Context: Increasing numbers of neonates with systemic acute respiratory coronavirus 2 (SARS-CoV-2) infection are occurring, and in a small number there are reports of intrauterine infection. Objective: To characterize the placental pathology findings in a preselected cohort of neonates infected by transplacental transmission arising from maternal infection with SARS-CoV-2, and to identify pathology risk factors for placental and fetal infection. Design: Case-based retrospective analysis by a multinational group of 19 perinatal specialists of the placental pathology findings from 2 cohorts of infants delivered to mothers testing positive for SARS-CoV-2 - liveborn neonates infected via transplacental transmission who tested positive for SARS-CoV-2 after delivery and had SARS-CoV-2 identified in cells of the placental fetal compartment by molecular pathology; and stillborn infants with syncytiotrophoblast positive for SARS-CoV-2. Results: In placentas from all 6 liveborn neonates acquiring SARS-CoV-2 via transplacental transmission the syncytiotrophoblast was positive for coronavirus using immunohistochemistry, RNA in situ hybridization, or both. All 6 placentas had chronic histiocytic intervillositis and necrosis of the syncytiotrophoblast. The 5 stillborn/terminated infants had placental pathology findings that were similar including SARS-CoV-2 infection of the syncytiotrophoblast, chronic histiocytic intervillositis and syncytiotrophoblast necrosis. Conclusions: Chronic histiocytic intervillositis together with syncytiotrophoblast necrosis accompany SARS-CoV-2 infection of syncytiotrophoblast in liveborn and stillborn infants. Their coexistence in all placentas from liveborn infants acquiring their infection prior to delivery indicates that that these findings constitute a pathology risk factor for transplacental fetal infection. Potential mechanisms of infection of the placenta and fetus with SARS-CoV-2, and potential future studies, are discussed.

NA Laryngoscope, 2018.

Human γ9δ2 T cells potently inhibit pathogenic microbes, including intracellular mycobacteria, but the key inhibitory mechanism(s) involved have not been identified. We report a novel mechanism involving the inhibition of intracellular mycobacteria by soluble granzyme A. γ9δ2 T cells produced soluble factors that could pass through 0.45 µm membranes and inhibit intracellular mycobacteria in human monocytes cultured below transwell inserts. Neutralization of TNF-α in co-cultures of infected monocytes and γ9δ2 T cells prevented inhibition, suggesting that TNF-α was the critical inhibitory factor produced by γ9δ2 T cells. However, only siRNA- mediated knockdown of TNF-α in infected monocytes, but not in γ9δ2 T cells, prevented mycobacterial growth inhibition. Investigations of other soluble factors produced by γ9δ2 T cells identified a highly significant correlation between the levels of granzyme A produced and intracellular mycobacterial growth inhibition. Furthermore, purified granzyme A alone induced inhibition of intracellular mycobacteria, while knockdown of granzyme A in γ9δ2 T cell clones blocked their inhibitory effects. The inhibitory mechanism was independent of autophagy, apoptosis, nitric oxide production, type I interferons, Fas/FasL and perforin. These results demonstrate a novel microbial defense mechanism involving granzyme A-mediated triggering of TNF-α production by monocytes leading to intracellular mycobacterial growth suppression. This pathway may provide a protective mechanism relevant for the development of new vaccines and/or immunotherapies for macrophage-resident chronic microbial infections.

MAP is highly associated with evidence of intraparenchymal placental hemorrhage villous changes of MVU, and a lymphoplasmacytic infiltrate at the implantation site. The contribution of this basal chronic inflammatory infiltrate to MAP requires further investigation.