Biology subjects

Adams, W.

Publications and source records attributed to Adams, W..

3 recordsLinked to original sources

bioRxiv2024

Streptococcus pneumoniae infection of lung epithelial cells induces internalization of surface GPI-anchored proteins through pneumolysin-mediated activation of host Rho GTPases

A return to homeostasis after infection-associated cellular injury can be accelerated by a rapid damage response. S. pneumoniae, a typically asymptomatic colonizer of the host upper respiratory tract, can cause serious and life-threatening infections when it gains access to the lungs and other organs. The cholesterol binding S. pneumoniae pore-forming toxin, pneumolysin (PLY), is central to the induction of host cell damage. Here, we first found that mouse lung infection by S. pneumoniae diminished pulmonary expression of CD73, a glycosylphosphatidylinositol anchored protein (GPI-AP) that modulates inflammation. Infection of the human pulmonary epithelial cell line H292 resulted in a PLY-dependent reduction of not only cell surface CD73, but also the population of surface expressed GPI-APs. The decrease in cell surface GPI-APs was rapid, required pore-forming activity, and could be recapitulated by purified PLY and other cholesterol binding cytolysins. In response to PLY-mediated insult, GPI-APs were not released from the surface of epithelial cells in extracellular vesicles but rather internalized by a mechanism dependent on the Rho GTPases RhoA and Cdc42. Internalization of GPI-APs was associated with lower levels of PLY-induced apoptosis and membrane permeabilization. These findings suggest that internalization of GPI-APs from epithelial cell membranes may constitute a rapid innate repair response to cell damage induced by PLY and other pore forming toxins that could help bacteria evade host defenses as many GPI-APs have roles in immunity. Author summaryStreptococcus pneumoniae causes serious infections that can result in mortality. The pore- forming toxin, pneumolysin (PLY) produced by these bacteria is important for their ability to cause disease. Understanding how the host responds to damage by this toxin can result in better treatment against infection. In this study, we found that PLY-mediated injury results in decreased expression of glycosylphosphatidylinositol anchored proteins (GPI-AP) from the cell surface by internalization. GPI-AP co-localize in cholesterol-rich areas of the membrane where PLY inserts to form pores and cells with decreased surface GPI-APs were associated with less of PLY-induced cell death and membrane permeabilization. These results suggest that GPI-AP are internalized as part of repair mechanisms activated in response to infection-induced cell injury. As many GPI-APs have important roles in the immune response, their removal from the cell may inadvertently help the bacteria establish better infection.

microbiology↗

bioRxiv2023

Pore-forming activity of S. pneumoniae pneumolysin disrupts the paracellular localization of the epithelial adherens junction protein E-cadherin

Streptococcus pneumoniae, a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration in vitro and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by S. pneumoniae at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation. Reducing the MOI to 2 decreased PMN recruitment two-fold and preserved the monolayer, but apical-to-basolateral translocation of S. pneumoniae remained relatively efficient. At both MOI of 2 and 20, PLY was required for maximal PMN recruitment and bacterial translocation. Co-infection by wild type S. pneumoniae restored translocation by a PLY-deficient mutant, indicating that PLY can act in trans. Investigating the contribution of S. pneumoniae infection on apical junction complexes in the absence of PMN transmigration, we found that S. pneumoniae infection triggered the cleavage and mislocalization of the adherens junction (AJ) protein E-cadherin. This disruption was PLY-dependent at MOI of 2 and was recapitulated by purified PLY, requiring its pore-forming activity. In contrast, at MOI of 20, E-cadherin disruption was independent of PLY, indicating that S. pneumoniae encodes multiple means to disrupt epithelial integrity. This disruption was insufficient to promote bacterial translocation in the absence of PMNs. Thus, S. pneumoniae triggers cleavage and mislocalization of E-cadherin through PLY-dependent and PLY-independent mechanisms, but maximal bacterial translocation across epithelial monolayers requires PLY-dependent neutrophil transmigration.

microbiology↗

bioRxiv2018

Top-down inputs drive neuronal network rewiring and context-enhanced sensory processing in olfaction

Much of the computational power of the mammalian brain arises from its extensive top-down projections. To enable neuron-specific information processing these projections have to be precisely targeted. How such a specific connectivity emerges and what functions it supports is still poorly understood. We addressed these questions in silico in the context of the profound structural plasticity of the olfactory system. At the core of this plasticity are the granule cells of the olfactory bulb, which integrate bottom-up sensory inputs and top-down inputs delivered by vast top-down projections from cortical and other brain areas. We developed a biophysically supported computational model for the rewiring of the top-down projections and the intra-bulbar network via adult neurogenesis. The model captures various previous physiological and behavioral observations and makes specific predictions for the cortico-bulbar network connectivity that is learned by odor exposure and environmental contexts. Specifically, it predicts that after learning the granule-cell receptive fields with respect to sensory and with respect to cortical inputs are highly correlated. This enables cortical cells that respond to a learned odor to enact disynaptic inhibitory control specifically of bulbar principal cells that respond to that odor. Functionally, the model predicts context-enhanced stimulus discrimination in cluttered environments ( olfactory cocktail parties) and the ability of the system to adapt to its tasks by rapidly switching between different odor-processing modes. These predictions are experimentally testable. At the same time they provide guidance for future experiments aimed at unraveling the cortico-bulbar connectivity.\n\nAuthor summaryIn mammalian sensory processing, extensive top-down feedback from higher brain areas reshapes the feedforward, bottom-up information processing. The structure of the top-down connectivity, the mechanisms leading to its specificity, and the functions it supports are still poorly understood. Using computational modeling, we investigated these issues in the olfactory system. There, the granule cells of the olfactory bulb, which is the first brain area to receive sensory input from the nose, are the key players of extensive structural changes to the network through the addition and also the removal of granule cells as well as through the formation and removal of their connections. This structural plasticity allows the system to learn and to adapt its sensory processing to its odor environment. Crucially, the granule cells combine bottom-up sensory input from the nose with top-down input from higher brain areas, including cortex. Our biophysically supported computational model predicts that, after learning, the granule cells enable cortical neurons that respond to a learned odor to gain inhibitory control of principal neurons of the olfactory bulb, specifically of those that respond to the learned odor. Functionally, this allows top-down input to enhance odor discrimination in cluttered environments and to quickly switch between odor tasks.

neuroscience↗