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Haldar A.K.,Duke University | Saka H.A.,Duke University | Piro A.S.,Duke University | Da Dunn J.,Duke University | And 7 more authors.
PLoS Pathogens | Year: 2013

Interferon-inducible GTPases of the Immunity Related GTPase (IRG) and Guanylate Binding Protein (GBP) families provide resistance to intracellular pathogenic microbes. IRGs and GBPs stably associate with pathogen-containing vacuoles (PVs) and elicit immune pathways directed at the targeted vacuoles. Targeting of Interferon-inducible GTPases to PVs requires the formation of higher-order protein oligomers, a process negatively regulated by a subclass of IRG proteins called IRGMs. We found that the paralogous IRGM proteins Irgm1 and Irgm3 fail to robustly associate with "non-self" PVs containing either the bacterial pathogen Chlamydia trachomatis or the protozoan pathogen Toxoplasma gondii. Instead, Irgm1 and Irgm3 reside on "self" organelles including lipid droplets (LDs). Whereas IRGM-positive LDs are guarded against the stable association with other IRGs and GBPs, we demonstrate that IRGM-stripped LDs become high affinity binding substrates for IRG and GBP proteins. These data reveal that intracellular immune recognition of organelle-like structures by IRG and GBP proteins is partly dictated by the missing of "self" IRGM proteins from these structures.

Coers J.,Duke University | Gondek D.C.,Harvard University | Olive A.J.,Harvard University | Rohlfing A.,Harvard University | And 3 more authors.
PLoS Pathogens | Year: 2011

The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of bacterial sexually transmitted diseases in the United States. In women C. trachomatis can establish persistent genital infections that lead to pelvic inflammatory disease and sterility. In contrast to natural infections in humans, experimentally induced infections with C. trachomatis in mice are rapidly cleared. The cytokine interferon-γ (IFNγ) plays a critical role in the clearance of C. trachomatis infections in mice. Because IFNγ induces an antimicrobial defense system in mice but not in humans that is composed of a large family of Immunity Related GTPases (IRGs), we questioned whether mice deficient in IRG immunity would develop persistent infections with C. trachomatis as observed in human patients. We found that IRG-deficient Irgm1/m3(-/-) mice transiently develop high bacterial burden post intrauterine infection, but subsequently clear the infection more efficiently than wildtype mice. We show that the delayed but highly effective clearance of intrauterine C. trachomatis infections in Irgm1/m3(-/-) mice is dependent on an exacerbated CD4+ T cell response. These findings indicate that the absence of the predominant murine innate effector mechanism restricting C. trachomatis growth inside epithelial cells results in a compensatory adaptive immune response, which is at least in part driven by CD4+ T cells and prevents the establishment of a persistent infection in mice.

Cummings-Vaughn L.A.,Geriatric Research and Education and Clinical Center | Cummings-Vaughn L.A.,Saint Louis University | Gammack J.K.,Saint Louis University
Medical Clinics of North America | Year: 2011

Osteoporosis and falls are distinct conditions that share the potential clinical endpoint of fracture. This article explores the associations between osteoporosis and falls by examining the epidemiology, risk factors, risk prevention, and treatments. It outlines the evidence on falls prevention, osteoporosis diagnosis, and fracture risk assessment. It includes several studies that challenge the common view on the use of fall prevention tools, dual energy X-ray absorptiometry testing, and postfracture bisphosphonate treatment. By understanding the evidence, it becomes clearer how to target populations at risk, interpret screening methods, and promote disease prevention and treatment. © 2011.

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