7 research outputs found

    Preexisting helminth challenge exacerbates infection and reactivation of gammaherpesvirus in tissue resident macrophages.

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    Even though gammaherpesvirus and parasitic infections are endemic in parts of the world, there is a lack of understanding about the outcome of coinfection. In humans, coinfections usually occur sequentially, with fluctuating order and timing in different hosts. However, experimental studies in mice generally do not address the variables of order and timing of coinfections. We sought to examine the variable of coinfection order in a system of gammaherpesvirus-helminth coinfection. Our previous work demonstrated that infection with the intestinal parasite, Heligmosomoides polygyrus, induced transient reactivation from latency of murine gammaherpesvirus-68 (MHV68). In this report, we reverse the order of coinfection, infecting with H. polygyrus first, followed by MHV68, and examined the effects of preexisting parasite infection on MHV68 acute and latent infection. We found that preexisting parasite infection increased the propensity of MHV68 to reactivate from latency. However, when we examined the mechanism for reactivation, we found that preexisting parasite infection increased the ability of MHV68 to reactivate in a vitamin A dependent manner, a distinct mechanism to what we found previously with parasite-induced reactivation after latency establishment. We determined that H. polygyrus infection increased both acute and latent MHV68 infection in a population of tissue resident macrophages, called large peritoneal macrophages. We demonstrate that this population of macrophages and vitamin A are required for increased acute and latent infection during parasite coinfection

    A Degenerate Birdcage with Integrated Tx/Rx Switches and Butler Matrix for the Human Limbs at 7 T

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    The theoretically known degeneracy condition of the band-pass birdcage coil has rarely been exploited in transmit coil designs. We have created an eight-channel degenerate birdcage for the human limbs at 7 T, with dedicated Tx/Rx switches and a Butler matrix. The coil can be split into two half cylinders, as required for its application to patients with limited mobility. The design of the coil, the Butler matrix, and Tx/Rx switches relied on a combination of analytical, circuital, and numerical simulations. The birdcage theory was extended to the degenerate case. The theoretical and practical aspects of the design and construction of the coil are presented. The performance of the coil was demonstrated by simulations, workbench, and scanner measurements. The fully assembled prototype presents good performance in terms of efficiency, B1 homogeneity, and signal-to-noise ratio, despite the asymmetry introduced by the splittable design. The first in vivo images of the knee are also shown. A novel RF coil design consisting of an eight-channel splittable degenerate birdcage has been developed, and it is now available for 7 T MRI applications of the human lower limbs, including high-resolution imaging of the knee cartilages and of the patellar trabecular structure

    Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine

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    Intestinal Paneth cells limit bacterial invasion by secreting antimicrobial proteins, including lysozyme. However, invasive pathogens can disrupt the Golgi apparatus, interfering with secretion and compromising intestinal antimicrobial defense. Here we show that during bacterial infection, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced endoplasmic reticulum (ER) stress, required extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in autophagy gene Atg16L1 that confers increased risk for Crohn's disease in humans. Our findings identify a role for secretory autophagy in intestinal defense and suggest why Crohn's disease is associated with genetic mutations that affect both the ER stress response and autophagy

    Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation.

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    A20 is an anti-inflammatory protein that is strongly linked to human disease. Here, we find that mice expressing three distinct targeted mutations of A20's zinc finger 7 (ZF7) ubiquitin-binding motif uniformly developed digit arthritis with features common to psoriatic arthritis, while mice expressing point mutations in A20's OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20ZF7 mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor and interleukin-17A, and persisted in germ-free conditions. A20ZF7 cells exhibited prolonged IκB kinase activity that drove exaggerated transcription of late-phase nuclear factor-κB response genes in vitro and in prediseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20's ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20's ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner
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