Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease

Abstract

Problem Placental pericytes are essential for placental microvascular function, stability, and integrity. Mechanisms of HCMV pathogenesis incorporating placental pericytes are unknown. Method of Study HCMV infected placental tissue was stained by dual-labeled immunohistochemistry. Primary placental pericytes, cytotrophoblasts, and villous fibroblasts were exposed to HCMV; infectivity was analyzed by microscopy and immunofluorescence. Cytokine expression was examined by Luminex assay. A HCMV-GFP recombinant virus was used to examine replication kinetics. Results Immunohistochemistry showed HCMV in trophoblast and the villous core with T-cell and macrophage infiltration. SBCMV-infected pericytes showed dysregulation of proinflammatory and angiogenic cytokines when compared to control cells. A tri-cell model of the villous floor showed a unique expression profile. Finally, we show pericytes infected in vivo with HCMV in placental tissue from a congenitally infected child. Conclusions Placental pericytes support HCMV replication, inducing proinflammatory and angiogenic cytokines that likely contribute to viral dissemination, placenta inflammation, and dysregulation of placental angiogenesis.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…Given that the main mediators for cell entry of SARS-CoV-2 were minimally expressed by the human placenta, we also investigated whether the receptors for congenital viruses such as CMV ( Stegmann and Carey, 2002 ; Arechavaleta-Velasco et al, 2002 ; Aronoff et al, 2017 ; Pereira et al, 2017 ; Al-Haddad et al, 2019 ; Faure Bardon et al, 2020 ) and ZIKV ( Coyne and Lazear, 2016 ; Adams Waldorf et al, 2016 ; Aldo et al, 2016 ; Cao et al, 2017 ; Aagaard et al, 2017 ; Mysorekar, 2017 ; Valentine et al, 2018 ; Adams Waldorf et al, 2018 ; Dudley et al, 2018 ; Walker et al, 2019 ; Nelson et al, 2020 ), which are known to infect and cross the placenta, were detectable using our pipeline. Known receptors for CMV include NRP2 ( Martinez-Martin et al, 2018 ), PDFGRA ( Martinez-Martin et al, 2018 ), and CD46 ( Stein et al, 2019 ).…”

Virome Analysis Reveals No Association of Head and Neck Vascular Anomalies with an Active Viral Infection

“…Similarly, cytomegalovirus (CMV) infection results in a disturbance of placental angiogenesis (21), which was related to infection of placental pericytes (22). Furthermore, endothelial cells infected with CMV displayed an aberrant vascular morphology (23) and exhibited elevated levels of leukotriene B4 and 5-lipoxygenase (24).…”

Human Vascular Pericytes and Cytomegalovirus Pathobiology

“…This may affect retinal neurovascular permeability as well as an increase in retinal inflammation and angiogenesis [12]. Previous studies by Alcendor et al and Wilkerson et al showed vascular pericytes to be the most permissive cell type to HCMV infection within the BBB and the IBRB [11,16]. These findings suggest that vascular pericytes may serve as amplification reservoir for HCMV dissemination within these vascular beds.…”

“…Placental pericytes are essential for endothelial cell proliferation as well as for placental microvasculature stability and integrity but have largely been ignored in placenta biology. Pericytes are also critical for placental vascular development and angiogenesis [15,16,17,18,19]. Mesangial cells are considered specialized pericytes of the renal glomerulus [20,21,22,23,24,25,26].…”