A placental model of SARS-CoV-2 infection reveals ACE2-dependent susceptibility and differentiation impairment in syncytiotrophoblasts

Published online: 13 July 2023SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the pathophysiological mechanisms underpinning SARS-CoV-2 infection during placentation and early pregnancy are not clear. Here, to shed light on this, we used induced trophoblast stem cells to generate an in vitro early placenta infection model. We identified that syncytiotrophoblasts could be infected through angiotensin-converting enzyme 2 (ACE2). Using a co-culture model of vertical transmission, we confirmed the ability of the virus to infect syncytiotrophoblasts through a previous endometrial cell infection. We further demonstrated transcriptional changes in infected syncytiotrophoblasts that led to impairment of cellular processes, reduced secretion of HCG hormone and morphological changes vital for syncytiotrophoblast function. Furthermore, different antibody strategies and antiviral drugs restore these impairments. In summary, we have established a scalable and tractable platform to study early placental cell types and highlighted its use in studying strategies to protect the placenta.J. Chen, J. A. Neil, J. P. Tan, R. Rudraraju, M. Mohenska, Y. B. Y. Sun, E. Walters, N. G. Bediaga, G. Sun, Y. Zhou, Y. Li, D. Drew, P. Pymm, W. H. Tham, F. J. Rossello, G. Nie, X. Liu, K. Subbarao and J. M. Pol

CIS controls the functional polarization of GM-CSF-derived macrophages

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.Shengbo Zhang ... Naiara G. Bediaga ... et al

Gas flow in microchannels - A lattice Boltzmann method approach

Gas flow in microchannels can often encounter tangential slip motion at the solid surface even under creeping flow conditions. To simulate low speed gas flows with Knudsen numbers extending into the transition regime, alternative methods to both the Navier-Stokes and direct simulation Monte Carlo approaches are needed that balance computational efficiency and simulation accuracy. The lattice Boltzmann method offers an approach that is particularly suitable for mesoscopic simulation where details of the molecular motion are not required. In this paper, the lattice Boltzmann method has been applied to gas flows with finite Knudsen number and the tangential momentum accommodation coefficient has been implemented to describe the gas-surface interactions. For fully-developed channel flows, the results of the present method are in excellent agreement with the analytical slip-flow solution of the Navier-Stokes equations, which are valid for Knudsen numbers less than 0.1. The present paper demonstrates that the lattice Boltzmann approach is a promising alternative simulation tool for the design of microfluidic devices