TY  - JOUR
A1  - Heinemann, Anna Sophie
A1  - Stalp, Jan Lennart
A1  - Bonifacio, João Pedro Pereira
A1  - Silva, Filo
A1  - Willers, Maike
A1  - Heckmann, Julia
A1  - Fehlhaber, Beate
A1  - Völlger, Lena
A1  - Raafat, Dina
A1  - Normann, Nicole
A1  - Klos, Andreas
A1  - Hansen, Gesine
A1  - Schmolke, Mirco
A1  - Viemann, Dorothee
T1  - Silent neonatal influenza A virus infection primes systemic antimicrobial immunity
JF  - Frontiers in Immunology
N2  - Infections with influenza A viruses (IAV) cause seasonal epidemics and global pandemics. The majority of these infections remain asymptomatic, especially among children below five years of age. Importantly, this is a time, when immunological imprinting takes place. Whether early-life infections with IAV affect the development of antimicrobial immunity is unknown. Using a preclinical mouse model, we demonstrate here that silent neonatal influenza infections have a remote beneficial impact on the later control of systemic juvenile-onset and adult-onset infections with an unrelated pathogen, Staphylococcus aureus, due to improved pathogen clearance and clinical resolution. Strategic vaccination with a live attenuated IAV vaccine elicited a similar protection phenotype. Mechanistically, the IAV priming effect primarily targets antimicrobial functions of the developing innate immune system including increased antimicrobial plasma activity and enhanced phagocyte functions and antigen-presenting properties at mucosal sites. Our results suggest a long-term benefit from an exposure to IAV during the neonatal phase, which might be exploited by strategic vaccination against influenza early in life to enforce the host’s resistance to later bacterial infections.
KW  - neonate
KW  - influenza A virus
KW  - influenza vaccination
KW  - innate immunity training
KW  - antimicrobial immunity
KW  - Staphylococcus aureus
KW  - sepsis
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304782
VL  - 14
ER  - 
TY  - JOUR
A1  - Kusch, Valentin
A1  - Bornschein, Grit
A1  - Loreth, Desiree
A1  - Bank, Julia
A1  - Jordan, Johannes
A1  - Baur, David
A1  - Watanabe, Masahiko
A1  - Kulik, Akos
A1  - Heckmann, Manfred
A1  - Eilers, Jens
A1  - Schmidt, Hartmut
T1  - Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors
JF  - Cell Reports
N2  - Spatial relationships between Cav channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Cav2.1 and Cav2.2 channels, alters the localization of Cav2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+-channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca2+ influx through Cav2.1 and Cav2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Cav2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Cav2.1 and Cav2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.
KW  - coupling
KW  - nanodomain
KW  - synapse
KW  - active zone
KW  - development
KW  - Ca2+ channels
KW  - Munc13-3
KW  - cerebellar cortex
KW  - transmitter release
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233468
VL  - 22
ER  -