As congenital cytomegalovirus (CMV) infection is the major cause of developmental abnormalities in children, the development of effective vaccines is critical to public health. Recent studies have demonstrated that the pentameric complex (Pentamer) of glycoproteins, which is required for human CMV infection of endothelial and epithelial cells, could be a potent vaccine antigen. As guinea pig CMV (GPCMV) infects congenitally and encodes homologues of all Pentamer components, GPCMV models are considered to be useful for the development of vaccine strategies. Here, to clarify the precise requirement of GP131, one of the GPCMV Pentamer components, for the infection of epithelial cells and macrophages, we prepared several mutants with a charged amino acid-to-alanine alteration in GP131 and found some differences in the effects of the mutations on the infection of the two cell types, suggesting the existence of cell type-dependent recognition or function of Pentamer in GPCMV infection.
The pelvic skeleton is formed via endochondral ossification. However, it is not known how the normal cartilage is formed before ossification occurs. Furthermore, the overall timeline of cartilage formation and the morphology of the cartilage in the pelvis are unclear. In this study, cartilage formation in the pelvic skeletons of 25 human fetuses (crown-rump length [CRL] = 11.9–75.0 mm) was observed using phase-contrast computed tomography and 7T magnetic resonance imaging. The chondrification center of the ilium, ischium, and pubis first appeared simultaneously at Carnegie stage (CS) 18, was located around the acetabulum, and grew radially in the later stage. The iliac crest formed at CS20 while the iliac body’s central part remained chondrified. The iliac body formed a discoid at CS22. The growth rate was greater in the ilium than in the sacrum-coccyx, pubis, and ischium. Connection and articulation formed in a limited period, while the sacroiliac joint formed at CS21. The articulation of the pubic symphysis, connection of the articular column in the sacrum, and Y-shape connection of the three parts of the hip bones to the acetabulum were observed at CS23; the connection of the ischium and pubic ramus was observed at the early-fetal stage. Furthermore, the degree of connection at the center of the sacrum varied among samples. Most of the pelvimetry data showed a high correlation with CRL. The transverse and antero-posterior lengths of the pelvic inlet of the lesser pelvis varied among samples (R2 = 0.11). The subpubic angle also varied (65–90°) and was not correlated with CRL (R2 = 0.22). Moreover, cartilaginous structure formation appeared to influence bone structure. This study provides valuable information regarding the morphogenesis of the pelvic structure.
A better understanding of the mechanisms underlying cell tropisms and the efficiency of viral infection is critical for the development of vaccines and antiviral drugs for viral diseases. In this study, we worked on the entry mechanisms of guinea pig cytomegalovirus and found that endogenous expression of a combination of two components (GP131 and GP133) of the pentameric glycoprotein complex, which is required for non-fibroblast cell tropisms, enhanced viral infection more than 10-fold. In addition, D138A alteration in GP131 increased this enhancement by an additional 10-fold. Although differences in the efficiency of viral infection among various cell types are usually explained by differences in viral entry or traffic processes, our experimental evidences dismissed such possibilities. Instead, our findings that i) endogenous expression of GP131 and GP133 after nuclear delivery of viral DNA still enhanced infection and ii) an HDAC inhibitor overcame the need of the endogenous expression led us to hypothesize a novel mechanism that controls the efficiency of viral infection through the activation of gene expression from viral DNA delivered to the nuclei. Further studies of this unexpected phenomena warrant to understand novel but also general mechanisms for cell tropisms of viral infection and determinants that control infection efficiency. Congenital human CMV (HCMV) infection occurs in 0.2-1% of all births and causes birth defects and developmental abnormalities, making the development of CMV vaccines an important issue. HCMV UL128, UL130, and UL131A are essential for viral entry into endothelial and epithelial cells, as well as for viral transmission to leukocytes 1-5. They form a pentameric complex (Pentamer) with glycoprotein H (gH) and gL 6. As the immunization of animals with purified or vectored Pentamer induces a significantly high level of neutralizing antibodies, and as sera from seropositive individuals contain strong neutralizing antibodies against Pentamer, Pentamer-based vaccines have received much attention 7-11. In contrast to murine and rat CMVs, guinea pig CMV (GPCMV) causes infection in utero, which makes GPCMV animal models useful for studies on congenital CMV diseases 12,13. Previously we noticed that the GPCMV stock purchased from ATCC was a mixture of two strains, one containing and the other lacking a 1.6 kb locus that encodes GP129, GP131, and GP133, homologs of HCMV UL128, UL130, and UL131A, respectively. Importantly, the locus was required for efficient viral growth in animals but not in fibroblast cell cultures 14,15. GP129/GP131/GP133 form a pentameric complex with gH/gL 16 , and each of GP129/ GP131/GP133 is required for the infection of macrophages 17 and epithelial cells 18,19. We prepared several mutants with a charged amino acid-to-alanine alteration in GP131 and found some differences in the effects of the mutations on the infection
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