RESUMO
Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to α- and ß-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections.
Assuntos
DNA Viral/imunologia , Gammaherpesvirinae/imunologia , Infecções por Herpesviridae/imunologia , Imunidade Inata/imunologia , Latência Viral/imunologia , Animais , Citosol/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Macrófagos/imunologia , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potential adjunct in pediatric trauma patients with noncompressible truncal and pelvic hemorrhage; however, there are little data evaluating the anatomic considerations of REBOA in children. We evaluated the vascular dimensions and anatomic limitations of using REBOA in children. METHODS: Computed tomography scans of pediatric patients performed between February 2016 and October 2019 were retrospectively reviewed by two investigators. Vascular measurements included diameters of aorta zones I and III, common iliac arteries, external iliac arteries, and common femoral arteries (CFAs), and distances between access site (CFA) and aorta zones I and III. Measurements were grouped within Broselow categories, based upon patient height. Interrater reliability for measurements was determined using intraclass correlation coefficients. Vascular dimensions were correlated with the patient's height, weight, and body mass index using linear regression analysis. RESULTS: A total of 557 computed tomography scans met the inclusion criteria and were reviewed. Measurements of vessel diameter and distance from the CFA to aorta zones I and III were determined and grouped by Broselow category. Patient age ranged from 0 to 18 years, with a male to female ratio of 1:1. Overall interrater reliability of vessel measurements was good (average intraclass correlation coefficient, 0.90). Vessel diameter had greatest correlation with height (R2 = 0.665, aorta zone I; R2 = 0.611, aorta zone III) and poorly correlated with body mass index (R2 = 0.318 and R2 = 0.290, respectively). CONCLUSION: This study represents the largest compilation of REBOA-related pediatric vessel diameter measurements and the first to provide data on distance between access site and balloon deployment zones. Based on our findings, the 7-Fr REBOA catheter would be appropriate for the Black, Green, and Orange Broselow categories, and a 4-Fr REBOA catheter would be warranted for Yellow, White, and Blue Broselow categories. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.