ABSTRACTThe human pathogens enterohemorrhagic and enteropathogenicEscherichia coli(EHEC and EPEC), as well as the related mouse pathogenCitrobacter rodentium, utilize a type III secretion system (T3SS) to inject multiple effector proteins into host cells. TheE. coliO157:H7 strain EDL933 carries two copies of non-locus of enterocyte effacement (LEE)-encoded protein H, designated NleH1 and NleH2, both of which bind to the human ribosomal protein S3 (RPS3), a subunit of NF-κB transcriptional complexes. In this study, we describe significant functional differences between NleH1 and NleH2 in their ability to regulate the host NF-κB pathway. We show that the EHEC and EPEC NleH effectors are functionally equivalent in their ability to affect RPS3 nuclear translocation. NleH1, but not NleH2, inhibited NF-κB activity without altering the kinetics of IκBα phosphorylation/degradation. We also determined that the class I PSD-95/Disc Large/ZO-1 (PDZ)-binding domain of NleH was important for its activity in the NF-κB pathway. In addition to binding RPS3, we found that NleH1 and NleH2 are able to bind to each otherin vitroandin vivo, suggesting an additional mechanism by which theE. coliNleH effectors may regulate the extent and duration of NF-κB activation after their T3SS-dependent translocation. We also performed mouse infection experiments and established that mouse mortality andCitrobactercolonization were reduced in mice infected with ΔnleH. Complementing ΔnleHwith NleH1 restoredCitrobactervirulence and colonization to wild-type levels, whereas complementing with NleH2 reduced them. Taken together, our data show that NleH1 and NleH2 have pronounced functional differences in their ability to alter host transcriptional responses to bacterial infection.
Solid organ transplantation is a life-saving procedure that has changed the prognosis for infants and children with end-stage organ disease. Cytomegalovirus (CMV) is one of the most common infections that occur after organ transplantation in pediatric patients, yet the standard of care for CMV prevention remains unclear. We review the literature regarding CMV disease effects, risk factors, diagnostics, prevention strategies, and antiviral treatment in pediatric solid organ transplantation. This discussion focuses on the current prevention strategies: prophylaxis, preemptive, and hybrid therapy, as well as novel strategies that may help better prevent the CMV disease in the pediatric solid organ transplant population.
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