Biology subjects

Fahmi, A.

Publications and source records attributed to Fahmi, A..

3 recordsLinked to original sources

bioRxiv2025

Cellular determinants of parvovirus B19 infection in the human placenta

Parvovirus B19 (B19V) is a prevalent human pathogen that can cross the placenta by a mechanism that remains unknown, posing a risk of severe fetal complications, particularly during the first trimester of pregnancy. We investigated the expression of B19V-specific receptors in the three trophoblast cell types, cytotrophoblasts (CTBs), syncytiotrophoblasts (STBs), and extravillous trophoblasts (EVTs), and assessed their susceptibility to infection. VP1uR, the erythroid-specific receptor that mediates viral uptake and infection in erythroid progenitor cells, is expressed in CTBs and STBs, but not in EVTs. Globoside, a glycosphingolipid that is essential for the escape of the virus from endosomes, is also expressed in these cells, except for choriocarcinoma-derived CTBs. In the latter, the absence of globoside can be overcome by promoting endosomal leakage with polyethyleneimine. While erythropoietin receptor (EpoR) signaling is associated with the strict erythroid tropism of B19V, it is not required for infection in trophoblasts. Transfection experiments revealed that highly proliferative first-trimester CTBs are more permissive to B19V infection than the low-proliferative CTBs from term placenta. These findings demonstrate that B19V targets and infects specific trophoblast cells, where viral entry and replication are collectively mediated by VP1uR, globoside, and high cellular proliferative activity, but are independent of EpoR signaling. HighlightsO_LITrophoblasts express the specific receptors necessary for B19V entry. C_LIO_LISusceptibility and permissiveness to B19V vary by trophoblast subtype and gestational age. C_LIO_LIHighly proliferative first-trimester cytotrophoblasts show increased permissiveness to B19V. C_LIO_LIB19V infection in trophoblasts depends on globoside but is independent of EpoR signaling. C_LI

microbiology↗

bioRxiv2023

Mpox virus spreads from cell-to-cell and leads to neuronal injury in human cerebral organoids

In 2022-23, the world experienced the largest recorded monkeypox virus (MPXV) outbreak outside of endemic regions. Remarkably, cases of neurological manifestations were reported, some of which fatal. MPXV DNA and MPXV-specific antibodies were detected in the cerebrospinal fluid of encephalitis-affected patients, suggesting neuroinvasive potential of MPXV. We explored the susceptibility of neural tissue to MPXV infection using human neural organoids (hNOs) exposed to a primary isolate belonging to clade IIb lineage. The virus efficiently replicates in hNOs as indicated by the exponential increase of infectious viral loads and the elevated frequency of MPXV-positive cells over time. Electron microscopy imaging revealed the presence of viral particles as well as perinuclear viral factories. We observed susceptibility of several cell types to the virus, including neural progenitor cells and neurons. Furthermore, we detected the presence of viral antigen in neurites and in foci of grouped cells distributed throughout the tissue. In line with this, we documented significantly more cell-associated than released infectious virus, suggesting viral spread by cell-to-cell contact. Using an mNeonGreen-expressing recombinant MPXV, we confirmed cell-associated virus transmission through live-cell imaging. While hNOs displayed no evident outer morphological changes upon infection, we detected the formation of beads in neurites, a phenomenon commonly associated with neurodegenerative disorders. Live-cell imaging further confirmed the recurrent formation of neuritic beads in neurons in the days following MPXV infection, with bead formation preceding neurite-initiated cell death. Notably, treatment of MPXV infected hNOs with the antiviral drug tecovirimat resulted in a significant reduction of infectious viral loads by several orders of magnitude. Taken together, our findings suggest viral manipulation of axonal transport driving neuronal degeneration and identify a mechanism potentially contributing to MPXV-mediated neuropathology that may have therapeutic implications.

microbiology↗

bioRxiv2020

The developing T-cell compartment of the neonatal lung orchestrates an atypical response to respiratory syncytial virus

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the specific features of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a state-of-the-art model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while {gamma}{delta} T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity. AUTHOR SUMMARYBy using a state-of-the-art translational model with full accessibility to the small airways at defined early life periods, we provide an unpreceded characterization of the developing T cell compartment in the distal lungs of healthy and RSV-infected neonates. This process is highly dynamic and tightly regulated, characterized by colonizing T-cell subsets that synergize towards a narrow pro-tolerogenic immunological window. We believe our work constitutes a solid basis to clarify the age dependency of RSV immunopathogenesis, and should be considered in vaccine design, which remains challenging after five decades of effort.

immunology↗