitis per year, primarily in Africa and Southeast Asia as an HIV/AIDS comorbidity. We use the temperature-limited Cryptococcus amylolentus as a comparator; it is an environmental strain that produces similar virulence factors to C. neoformans and is fully virulent in surrogate invertebrate hosts at permissive temperatures. We have discovered that host temperature adaptation in C. neoformans is accompanied by a reprogramming of gene expression at the level of messenger RNA (mRNA) stability. In response to temperature stress, C. neoformans rapidly degrades mRNAs that encode energy consuming machinery such as ribosomes. At the same time, it prioritizes the translation of stress-responsive mRNAs on existing ribosomes. Because mRNA synthesis and decay are coupled processes, we seek to identify the protein components of mRNA complexes that mediate the specificity of this decay process and posttranslational modifications, such as arginine methylation and phosphorylation, that modify their function. In addition, we are investigating the signaling pathways that accelerate or slow mRNA decay in response to specific environmental stimuli such as host temperature and nutrient deprivation. Finally, mRNA decay not only alters gene expression at the posttranscriptional level, but the degradation of abundant mRNAs during stress releases nucleotide intermediates that can be utilized by the stressed cell to promote genome stability. We are investigating the process of mRNA degradation as well as nucleotide metabolic pathways as drug targets in C. neoformans and other fungal pathogens. Our goal is to define the unique attributes of C. neoformans that confer pathogenicity and to identify potential targets for novel therapeutics. Each of my students has a project that contributes to the overall goals of my research team. Students in my laboratory work independently, though with frequent interaction with me regarding the direction of investigation and interpretation of data. Regular meetings allow us to provide input on each other’s projects. I expect my students to present their work at least once per year at a national or international meeting, and I expect them to do the bulk of the work in writing papers describing their findings for publication.
Internal Medicine; Pulmonary Disease; Infectious Disease
My area of expertise is in infectious diseases in adults and I evaluate and treat adults with all infections, without restriction to a special area, and see patients within the Veterans Affairs hospital system. I act as a consultant for other physicians treating patients who have, or are suspected to have, infectious diseases in hospital settings or outside the hospital. Prior to becoming an infectious disease specialist, I had training and work experience in surgery as well as internal medicine. This exposure has helped me in my current clinical practice since infections occur in patients after surgical procedures. Having a firsthand understanding of what surgeons do allows me to understand the patient’s overall situation better. I teach first- and second-year medical students, primarily in pulmonary, in small group sessions. My research is focused on bacterial infections in patients with chronic obstructive pulmonary disease (emphysema and chronic bronchitis, known also as COPD). I am especially interested in how the host (the human body) reacts to the pathogen (the bacteria), and how differences in the host determine the outcome of the encounter between host and pathogen. Recently, we found that airway epithelial cells from patients with COPD respond to pathogenic bacteria in a manner that is different from healthy, non-COPD people. My goal is to further characterize and understand the cellular mechanisms underlying this aberrant behavior in COPD. I expect this research to open new avenues of therapy specially tailored to intervene in the host-pathogen interaction. Students and fellows have the opportunity to conduct research with me. I collaborate with Sanjay Sethi, MD and Charles Berenson, MD from the department of medicine and with Anders Hakansson, PhD, from the department of microbiology and immunology.
Eukaryotic Pathogenesis; Gene Expression; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; RNA
Trypanosoma brucei is a eukaryotic pathogen that causes human African trypanosomiasis, a disease that is invariably fatal if not treated. Essential and novel processes in this parasite may serve as starting platforms for new chemotherapeutics, which are urgently needed. Our laboratory combines biochemical, genetic, genomic and proteomic approaches toward understanding gene regulation and protein modification in this pathogenic eukaryote. One focus in my laboratory is RNA editing, a novel mechanism for regulating mitochondrial gene expression in which sequence information is added to mRNAs after transcription by specific insertion and deletion of uridine residues. RNA editing is essential for creating translatable open reading frames (ORFs). We are performing functional and biochemical characterization of the large, dynamic RNA-protein complex termed MRB1, which coordinates multiple aspects of the RNA editing process. A second focus is on regulating RNA stability and translational control in T. brucei, which constitute the major methods of gene regulation in this organism. We identified an RNA binding protein, DRBD18, that impacts the stabilities of hundreds of mRNAs. Our data support a model in which posttranslational modification of DRBD18 by arginine methylation acts as a switch to change DRBD18 from an mRNA destabilizer to an mRNA stabilizer by regulating specific protein-protein and protein-RNA interactions. We are testing this model in vitro and in vivo using reporter assays, in vivo protein-RNA cross-linking and protein-protein interaction assays. A third focus is on understanding the mechanisms by which protein arginine methylation modulates trypanosome biology. We performed a global proteomic analysis of the arginine methylome of T. brucei, identifying >1100 methylproteins spanning most cellular compartments and a wide array of functional classes. We are now analyzing novel mechanisms of protein arginine methyltransferase regulation and defining the physiological and molecular functions of arginine methylmarks on selected proteins. I foster a collaborative and flexible laboratory environment, and I encourage my students to explore the research topics that interest them.
Gene therapy; Genomics and proteomics; Immunology; Infectious Disease; Neurobiology; Neuropharmacology; Viral Pathogenesis; Virology
As a postdoctoral fellowship in the Division of Allergy, Immunology & Rheumatology at University at Buffalo I received a NIDA funded National Research Service Award (NRSA) F32 to study the mechanisms of cocaine-induced HIV-1 infection in astrocytes. This was a two year fellowship award ($99,224). I received several Young Investigator Travel Awards to attend and present my research at national conferences including the Society for NeuroImmune Pharmacology, the College on Problems of Drug Dependence and the International Society for NeuroVirology. I was the first to demonstrate that cocaine enhances the replication of HIV in astrocytes, specialized glial cells in the central nervous system. During this time I was first author on 3 publications and contributed as a co-author on 6 publications in internationally recognized, peer reviewed journals including the Journal of Immunology, Brain Research and Biochimica et Biophysica Acta. As a Research Assistant Professor in the Division of Immunology I was funded through a NIDA Mentored Research Scientist Development Award (K01) award to investigate targeted nanoparticles for gene silencing in the context of HIV and drug abuse. This K01, was a five year award, $785000 that allowed for advanced training in nanotechnology and immunology. I applied this new expertise in nanotechnology to the development of innovative methods to control HIV-1 infections, particularly those associated with methamphetamine abuse. I was an invited panel speaker at the International Symposium on NeuroVirology and the American College of Neuropsychopharmacology. During this time, I published approximately 30 peer-reviewed publications in internationally recognized, peer-reviewed journals, including journals such as the Journal of Immunology, Brain Research, and the Journal of Pharmacology Experimental Therapeutics. Six as first author, 1 as senior author and 23 as a co-author. Presently, I am a Associate Professor and Proposal Development Officer in the Department of Medicine at University at Buffalo where I continue to develop my research in drug delivery methods. I am currently investigating exosomes as potential delivery vehicles. Exosomes are one of several types of membrane vesicles known to be secreted by cells including microvesicles, apoptotic bodies, or exosome-like vesicles. Exosomes, unlike synthetic nanoparticles, are released from host cells and have the potential to be novel nanoparticle therapeutic carriers I have recently been invited to be a panel speaker at the American Society of Nanomedicine and the American Society of Gene & Cell Therapy conferences. I have been a principal investigator and co-instigator on NIH funded projects studying multimodal nanoparticles for targeted drug delivery and immunotherapy in Tuberculosis and HIV and a co-investigator on a NYS Empire Clinical Research Investigator Program (ECRIP) to develop a Center for Nanomedicine at UB and Kaleida Health. I have had over eight years of NIH supported funding.
Infectious Disease; Infectious Disease; Microbial Pathogenesis
I am an expert in infectious diseases, and I care for hospitalized patients at the Buffalo VA Medical Center (Buffalo VAMC). I have an active, nationally funded translational research program. My research focuses on Gram-negative bacilli (GNB), including Escherichia coli, Acinetobacter baumannii and a new hypervirulent variant of Klebsiella pneumoniae. These GNB cause infection in nearly every nonintestinal site in the body. The hypervirulent variant of K. pneumoniae is both fascinating and worrisome. Unlike its predecessors, it is capable of causing infection in young, healthy hosts and spreading nearly anywhere in the body from the initial infected site, including the eyes and brain. GNB-caused infections result in the loss of billions of health care dollars, millions of work days and hundreds of thousands of lives each year. GNB are becoming increasingly resistant to antibiotics, including strains that have become resistant to all available antibiotics. Unfortunately, there are virtually no new antimicrobial agents active against highly resistant GNB in the pharmaceutical “pipeline.” To address this formidable clinical challenge, my collaborators and I have increased our understanding of the bacterial factors that are critical for these GNB to cause infection. We use this information to develop vaccines that will prevent infection and antibodies that can be used to treat infection. My UB collaborators include Dr. Campagnari (microbiology), Dr. Gulick (structural biology) and Drs. Elkin and Zola (biomedical informatics). My research also involves identifying potential bacterial drug targets; this information will be used to develop new classes of antibiotics. I intermittently have students in my lab, and I participate in a grant designed to encourage medical students to become physician-scientists. I welcome interested students to contact me about conducting research with me. The Buffalo VAMC is the site of my clinical teaching. I teach first- and second-year medical students in lecture settings and small group sessions, including courses in lung respiration, musculoskeletal, renal and microbiology-immunology. Residents attend my grand rounds; I also teach fellows in all aspects of their training and mentor those who perform their research projects in my lab.
Infectious Disease; Oncology
I care for hospitalized patients and outpatients at Roswell Park Cancer Institute (RPCI), where I am head of Infectious Diseases. My area of clinical expertise relates to infections in patients with cancer and stem cell transplant recipients, and I have served on several national panels that establish guidelines for preventing, diagnosing, and managing infections in these patients. I also have a specific interest in patients with primary phagocytic disorders (e.g., chronic granulomatous disease). RPCI is the site of my clinical teaching. I also teach medical students in lecture settings and in small group sessions in their first and second years, including courses in lung pathophysiology and microbiology-immunology. We intermittently have students in our lab and participate in a grant designed to encourage medical students to become physician-scientists. I mentor residents in their clinical training and in research. I also teach fellows in all aspects of their training and mentor those who perform their research projects in my lab. I have an active, nationally funded translational research program. The major focus of our lab is studying NADPH oxidase as a critical regulator of inflammation and host defense. NADPH oxidase is an emergency host defense pathway that is rapidly activated in response to certain microbial products, and converts molecular oxygen to superoxide anion and downstream reactive oxidant intermediates (ROIs). Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections (e.g., invasive aspergillosis) and by excessive inflammation. In addition to its critical host defense role, our lab, in collaboration with colleagues, found that NADPH oxidase also functions to restrain inflammation by modulating redox-sensitive innate immune pathways. NADPH oxidase also affects T-cell responses, including the balance between Tn17 and regulatory T-cells. We have an NIH grant to further elucidate mechanisms by which NADPH oxidase regulates inflammation. We believe that our work has broad relevance to human diseases associated with inflammation, such as inflammation-induced injury and tumor immunology. Indeed, several of the pathways that NADPH oxidase regulates are important in tumorigenesis and the tumor microenvironment (e.g., NF-kB, Nrf2, IL-17, Tregs), and are potential therapeutic targets. In collaboration with colleagues, we are examining how NADPH oxidase influences tumor immunity.
Infectious Disease; Infectious Disease
My primary patient care activites involve hospitalized patients at the Department of Veterans Affairs Medical Center (VA) in Buffalo. I also have an outpatient clinic at UB’s Student Health Center on the South Campus where I see students for general ambulatory infectious diseases such as skin infections, positive tuberculosis skin tests, etc. I also see students before they travel internationally for care such as immunizations and risk avoidance education and, if needed, for post-travel care and follow-up. I teach first- and second-year medical students in lectures and small group sessions, primarily in the microbiology, respiration, musculoskeletal and reproductive modules. I also teach third- and fourth-year medical students, residents, and fellows on the infectious diseases and internal medicine services at the VA. In addition to patient care and teaching, I have significant roles related to infection prevention and antimicrobial stewardship at two of Buffalo’s major health care systems, and I serve as Hospital Epidemiologist for both. My work includes pandemic and bioterrorism planning activities for these hospital systems as well as the University at Buffalo. These responsibilities require that I collaborate with hospital infection control teams, pharmacists, microbiologists and administrators (particularly the offices of quality management, risk management and patient safety) and with UB’s Student Affairs team. I also interact frequently with local health department staff. Our infection control efforts have been based on the epidemiologic paradigm of hypothesis development, data collection and critical interpretation of the data followed by a rational and directed action plan. This is done for routine infection prevention, outbreak and cluster investigation, healthcare worker safety and antimicrobial stewardship.
Infectious Disease; Internal Medicine - General
I provide infectious diseases consultations for hospitalized patients at the Erie County Medical Center (ECMC). At the Immunodeficiency Clinic at ECMC, I care for HIV infected patients. HIV infection has become a chronic illness with antiretroviral therapy, and patients with HIV need primary care as well as HIV care. The Immunodeficiency Clinic offers comprehensive care to these patients and gives me the opportunity to practice primary care for HIV infected patients in addition to my infectious disease practice. I also participate in antiretroviral therapy clinical trials at the clinic. These studies are crucial in evaluating the effectiveness and safety of new medications and new combination regimens. Patients are screened for eligibility for ongoing trials during their visit, and eligible candidates are enrolled. I enjoy teaching medical students, residents, and fellows at ECMC where I supervise them on crucial skills in infectious diseases: recognizing important physical findings, developing differential diagnosis and selecting appropriate antibiotic treatment. I feel fortunate to be part of their medical training.
Gastroenterology; Liver (Hepatology); Infectious Disease
I am a leading expert in liver disease. My work through UBMD at Erie County Medical Center’s liver clinic has tripled the clinic’s capacity to treat patients with viral hepatitis and other forms of liver disease. Colleagues and I also have established comprehensive liver clinics at Buffalo General Medical Center to evaluate patients with liver disease referred from throughout Western New York. In addition, we provide clinical support to the Buffalo VA Medical Center in order to deliver uniformly excellent clinical care to patients with liver disease cared for at hospitals and clinics affiliated with UB’s medical school. We offer trial therapies to patients with viral hepatitis and other forms of liver disease if they meet the protocol criteria of our clinical trials. Our patient-care efforts include digital outreach: my colleagues and I co-authored an article for the inaugural issue of the patient-oriented online magazine “HCV Next.” My lab has received multi-year funding for its research programs in translational and clinical research. During the course of our translational research, members of my lab and I developed techniques for animal and human liver sampling that will enable sorting of liver cells in order to understand drug distribution in the liver during treatment and to develop ways to measure liver drug concentration. These translational research techniques will enable physicians to base drug dosing on the data gathered from the site of antiviral action in the liver instead of measuring the plasma concentration that is more reflective of systemic exposure. This may be an important breakthrough because of the fine line between drug efficacy and toxicity: the techniques will help physicians pinpoint the precise amount of drug needed for maximum benefit to the patient. In the area of clinical research, we are studying care models for viral hepatitis. We are conducting a study sponsored by the Centers for Disease Control and Prevention (CDC) Foundation to assess telemedicine to treat hepatitis C (HCV) in patients who are in treatment for substance use. By creating processes that simplify testing and improve provider and patient awareness and by expanding recommendations for HCV screening, patients can receive more timely care and treatment. I teach GI fellows, residents and students in outpatient and inpatient settings. I also teach first- and second-year medical students in small groups and research seminars with pharmacology graduate students. I am very interested in mentoring, and I supervise residents and fellows in clinical research as well as in my laboratory. The enriching experience my trainees receive affords them excellent placement opportunities once their training is complete. A number of my former trainees so valued their work with my lab that they joined our division as faculty members.
Structural Biology; X-ray Crystallography; Bioinformatics; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Molecular and Cellular Biology; Protein Function and Structure; Proteins and metalloenzymes; Virology
The overarching goal of the Umland Lab is to use structural biology combined with biochemical, molecular biology, and genetics to explore important elements of infectious disease. The objective is to both extend the fundamental understanding of how microbial pathogens interact with their respective hosts and to identify new antimicrobial targets and new antimicrobial therapeutics. Two major projects on this theme are on going within the lab. In the first, unrecognized and underexploited potential antimicrobial targets within multi-, extreme, and pan-drug resistant gram-negative bacilli (GNB) are being identified and then characterized using the phenotype of in vivo essentiality. That is, our interest is in genes and their corresponding gene products that are essential for bacterial growth and survival during infection of a host (i.e., in vivo) rather than only essential under ideal laboratory growth conditions (e.g., rich laboratory media, absence of immune responses, etc.). The class of genes that are in vivo essential but not in vitro essential has largely been neglected as antimicrobial targets, and so represents a rich set for expanding target space in the urgent race to develop new antimicrobials. The second project is focused upon identifying and characterizing virus protein - host protein interactions. Viruses encode a highly limited set of functionality, and therefore rely on subverting cellular machinery. This high jacking of cellular functions for the benefit of the virus often involved virus-host protein-protein interactions (PPIs). Study of these virus-host PPIs reveals both the mechanisms by which viruses co-opt cellular functions and potential new antiviral targets recalcitrant to the development of drug resistance. An additional rationale for studying virus-host PPIs is to understand virus evolution with respect to PPI involvement in virulence, pathogenesis, and host tropism. In conjunction with both of these projects, the Umland Lab is using structurally enabled fragment-based lead discovery (FBLD) methods to identify small molecules with potential to be developed into antimicrobial therapeutics.
Infectious Disease; Microbiology; Microbial Pathogenesis; Molecular and Cellular Biology; Gene Expression; Transcription and Translation; Protein Function and Structure; RNA; Eukaryotic Pathogenesis
In my laboratory, we use molecular biological and biochemical approaches to study Trypanosoma brucei, the causative agent of African sleeping sickness, and Trypanosoma cruzi, which causes Chagas disease in South and Central America. Treatment for these diseases is severely limited due to increasing drug resistance and lack of available drugs. The goal of our work is to discover and exploit critical events that occur in the parasite life cycle that may be used to prevent growth or transmission of the parasite. The major project in my laboratory examines the ribosome, the complex molecular machine that drives protein synthesis. While many features of the ribosome and its assembly pathway are conserved in the parasites we study, we have identified features that are very different from the human host. Our laboratory discovered a pair of trypanosome-specific RNA binding proteins, P34 and P37, that are part of a unique preribosomal complex that is essential for ribosomal biogenesis and survival of trypanosomes. This may suggest that the interaction of these proteins with other components of the ribosomal assembly pathway can be developed as targets for chemotherapy. We are developing a high-throughput screen for small molecules that disrupt the complex in trypanosomes and do not harm the human host. My team and I also collaborate with Dr. Joachim Frank at Columbia University on a project to examine the structure of the ribosome and intermediates in the pathway of assembly using cryo-electron microscopy (cryo-EM). These experiments will provide important information about the unique features of the structure and function of the trypanosome ribosome and further our discovery of potential drug targets. In addition, we continue in a long-standing collaboration with Dr. Beatriz Garat at the Universidad de la Républica in Uruguay, examining both DNA and RNA binding proteins which regulate gene expression in Trypanosoma cruzi. The balance of graduate, undergraduate and medical students and postdoctoral researchers I mentor changes from year to year, though the international quality I strive to maintain has distinguished my laboratory for years: I enjoy having students from around the world as part of my research team. I am the course director for, and lecture in Critical Analysis and Eukaryotic Pathogens. I am also the course director for Eukaryotic Gene Expression and the co-course director for Molecular Parasitology. Additionally, I lecture in Microbiology for Undergraduates.
Immunology; Infectious Disease
The focus of my laboratory is to understand regulatory mechanisms during infection and autoimmunity at mucosal sites, particularly within the gastrointestinal tract. The adult human intestine alone contains up to 100 trillion micro-organisms─and no other tissue is submitted to a greater level of antigenic pressure than the gut, which is constantly exposed to food and environmental antigens and the threat of invasion by pathogens. At birth, for example, the human gastrointestinal tract undergoes a massive exposure to these antigens, and throughout the average human life there are multiple instances of the remodeling of the gut flora following infection. All these occurrences impose a unique challenge to the gastrointestinal environment. In response, to maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. Several subsets of immune cells with immune modulatory function reside within the gastrointestinal tract. Specifically, we study Foxp3 expressing regulatory T cells (Tregs), which play a central role in controlling intestinal homeostasis. Recent studies have demonstrated that the ability of Tregs to control defined polarized settings requires plasticity, the acquisition of characteristics specific to the glycoprotein CD4+ T effector subsets. Such adaptation comes with an inherent cost, however; as my research team and other researchers have demonstrated, in extreme instances of inflammation such adaptation can actually be associated with the expression of pro-inflammatory effector cytokines (i.e., interferon gamma and interleukin 17A). We recently identified GATA3, the canonical Th2 transcription factor, as a critical regulator of Treg adaptation during inflammation in tissues. Our goal is to understand how GATA3 regulates this and to identify other factors involved in Treg adaptation during inflammation. Our laboratory employs natural enteric parasitic infections of mice and the T cell dependent model of colitis to decipher both the environmental cues and cell- intrinsic requirements for Treg cell plasticity, stability and function at mucosal sites. The ultimate goal of our research is to clarify the pathogenesis of inflammatory bowel disease (IBD) and develop novel treatment modalities for patients.