Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region–specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS.
Brian P. Daniels, Harsha Jujjavarapu, Douglas M. Durrant, Jessica L. Williams, Richard R. Green, James P. White, Helen M. Lazear, Michael Gale Jr., Michael S. Diamond, Robyn S. Klein
Cerebral malaria is characterized by cytoadhesion of
Julio Gallego-Delgado, Upal Basu-Roy, Maureen Ty, Matilde Alique, Cristina Fernandez-Arias, Alexandru Movila, Pollyanna Gomes, Ada Weinstock, Wenyue Xu, Innocent Edagha, Samuel C. Wassmer, Thomas Walther, Marta Ruiz-Ortega, Ana Rodriguez
Federico Iovino, Disa L. Hammarlöf, Genevieve Garriss, Sarah Brovall, Priyanka Nannapaneni, Birgitta Henriques-Normark
Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to mucormycosis, an angioinvasive fungal infection with high mortality. Previously, we demonstrated that
Teclegiorgis Gebremariam, Lin Lin, Mingfu Liu, Dimitrios P. Kontoyiannis, Samuel French, John E. Edwards Jr., Scott G. Filler, Ashraf S. Ibrahim
IFN-γ is a critical mediator of host defense against
Andreas Kupz, Ulrike Zedler, Manuela Stäber, Carolina Perdomo, Anca Dorhoi, Roland Brosch, Stefan H.E. Kaufmann
Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis–inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury.
Christin Peteranderl, Luisa Morales-Nebreda, Balachandar Selvakumar, Emilia Lecuona, István Vadász, Rory E. Morty, Carole Schmoldt, Julia Bespalowa, Thorsten Wolff, Stephan Pleschka, Konstantin Mayer, Stefan Gattenloehner, Ludger Fink, Juergen Lohmeyer, Werner Seeger, Jacob I. Sznajder, Gökhan M. Mutlu, G.R. Scott Budinger, Susanne Herold
In extrapulmonary tuberculosis, the most common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for
Thomas R. Lerner, Cristiane de Souza Carvalho-Wodarz, Urska Repnik, Matthew R.G. Russell, Sophie Borel, Collin R. Diedrich, Manfred Rohde, Helen Wainwright, Lucy M. Collinson, Robert J. Wilkinson, Gareth Griffiths, Maximiliano G. Gutierrez
Simone Lanini, Gina Portella, Francesco Vairo, Gary P Kobinger, Antonio Pesenti, Martin Langer, Soccoh Kabia, Giorgio Brogiato, Jackson Amone, Concetta Castilletti, Rossella Miccio, Alimuddin Zumla, Maria Rosaria Capobianchi, Antonino Di Caro, Gino Strada, Giuseppe Ippolito, INMI-EMERGENCY EBOV Sierra Leone Study group
BACKGROUND. Ebola virus (EBOV) causes periodic outbreaks of life-threatening EBOV disease in Africa. Historically, these outbreaks have been relatively small and geographically contained; however, the magnitude of the EBOV outbreak that began in 2014 in West Africa has been unprecedented. The aim of this study was to describe the viral kinetics of EBOV during this outbreak and identify factors that contribute to outbreak progression.
METHODS. From July to December 2014, one laboratory in Sierra Leone processed over 2,700 patient samples for EBOV detection by quantitative PCR (qPCR). Viremia was measured following patient admission. Age, sex, and approximate time of symptom onset were also recorded for each patient. The data was analyzed using various mathematical models to find trends of potential interest.
RESULTS. The analysis revealed a significant difference (
CONCLUSIONS. Our results indicate that initial viremia is associated with outcome of the individual and outbreak duration; therefore, care must be taken in planning clinical trials and interventions. Additional research in virus adaptation and the impacts of host factors on EBOV transmission and pathogenesis is needed.
Marc-Antoine de La Vega, Grazia Caleo, Jonathan Audet, Xiangguo Qiu, Robert A. Kozak, James I. Brooks, Steven Kern, Anja Wolz, Armand Sprecher, Jane Greig, Kamalini Lokuge, David K. Kargbo, Brima Kargbo, Antonino Di Caro, Allen Grolla, Darwyn Kobasa, James E. Strong, Giuseppe Ippolito, Michel Van Herp, Gary P. Kobinger
The identification of the molecular events responsible for strain emergence, enhanced virulence, and epidemicity has been a long-pursued goal in infectious diseases research. A recent analysis of 3,615 genomes of serotype M1 group A
Luchang Zhu, Randall J. Olsen, Waleed Nasser, Stephen B. Beres, Jaana Vuopio, Karl G. Kristinsson, Magnus Gottfredsson, Adeline R. Porter, Frank R. DeLeo, James M. Musser
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