Oropharyngeal and esophageal candidiases remain significant causes of morbidity in human immunodeficiency virus (HIV)-infected patients, despite the dramatic ability of antiretroviral therapy to reconstitute immunity. Notable advances have been achieved in understanding, at the molecular level, the relationships between the progression of HIV infection, the acquisition, maintenance, and clonality of oral candidal populations, and the emergence of antifungal resistance. However, the critical immunological defects which are responsible for the onset and maintenance of mucosal candidiasis in patients with HIV infection have not been elucidated. The devastating impact of HIV infection on mucosal Langerhans' cell and CD4+ cell populations is most probably central to the pathogenesis of mucosal candidiasis in HIV-infected patients. However, these defects may be partly compensated by preserved host defense mechanisms (calprotectin, keratinocytes, CD8+ T cells, and phagocytes) which, individually or together, may limit Candida albicans proliferation to the superficial mucosa. The availability of CD4C/HIV transgenic mice expressing HIV-1 in immune cells has provided the opportunity to devise a novel model of mucosal candidiasis that closely mimics the clinical and pathological features of candidal infection in human HIV infection. These transgenic mice allow, for the first time, a precise cause-and-effect analysis of the immunopathogenesis of mucosal candidiasis in HIV infection under controlled conditions in a small laboratory animal

IntroductionOne of the aims of regenerative medicine is to repair or restore functional organs by engrafting adult or fetal somatic stem cells into a damaged tissue. These cells, present in most self-renewing tissues, such as skin, intestine, and the hematopoietic system, can be purified, expanded ex vivo, and then used for reconstitution of damaged tissues. 1,2 Many major advances have been achieved in purification and ex vivo amplification of somatic stem cells, 1,3 but few data are available on the prerequisites that will enhance their in vivo biologic activities. New methods to improve the efficiency of bone marrow transplantation and, more generally, reconstitution of damaged tissues by somatic stem cells, depend on tracking of stem cells injected into the animal and thus on the development of imaging strategies that reveal the recruitment, homing, and initial proliferation of these injected somatic stem cells in the context of a living body.The best-characterized mammalian adult somatic stem cells are the hematopoietic stem cells (HSCs) 4,5 whose maintenance and development in the bone marrow are dependent on the HSC niche through niche-regulating pathways. 6 HSCs can be purified close to homogeneity, 7 and a single HSC can produce lifelong complete hematopoietic reconstitution of a lethally irradiated recipient mouse. 4 Many adhesion molecules, signaling pathways, and transcription factors that regulate hematopoietic reconstitution have been characterized, and the roles of these regulatory factors have been shown in vivo using overexpression or genetic inactivation.Yet, the critical early events of recruitment to the bone marrow, homing in the bone marrow microenvironment, and initial proliferation of HSCs after transplantation into lethally irradiated mice are poorly characterized because few methods are available to study these dynamics processes at the cellular level.The early cellular events that precede hematopoietic reconstitution from a small number of HSCs cannot be studied in vitro on hematopoietic cells recovered from recipient animals and presents a demanding challenge for imaging studies as the initial signals that can be detected are very weak. Among imaging techniques, 4 can presently be used to follow the reconstitution of the hematopoietic system at the cellular level. The first technique combines local surgery for placement of a bone window that is used for fluorescent microscopy, but this technique is invasive and limited by the size of the window. 8 The second technique combines high-resolution confocal microscopy and 2-photon video imaging and has greatly improved detection of multiple fluorescent signals in a living animal. This intravital microscopy permits high-resolution imaging of small tissue volume but, in the case of hematopoietic reconstitution, is limited by the thickness of the bone. [9][10][11][12] It cannot be used to study hematopoietic reconstitution in long bones and has been used to image hematopoietic reconstitution in mouse calvarium bone marrow. The third technique ...

Despite numerous observations linking protracted exposure to low-dose (LD) radiation and leukemia occurrence, the effects of LD irradiation on hematopoietic stem cells (HSCs) remain poorly documented. Here, we show that adult HSCs are hypersensitive to LD irradiation. This hyper-radiosensitivity is dependent on an immediate increase in the levels of reactive oxygen species (ROS) that also promotes autophagy and activation of the Keap1/Nrf2 antioxidant pathway. Nrf2 activation initially protects HSCs from the detrimental effects of ROS, but protection is transient, and increased ROS levels return, promoting a long-term decrease in HSC self-renewal. In vivo, LD total body irradiation (TBI) does not decrease HSC numbers unless the HSC microenvironment is altered by an inflammatory insult. Paradoxically, such an insult, in the form of granulocyte colony-stimulating factor (G-CSF) preconditioning, followed by LD-TBI facilitates efficient bone marrow transplantation without myeloablation. Thus, LD irradiation has long-term detrimental effects on HSCs that may result in hematological malignancies, but LD-TBI may open avenues to facilitate autologous bone marrow transplantation.

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown.