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Feb 26, 2010

Salmonella-Infected Mice Represent Potential Model of Hemophagocytic Lymphohistiocytosis

  • Scientists at the University of Colorado at Boulder state that salmonella-infected mice could represent a valuable animal model for studying the pathogenesis of secondary hemophagocytic lymphohistiocytosis (HLH). This rare and often fatal inflammatory disease is characterized by overactivation of macrophages and T lymphocytes.

    Their research found that while infecting mice orally with Salmonella enterica serotype Typhimurium resulted in the animals developing acute and subacute inflammatory responses typical of murine typhoid fever, they also developed clinico-pathologic features of HLH. These include fever, enlarged spleens, anemia, reduced numbers of platelets, dangerously high levels of an iron storage protein, and neurological signs as well as the accumulation of hemophagocytic macrophages in body organs including bone marrow.

    The most severely infected mice met six of the eight HLH diagnostic criteria, only five of which are needed to diagnose HLH in humans. The researchers’ results are published in PLoS One in a paper titled “Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis.”

    HLH occurs either as a primary, inherited form of the disease or as a secondary form in people with no known genetic defect, according to lead author, Diane Brown, Ph.D., adjoint curator at the University of Colorado Museum of Natural History, and colleagues at the university’s molecular, cellular, and developmental biology department. Both forms are usually triggered by an infection of some kind, but scientists have to date been unable to generate an animal model of secondary HLH. 

    The Colorado researchers had previously found that salmonella-infected mice develop hemophagocytic macrophages, and this observation “helped lead us down the current research path,” explains co-author and assistant professor Corrella Detweiler, Ph.D.

    Drs. Brown and Detweiler and their co-workers claim the mouse model demonstrates a number of features that make it a potentially valuable model for HLH. In addition to a natural host-pathogen interaction and the lack of a known single-locus genetic component, the aniamls exhibit a low death rate, allowing the disease to be followed over time, even without treatment intervention.

    “The availability of this animal model for HLH will help to advance the research and understanding of the underlying mechanisms of this immune system disorder,” Dr. Detweiler states. “It should also provide a means to test new therapies for HLH.” The Colorado team now aims to unravel how anemia develops in the infected mice, in the hope that this will provide new insights into the pathogenesis of HLH in humans.

     



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