Immunobiology

The Doyle lab investigates the role of the immune system in causing dementia after stroke. Up to 30% of stroke patients develop dementia in the months and years after their stroke and we are testing the hypothesis that in some patients this is due to a chronic inflammatory response that persists at the site of the stroke infarct. We suspect that in the weeks, months and possibly years after stroke, neurotoxic inflammatory mediators, including T cells, cytokines and antibodies, leak out of the stroke infarct and cause bystander damage to the surrounding tissue, which then both impairs recovery, and in some instances leads to cognitive decline. In support of this hypothesis we have data that demonstrates that inflammation persists for months at the site of the infarct after stroke, and that a single stroke can directly lead to the development of immune-mediated delayed cognitive deficits. We are currently in the process of targeting different components of the prolonged inflammatory response to stroke to determine if post stroke dementia can be treated by selectively ablating individual immune mediators such as B lymphocytes, T lymphocytes, and CCR2. Keywords: Neuroinflammation, stroke, dementia, Alzheimer's disease

Samuel Campos, PhD, studies early events of Human Papillomavirus (HPV) infection. HPVs are small, non-enveloped DNA viruses that cause a variety of lesions ranging from benign waters to cervical cancers. Although over 100 types of HPVs have been identified, HPV16 is the most prevalent, and is alone responsible for more than 50% of cervical cancers in women worldwide. Dr. Campos and his lab study the mechanisms of HPV virus transmission at a cellular level, in hopes to discover new approaches for the prevention and treatment of HPV.HPV16 virions consist of an ~8kb circular dsDNA genome packaged into a ~60 nm protein capsid. The genome is condensed with cellular histones and exists in a chromatin-like state. The capsid is comprised of 72 pentamers of the major capsid protein L1 and up to 72 molecules of the minor capsid protein L2, localized along the inner capsid surface, within the central cavities beneath the L1 pentamers. Mature HPV16 virions exist in an oxidized state, with adjacent L1 pentamers crosslinked together by disulfide bonds to stabilize the capsid. In order to establish an infection, HPV16 virions must bind and penetrate host cells, ultimately delivering their genomes to the host cell nucleus to initiate early gene expression, cell cycle progression, and genome replication. Non-enveloped viruses are faced with the challenge of getting their genetic material across a cellular membrane and often overcome this by disrupting the endosomal or lysosomal membranes and translocating to the cellular cytoplasm during the course of intracellular virion trafficking. Keywords: virology, microbiology, virus-host interaction, HPV

Research in the Bhattacharya lab focuses on molecular approaches to direct B cell differentiation to establish immunity to infectious disease, and stem cell differentiation for regenerative medicine. Current projects in the lab include: 1) Understanding the cellular basis of antibody-mediated immunity to variable viruses. After infection or vaccination, B cells that recognize the pathogen proliferate and undergo a massive level of expansion. Upon clearance of the infection a small fraction of the "best" B cells are retained to become memory B cells or long-lived plasma cells. Our recent work has established that memory B cells are excellent at recognizing not only the original pathogen, but also mutant escape variants of the pathogen. In contrast, long-lived plasma cells are highly specific only for the original pathogen. We are studying the transcription factors that regulate the memory B cell vs. long-lived plasma cell fate, and are studying mechanisms to alter this fate to provide effective immunity against mutable viruses such as influenza and Dengue. 2) Identifying molecular regulators of the duration of immunity. Most clinically used vaccines rely on the production of antibodies to confer immunity. The duration of immunity can vary greatly between different vaccines, yet the molecular basis of this remains unknown. Current efforts are focused on the identification of genes that regulate plasma cell lifespan and on the features of the vaccine that confer durable antibody immunity. 3) Engineering human pluripotent stem cells to generate antibody-mediated immunity. A small fraction of patients infected with HIV or dengue virus, or vaccinated against influenza develop remarkable antibodies that neutralize nearly all clinical isolates of these viruses. Yet it is unclear how to induce these types of antibodies in the broader population through standard vaccination. Using novel targeted nuclease technologies, we are engineering human embryonic stem cells to express these antibodies and differentiating them into transplantable long-lived plasma cells. The long-term goal of this project is to provide permanent immunity to recipients of these engineered plasma cells.

Nafees Ahmad, Ph.D., Professor of ImmunobiologyResearch Interests:1. Molecular mechanisms of HIV-1 vertical transmission2. Molecular mechanisms of HIV-1 pathogenesis in infants and children 3. Molecular mechanisms of HIV-1 infection in immature and mature mononuclear cells4. Identification and characterization of cellular factors involved in HIV-1 replication in immature and mature mononuclear cells5. Biological activity of anti-HIV compoundsThe main focus of my laboratory is understanding the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) mother-to-infant transmission and pathogenesis of pediatric AIDS (HIV-1 infection in children). Areas of investigation include: Molecular and biological characterization of HIV-1 isolates involved in maternal-fetal transmission; Genetic variability of HIV-1 following mother-to-infant transmission; Viral determinants, including viral heterogeneity, functional conservation/divergence of various HIV-1 genes, presence/absence of motifs in HIV-1 genes, replication efficiency, cell tropism, and cytopathic effects associated with HIV-1 maternal-fetal transmission; Viral and host factors associated with HIV-1 evolution, replication, pathogenesis and disease progression in infected infants and children; Molecular mechanisms of HIV-1 infection in immature and mature mononuclear cells; Kinetics of HIV-1 replication in immature hosts (infants) primary lymphocytes and monocytes/macrophages; Mechanisms of HIV-1 infection in immature and mature mononuclear cells, including entry and post-entry events, HIV-1 gene expression and T-cell development, Biological activity of anti-HIV compounds in tissue culture system of T-cell lines, primary lymphocytes and monocytes/macrophages and receptor/coreceptor cell lines, Characterization of cellular factors in immature and mature mononuclear cells that may influence HIV replication differentially.