OHSU

Lancioni Lab

Introduction:

During my training as a Pediatric Infectious Disease physician, I became interested in understanding why infants and young children experience more severe disease from infectious agents than older children and adults. Specifically, through work in several sub-Saharan countries, I witnessed the tremendous burden that the pathogen Mycobacterium tuberculosis (Mtb) places on the health of children worldwide. Mtb exposure leads to Tuberculosis disease in about 5-10% of otherwise healthy adults; however, nearly 50% of all Mtb-exposed infants less than 1 year old will develop Tuberculosis disease and the immunologic failures permissive to Tuberculosis disease in young infants are not understood. Moreover, our lack of understanding of the immune response of infants and young children against Mtb has limited the development of more effective Mtb vaccines, as well as the development of improved diagnostics for Mtb infection and Tuberculosis disease in children. The focus of my laboratory is to develop our scientific understanding of why young children, specifically infants, are uniquely vulnerable to severe infections with organisms such as Mtb. In addition, we have developed collaborations with US and African-based investigators to develop and test novel immune-based diagnostics for Mtb-infection and Tuberculosis disease among young, Ugandan children. I work in close collaboration with Drs. Deborah and David Lewinsohn at Oregon Health & Sciences University, Dr. W. Henry Boom at Case Western Reserve University, Dr. Larry Schlesinger at Ohio State University, Dr. Harriett Myanja and Dr. Sarah Kiguli at Makerere University, Kampala, Uganda

Current Research Program:

The Lancioni laboratory studies infant immune responses to the pathogen the causes Tuberculosis disease, Mycobacterium tuberculosis (Mtb). In order to define deficiencies in the infant immune response to Mtb we are studying two types of immune cells known to contribute to control of this infection: CD4+ T cells and macrophages.
Our research examines the ability of naïve CD4+ T cells from newborn infants to directly respond to molecules termed “Pathogen-Associated Molecular Patterns” (PAMPs) using “Toll Like Receptors” (TLRs). Although TLRs have traditionally been described on innate antigen presenting cells, it is now recognized that T cells also use TLRs as co-stimulatory receptors. Mtb expresses PAMPs during the course of human infection, and CD4+ T cells from adults have been shown to utilize TLR-1/2 to directly receive co-stimulatory signals from Mtb-dervied PAMPs that lead to CD4+ T cell activation, proliferation, and pro-inflammatory cytokine production. It remains unknown if CD4+ T cells from newborn infants can also be directly co-stimulated via TLRs, and if the newborn’s CD4+ TLR response is regulated in the same manner as adult CD4+ TLR responses. Elucidating the biology of newborn T cell TLR responses will contribute to the development of novel Mtb-vaccines that utilize TLR-ligands as adjuvants.
Macrophages are the primary host cell infected with Mtb, and it is believed that the ability of macrophages to contain and/or eliminate Mtb plays an important role in determining whether or not Tuberculosis disease develops. There have been no published studies examining the capacity of macrophages from newborn infants to uptake and eliminate Mtb, and it remains unknown if deficiencies in macrophage responses to Mtb contribute to disease progression in young infants. Our overarching hypothesis is that following Mtb infection, newborn macrophages exhibit poor mycobacterial containment and elimination as compared to adult macrophages, and promote an immunosuppressive environment permissive to progressive infection. We hope to identify unique characteristics of newborn macrophage antimycobacterial responses that can be targeted by novel vaccines and immunotherapeutics.

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