Mark R. Schleiss, M.D.
With respect to the research program of Dr. Schleiss, his basic science clinical work is broadly devoted to the study of human and animal cytomegaloviruses. Congenital infection with CMV is a major public health problem in the United States today, and is responsible for substantial morbidity in newborns. Dr. Schleiss has NIH and March of Dimes funding to pursue studies of the biology of CMV in three major areas: vaccines, immunopathogenesis, and placental infection. One grant focuses on testing hypotheses about vaccine-mediated protection against congenital CMV infection. Using a variety of vaccine expression strategies, including purified protein subunit and DNA vaccines, his lab is evaluating the extent of protection of the maternal-placental-fetal unit against CMV infection and disease, using animal models. These studies integrate molecular virology (cloning and gene expression) with immunological endpoints (humoral and cell-mediated immunity) to attempt to understand in greater detail the aspects of the maternal immune response that are critical in protection of the fetus. Major humoral immune targets include the viral envelope glycoproteins. The second area of research is to study viral immune modulation genes as they relate to the biology and pathogenesis of CMV infection in vivo. CMVs are remarkable in encoding a plethora of putative immune modulation genes, including homologs of cellular G-protein coupled receptor, chemokines, and cytokines. The role of these genes in the in vivo pathogenesis of infection is unclear. Using a molecular genetic approach, Dr. Schleiss, in collaboration with Dr. McGregor, has developed techniques, using viral genomes cloned as infectious bacterial artificial chromosomes (BACs) in E. coli, to perform targeted mutagenesis of viral genes. Systemic mutagenesis of viral immune modulation genes will allow assessment of their function in inflammation, transplacental transmission, and immune evasion. In the third area of research currently being conducted in Dr. Schleiss’s lab, Dr. Schleiss is examining the patterns of transcriptional dysregulation induced following cytomegalovirus infection of placental trophoblasts. Microarray analysis is being performed to test the hypothesis that viral immune modulation genes are responsible for alterations in trophoblast genetic programming, which in turn may facilitate viral transmission to the fetus.
Patricia Ferrieri, M.D.
Dr. Ferrieri’s research emphasis has been in the following areas: the pathogenesis of infections with group B streptococci (GBS) and host immunity to streptococcal antigens, specifically surface-localized proteins. Earlier research focused on the isolation, biochemical, and immunological characterization of GBS antigens and human and animal immune responses to these antigens and the role of antibodies in protection against infection, as studied in animal models of neonatal sepsis and meningitis. Other studies during this period have included novel approaches in the typing of nontypeable isolates of group B streptococci and molecular characterization of them with recent, additional polysaccharide biochemical characterization carried out in collaboration with the Channing Laboratory, Harvard Medical School. Molecular epidemiological work has continued with the application of pulsed-field gel electrophoresis (PFGE) to nontypeable GBS as well as defined serotypes of established polysaccharide capsule. A new rapid PFGE method for group B Streptococcus isolates has been described from her laboratory, as well as improved methods to upregulate capsular polysaccharide of putative nontypeable GBS isolates from epidemiological studies. The studies of Dr. Ferrieri and others of the surface-localized proteins have particular translational value because of the consideration of conjugating these proteins to purified GBS polysaccharides for vaccine development.
The long-term goal of Dr. John’s research is to identify and characterize immune correlates of protection from clinical malaria in epidemic-prone highland areas. Thirty-four million individuals are estimated to be at risk for malaria outbreaks in highland areas of East Africa. Lack of specific immune responses to P. falciparum and introduction of novel parasite genotypes may be important factors in the susceptibility of these populations to malaria outbreaks. One objective of Dr. John’s research is to determine how specific measures of immunity and P. falciparum genotype relate to risk of clinical malaria in different epidemic-prone areas. The central hypothesis of this aspect of his research program is that, in epidemic-prone areas, transmission intensity, age and functional antibody activity are key components of protective immunity to P. falciparum, which interact with the strain causing infection to determine clinical disease. Specific goals of his research program are to: 1) determine the effect of P. falciparum transmission on antigen-specific immunity and associated protection from infection; 2) identify antigen-specific immune responses protective against P. falciparum disease; and 3) elucidate the relationship of novel parasite genotype to P. falciparum disease. Some of Dr. John’s research takes place in two highland areas of Kenya with highly seasonal and sporadic transmission. Immune responses (MSP-119, IgG antibodies and mononuclear cell IL-4, IL-10 and IFN-gamma to CSP, LSA-1, TRAP, and MSP-1) are being compared between the cohorts in the two areas and the associated risk of new P. falciparum infection in both areas is being studied. The epidemiology of malaria in this population is also being examined in a nested case-control study, in which serum samples are obtained from the entire population in both sites and presence of immune responses is compared in individuals who do ("cases") and do not ("controls") develop malaria over the subsequent year. There is an ongoing comparison of the frequency of specific genotypes in individuals presenting to the health centers with clinical malaria ("cases") in 1 outbreak and 3 non-outbreak months. Genotype is determined by PCR testing for polymorphisms in 3 antigens (MSP-1, MSP-2, and GLURP) and 4 microsatellites. It is anticipated that these findings will generate strategies for vaccine induction of robust immune responses against multiple antigenic variants in vulnerable populations experiencing malaria epidemics. Parallel studies by Dr. John on the pathogenesis of cerebral malaria are being conducted to relate specific immune responses to subsequent neurological and neuropsychological deficits. The relationship between serum IL-10 and TNF-alpha levels and neurological and neuropsychological deficits in children with cerebral malaria (CM) is being examined in children under 5 years of age in Uganda. Future studies will focus on antecedent immune factors in CM and relationship to neurological and cognitive function.
Edward L. Kaplan, M.D.
Dr. Kaplan is Professor in the Divisions of Pediatric Infectious Disease and of Pediatric Cardiology, and is an internationally recognized authority in his field. As Head of the World Health Organization Collaborating Center for Reference and Research on Streptococci, Dr. Kaplan is primarily interested in the study of group A streptococcal infections and their sequelae. Currently, the laboratory addresses the epidemiology, microbiology, immunology of group A streptococcal applied research. Laboratory opportunities have concentrated on understanding more comprehensively the shifting prevalence of group A streptococcal strains and their M serotypes (emm types when genotyped) by correlation of classical laboratory techniques for characterizing group A streptococci with newer molecular techniques, such as using DNA sequencing of the N terminus or variable region of the M protein. His laboratory is an active participant in an international network of reference laboratories focusing on group A streptococcal infections as well as their sequelae. Currently, active clinical laboratory collaborations between his laboratory and other countries include those in Europe, Eastern Europe, Asia, Egypt, North Africa, and South America. A program to further delineate possible genetic predisposition to development of rheumatic fever has been carried out in collaboration with the Post-graduate Institute for Medical Education and Research in India. With these major collaborations, his laboratory has received many post-graduate students for training in applied research and laboratory techniques. Some of our trainees who have studied in his laboratory have coordinated their research training with obtaining a Master’s Degree in the School of Public Health. In collaboration with the University of Rochester, the lab focuses on tic disorder or obsessive-compulsive disorders occurring in associated with streptococcal infection.
Jin-Young Han, M.D., Ph.D.
The research program of Dr. Han addresses the immunology and treatment of human herpesviruses. Areas of focus include induction of programmed cell death in T cells by human herpes simplex virus, control of recurrent herpes lesions by T cells, and treatment of congenital cytomegalovirus infections.
Studies in Dr. Han’s laboratory have identified viral and cellular gene products that are involved in induction of apoptosis in T cells following herpes simplex virus infection. Ongoing efforts will elucidate the mechanism behind this induction of cell death and assess its impact on recurrent herpes lesions. The results from these studies will have profound implications for our understanding of herpesvirus immunology in reactivation of genital and neonatal infections and lay foundation for novel therapies in the future. Dr. Han also serves as a site investigator for a clinical trial in treatment of congenital cytomegalovirus infections.
SingSing Way, M.D., Ph.D.
Worldwide, infectious agents remain the leading cause of mortality in infants, children, and adults. Vaccination is a highly efficacious and cost-effective means for infectious disease control, however existing vaccines primarily trigger antibody-mediated immunity that does not confer protection to intracellular pathogens such as Salmonoella, Mycobacterium tuberculosis, and most viruses. Our laboratory uses experimental infection with the intracellular bacterium Listeria monocytogenes as a model to examine how pathogen specific CD8 and CD4 T cells are generated after infection in vivo with the long-term goal of more rational vaccine design that triggers protective T cell-mediated immunity.