Marginal zone (MZ) B cells optimize protection against blood-borne bacteria by rapidly producing plasma cells in response to Toll-like receptor (TLR) ligands. Here, we demonstrate that Notch2 instructs this responsiveness for both the dsRNA sensor TLR3 and LPS sensor TLR4. Using mathematical modeling of cell trace time-course data, we reveal that constitutive Notch2 experience affords lipopolysaccharide (LPS) hyperresponsiveness in Notch2-independent follicular B cells. This resulted in earlier Myc induction and accelerated cell cycle entry, ultimately augmenting division kinetics. Further, Notch2 engagement drove TLR3 expression and instructed an otherwise absent TLR3 response program, dependent on both the TIR-domain-containing-adaptor, TRIF and the kinase BTK. Access to Notch2 ligands instructed a T-independent plasma cell differentiation program. We conclude that Notch2 controls several aspects of TLR3 and TLR4 function in B cells and further suggest that MZ B cells may play previously unappreciated roles in immunity against RNA viruses.
Jennifer Londregan, Isaiah Rozich, Brian T. Gaudette et al.· Cell Reports· 0 citations
Highly pathogenic avian influenza viruses (HPAIs) continue to threaten both agriculture and human health. Recent H5N1 clades have caused zoonotic infections in humans with mortality rates approaching 50%. However, currently licensed H5 vaccines are based on ancestral strains and may provide suboptimal protection against circulating variants. Rapidly adaptable DNA vaccine platforms offer a promising approach for clade-specific protection.
Codon-optimized plasmid DNA vaccines expressing hemagglutinin (HA) from two recently circulating H5N1 clades (2.3.2.1c and 2.3.4.4b) were generated and delivered by either intramuscular electroporation (EP) or a lipid nanoparticle (LNP) formulation. Cellular and humoral responses were evaluated by multiparameter flow cytometry and ELISpot and by ELISA and pseudovirus neutralization, respectively. Protective efficacy was evaluated in lethal H5N1 murine challenge models.
EP delivery of clade 2.3.2.1c HA (pCamb) elicited strong humoral and cellular responses and achieved complete protection against homologous viral challenge, but only partial protection against heterologous 2.3.4.4b challenge. In contrast, vaccination with clade 2.3.4.4b HA (pMich) DNA supported robust immune responses and full protection against contemporary clade challenge. Co-immunization with both plasmids via EP induced broad binding and neutralizing antibodies and conferred complete protection from clade 2.3.4.4b challenge. Moreover, formulation of the pMich plasmid optimized LNPs generated durable, protective immunity following a single dose, effective at both acute and memory timepoints.
These studies demonstrate that antigenic clade-matching is likely critical for protection against H5N1 and suggest that currently stockpiled H5N1 vaccines may not protect against contemporary viruses. Further this data suggests that DNA vaccine platforms including EP or LNP formulations can provide a flexible approach for rapid adaptation to evolving influenza strains.
NIH NIAID CIVICs
Vaccines and Immunotherapy (VAC)
Ebony N. Gary, Nicholas J. Tursi, Casey E. Hojecki et al.· Journal of Immunology· 0 citations
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