Defective Influenza A Virus RNA Products Mediate MAVS-Dependent Upregulation of Human Leukocyte Antigen Class I Proteins
JOURNAL OF VIROLOGY
Authors: Rahim, Mir Munir A.; Parsons, Brendon D.; Price, Emma L.; Slaine, Patrick D.; Chilvers, Becca L.; Seaton, Gregory S.; Wight, Andrew; Medina-Luna, Daniel; Dey, Sayanti; Grandy, Shannen L.; Anderson, Lauryn E.; Cuervo, Natalia Zamorano; Grandvaux, Nathalie; Gaglia, Marta M.; Kelvin, Alyson A.; Khaperskyy, Denys A.; McCormick, Craig; Makrigiannis, Andrew P.
Influenza A virus (IAV) increases the presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms for these processes have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947(H1N1) IAV significantly increased the presentation of HLA-B, -C, and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation because UV-inactivated virus had no effect. Aberrant internally deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs) expressed from an IAV minireplicon were sufficient for inducing HLA upregulation. These defective RNAs bind to retinoic acid-inducible gene I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signaling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-beta and IFN-lambda 1 and conditioned media from these cells elicited a modest increase in HLA surface levels in naive epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by the Janus kinase (JAK) inhibitor ruxolitinib. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity. IMPORTANCE Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell.
A numerical investigation of balcony geometry impact on single-sided natural ventilation and thermal comfort
BUILDING AND ENVIRONMENT
Authors: Izadyar, Nima; Miller, Wendy; Rismanchi, Behzad; Garcia-Hansen, Veronica
Balconies could enhance natural ventilation (NV) and reduce reliance on mechanical ventilation in cooling dominant climates. Indoor environment and thermal comfort under NV mode are usually less predictable than Mechanical Ventilation (MV), and balcony geometry's impacts on these parameters have not yet been classified. This study aims to investigate the effects of balcony depth and door opening scale on the NV performance and thermal comfort of the attached Livingroom. The present article conducted a 3D - steady-state Computational Fluid Dynamics (CFD) simulations using ANSYS Fluent. The simulation results were validated against measured data in a residential high-rise building in subtropical Brisbane, Australia. Five different openings and nine depth scenarios are defined as configuration tests. The simulation results reveal that both the opening and depth sizes affected the Indoor Air Distribution (IAD), mean Indoor Air Velocity (IAV) and temperature, while these effects are not identical in the defined scenarios and opening size had more significant effects. The smaller openings, including the case study, led to a better thermal comfort than other scenarios. Contrary, the smaller depth sizes (less than 2 m) led to a non-uniform and unstable IAD at the attached Livingroom. The best thermal comfort and the highest IAV also occurred, respectively, in the deeper balconies with 35 and 30% depth ratio. Finally, a comparison between the findings and literature reveals the balcony's depth scale effects on mean IAV significantly depends on the orientation of buildings.