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Viral and parasitic coinfections are known to lead to both enhanced disease progression and altered disease states. HTLV-1 and Strongyloides stercoralis are co-endemic throughout much of their worldwide ranges resulting in a significant incidence of coinfection. Independently, HTLV-1 induces a Th1 response and S. stercoralis infection induces a Th2 response. However, coinfection with the two pathogens has been associated with the development of S. stercoralis hyperinfection and an alteration of the Th1/Th2 balance. In this study, a model of HTLV-1 and S. stercoralis coinfection in CD34+ umbilical cord blood hematopoietic stem cell engrafted humanized mice was established. An increased level of mortality was observed in the HTLV-1 and coinfected animals when compared to the S. stercoralis infected group. The mortality was not correlated with proviral loads or total viral RNA. Analysis of cytokine profiles showed a distinct shift towards Th1 responses in HTLV-1 infected animals, a shift towards Th2 cytokines in S. stercoralis infected animals and elevated TNF-α responses in coinfected animals. HTLV-1 infected and coinfection groups showed a significant, yet non-clonal expansion of the CD4+CD25+ T-cell population. Numbers of worms in the coinfection group did not differ from those of the S. stercoralis infected group and no autoinfective larvae were found. However, infective larvae recovered from the coinfection group showed an enhancement in growth, as was seen in mice with S. stercoralis hyperinfection caused by treatment with steroids. Humanized mice coinfected with S. stercoralis and HTLV-1 demonstrate features associated with human infection with these pathogens and provide a unique opportunity to study the interaction between these two infections in vivo in the context of human immune cells., Competing Interests: The authors have declared that no competing interests exist.

Programmed cell death 2 (Pdcd2) is a highly conserved protein of undefined function, and is widely expressed in embryonic and adult tissues. The observations that knockout of Pdcd2 in the mouse is embryonic lethal at preimplantation stages, and that in Drosophila, Zfrp8, the ortholog of Pdcd2, is required for normal lymph gland development suggest that Pdcd2 is important for regulating hematopoietic development. Through genetic and functional studies, we investigated pdcd2 function during the zebrafish ontogeny. Knockdown of pdcd2 expression in zebrafish embryos resulted in defects in embryonic hematopoietic development. Loss of pdcd2 function caused increased expression of progenitor markers, and accumulation of erythroid progenitors during primitive hematopoiesis. Additionally, hematopoietic stem cells (HSCs) failed to appear in the aorta-gonad mesonephros, and were not able to terminally differentiate or reconstitute hematopoiesis. Pdcd2 effects on HSC emergence were cell autonomous and P53-independent, and loss of pdcd2 function was associated with mitotic defects and apoptosis. Restoration of runx1 function(s) and modulation of apoptosis through the inhibition of Jak/Stat signaling rescued the hematopoietic and erythroid defects resulting from pdcd2 knockdown. Our studies suggest that pdcd2 plays a critical role in regulating the transcriptional hierarchy controlling hematopoietic lineage determination. Furthermore, the effects of pdcd2 in regulating mitotic cell death may contribute to its role(s) in directing hematopoietic differentiation during development.

Programmed cell death-2 (PDCD2) protein is enriched in embryonic, hematopoietic, and neural stem cells, however, its function in stem/progenitor cell differentiation is unclear. We investigated the effects of PDCD2 knockdown on the development and differentiation of hematopoietic progenitor cells (HPC). CD34(+) cells derived from normal human bone marrow and K562 leukemic cells were effectively transduced with short-hairpin RNA to knockdown PDCD2. Colony-forming assays were used to investigate the effects of PDCD2 loss on HPC clonogenic potential and on 12-O-tetradecanoyl-phorbol-13-acetate-and arabinofuranosylcytosine-induced terminal differentiation. In CD34(+) clonogenic progenitors, PDCD2 knockdown decreased the total number of colony-forming units, increased the number of colony-forming units-granulocyte-erythroid-macrophage-megakaryocyte and burst-forming unit-erythroid primitive colonies, and decreased the number of burst-forming unit-erythroid mature colonies. Similar results were observed in K562 cells, suggesting that PDCD2 is important for HPC differentiation and/or survival, and for erythroid lineage commitment. Furthermore, 12-O-tetradecanoyl-phorbol-13-acetate-induced megakaryocytic differentiation and proliferation of K562 cells was not affected by PDCD2 knockdown. In contrast, arabinofuranosylcytosine-induced erythroid differentiation of K562 cells was significantly reduced with PDCD2 knockdown, with no effect on cell proliferation. The effects of PDCD2 knockdown were attributed to a cell cycle arrest at G(0)/G(1), along with increased messenger RNA expression of early progenitor factors c-MYB and GATA-2, and decreased expression of erythroid factors GATA-1, EpoR, and γ-globin. We conclude that PDCD2 loss of function(s) impedes erythroid differentiation by inducing cell cycle arrest and increasing expression of early hematopoietic progenitor factors. These findings suggest that PDCD2 has a novel regulatory role in human hematopoiesis and is essential for erythroid development., Competing Interests: disclosure No financial interest/relationships with financial interest relating to the topic of this article have been declared., (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)