ChvE is a chromosomally encoded protein inThe expression of vir genes in A. tumefaciens is activated by plant-released signals, namely, phenolic derivatives, acidic pH, and monosaccharides (for a review, see reference 6), via the combined activities of the periplasmic protein ChvE and the VirA/VirG two-component regulatory system. Upon perception of these plant signals, autophosphorylated VirA, a transmembrane histidine kinase, transfers a phosphoryl group to VirG, a response regulator, and then the phosphorylated VirG activates the expression of vir genes by binding vir boxes in their promoters (8,19,24,31,52).Perception and transduction of the sugar signals is crucial to the virulence of A. tumefaciens: strains lacking ChvE, a chromosomally encoded putative sugar-binding protein, are significantly less virulent than wild-type strains (17,18). Previous studies have shown that, in fact, sugar signaling is neither sufficient for nor absolutely required for vir gene expression. Rather, sugars vastly increase both the sensitivity of VirA to phenol derivatives, such as acetosyringone (AS), and the maximal levels of vir gene expression observed at saturating levels of such compounds (for a review, see reference 26). The periplasmic domain of VirA is required for transduction of the sugar and pH signals (7,8,16,41), whereas the so-called "linker" domain, located in the cytoplasm between the second transmembrane domain and the kinase domain, is required for perception and transduction of the phenolic signals (8,46,47).A working model for the ChvE/sugar/VirA signaling pathway suggests that monosaccharide-bound ChvE interacts with the periplasmic domain of VirA to relieve periplasmic repression, resulting in maximal sensitivity of VirA to phenolic signals (7,11,32,41). However, limited evidence has been presented to reveal how ChvE recognizes monosaccharides and how it interacts with the periplasmic domain of VirA. Shimoda et al. (41) identified a mutant chvE allele [chvE(T211M)] that is able to suppress a sugar-insensitive virA allele [virA(E210V)], thereby restoring the sugar-sensing ability. The suppressing effect of chvE(T211M) was then proposed to be the result of the specific restoration of the capacity of VirA E210V to bind ChvE T211M . However, ChvE T211M also activated wild-type VirA in the absence of sugars (32), suggesting that this mutant may not be a site-specific suppressor of VirA E210V . Based on a homology model of ChvE, a recent study (16) does predict, though, that the residue T211 is located on the surface of the
The recognition by a viral envelope of its cognate host-cell receptor is the initial critical step in defining the viral host-range and tissue specificity. This study combines a single-round of selection of a random envelope library with a parallel cDNA screen for receptor function to identify a distinct retroviral envelope/receptor pair. The 11-aa targeting domain of the modified feline leukemia virus envelope consists of a constrained peptide. Critical to the binding of the constrained peptide envelope to its cellular receptor are a pair of internal cysteines and an essential Trp required for maintenance of titers >10 5 lacZ staining units per milliliter. The receptor used for viral entry is the human GPR172A protein, a G-proteincoupled receptor isolated from osteosarcoma cells. The ability to generate unique envelopes capable of using tissue-or diseasespecific receptors marks an advance in the development of efficient gene-therapy vectors.library screening ͉ retroviral entry ͉ viral envelope ͉ viral receptor
We present here the first published use of letermovir for the treatment of resistant cytomegalovirus (CMV) in a pediatric patient. A 14-year-old girl underwent a double unrelated umbilical cord blood transplantation to treat her sickle cell disease (hemoglobin SS) and developed ganciclovir-resistant CMV DNAemia with end-organ involvement that was treated successfully with a combination of foscarnet and letermovir. After she was transitioned to letermovir monotherapy for secondary prophylaxis, she developed recurrent DNAemia with laboratory-confirmed ganciclovir, foscarnet, and letermovir resistance.
Background Children undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients. Methods We performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997–2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI. Results Of 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI (P = .021) and, specifically, fungal HA-BSIs (P = .002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01–1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19–2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21–2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%; P = .002). Conclusions Over the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT.
Background Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. Methods This multinational observational cohort study enrolled patients aged >120 days and <18 years with concern for IC from 1 January 2015 to 26 September 2019 at 25 centers. Blood collected at onset of symptoms was tested using T2Candida, Fungitell (1→3)-β-D-glucan, Platelia Candida Antigen (Ag) Plus, and Platelia Candida Antibody (Ab) Plus assays. Operating characteristics were determined for each biomarker, and assays meeting a defined threshold considered in combination. Sterile site cultures were the reference standard. Results Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%–93.2%), specificity 97.1% (95.0%–98.5%), positive predictive value, 62.5% (43.7%–78.9%), and negative predictive value, 98.8% (97.2%–99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%– 97.1%); specificity, 94.7% (92.0%–96.7%); positive predictive value, 47.5% (31.5%–63.9%); and negative predictive value, 99.2% (97.7%–99.8%). Conclusions T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC. Clinical Trials Registration NCT02220790.
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