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Katherine Spindler

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Primary Appointment: Microbiology and Immunology
Primary PIBS Dept.: Microbiology and Immunology
PubMed Name: Spindler KR
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 DESCRIPTION OF RESEARCH
  We study the molecular genetics of virus-host cell interactions in mouse adenovirus type 1 (MAV 1). Human adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries. Also, adenovirus infections are a serious complication of pediatric bone marrow transplants. MAV-1 affords us the opportunity to address adenovirus–host interactions in the natural host as well as in cell culture. By understanding how viral and cellular gene functions are regulated during infection, we can gain insight into disease processes.

MAV-1 causes acute and persistent viral infections in susceptible mice via infection of cells of the monocyte/macrophage lineage and endothelial cells. MAV-1 causes encephalitis, due to breakdown of the blood-brain barrier (BBB), and we are investigating the mechanism by which it does this, and the interaction of the virus with innate and adaptive immune components. MAV-1 infects endothelial cells and other cells of the neurovascular unit (microglia and/or astrocytes), which can produce matrix metalloproteinases (MMPs). MMPs can digest basement membrane and tight junction proteins whose function is important for blood-brain barrier integrity. We have evidence that MAV-1 infection alters MMP expression. We are also investigating the contributions of pattern recognition receptors (TLRs, inflammasomes) in the host response to MAV-1 infection.

We are also studying virus-host interactions by investigating the contributions of host genetics to adenovirus disease. We have identified some inbred strains of mice that are far more susceptible to MAV-1 disease than other strains. Using rigorous genetic analysis (positional cloning) of the basis for mouse susceptibility to MAV-1 infection, we have evidence for a major quantitative trait locus (QTL) for susceptibility to MAV-1 on mouse Chromosome 15. This region encompasses 14 members of the Ly6 gene family. We are using genetic, molecular, immunological, and cell biology methods to further understand the genetic basis for host susceptibility to MAV-1 infection.