Influenza viruses remain a persistent challenge to human health owing to their inherent ability to evade the immune response by antigenic drift. However, the discovery of broadly neutralizing antibodies (bnAbs) against divergent viruses has sparked renewed interest in a universal influenza vaccine and novel therapeutic opportunities. Here, a crystal structure at 1.70 Å resolution is presented of the Fab of the human antibody CH65, which has broad neutralizing activity against a range of seasonal H1 isolates. Previous studies proposed that affinity maturation of this antibody lineage pre-organizes the complementaritydetermining region (CDR) loops into an energetically favorable HA-bound conformation. Indeed, from the structural comparisons of free and HA-bound CH65 presented here, the CDR loops, and in particular the heavy-chain CDR3, adopt the same conformations in the free and bound forms. Thus, these findings support the notion that affinity maturation of the CH65 lineage favorably preconfigures the CDR loops for high-affinity binding to influenza hemagglutinin.
FlhDC is a heterohexameric complex that acts as a master regulator of flagellar biosynthesis genes in numerous bacteria. Previous studies have identified a single flhDC operon encoding this complex. However, we found that two flhDC loci are present throughout Paraburkholderia and two additional flhC copies also present in P. unamae. Systematic deletion analysis in P. unamae of the different flhDC copies showed that one of the operons, flhDC1 , plays the predominant role, with deletion of its genes resulting in a severe inhibition of motility and biofilm formation. Expression analysis using promoter- lacZ fusions and real-time quantitative PCR support the primary role of flhDC1 in flagellar gene regulation, with flhDC2 a secondary contributor. Phylogenetic analysis shows the presence of the flhDC1 and flhDC2 operons throughout Paraburkholderia . In contrast, Burkholderia and other bacteria only carry the copy syntenous with flhDC2 . The varying impact each copy of flhDC has on downstream processes indicates that regulation of FlhDC in P. unamae, and likely other Paraburkholderia, is regulated at least in part by the presence of multiple copies of these genes. IMPORTANCE Motility is important in the colonization of plant roots by beneficial and pathogenic bacteria, with flagella playing essential roles in host cell adhesion, entrance, and biofilm formation. Flagellar biosynthesis is energetically expensive. Its complex regulation by the FlhDC master regulator is well-studied in peritrichous flagella expressing enterics. We report the unique presence throughout Paraburkholderia of multiple copies of flhDC . In P. unamae , the flhDC1 copy showed higher expression and greater effect on swim motility, flagellar development, and regulation of downstream genes, than the flhDC2 copy that is syntenous to flhDC in E. coli and pathogenic Burkholderia spp. The flhDC genes have evolved differently in these plant-growth promoting bacteria, giving an additional layer of complexity in gene regulation by FlhDC.
HIV has evolved many mechanisms to avoid antibody recognition, but one neutralizing antibody, PGT128, is able to recognize the virus and prevent HIV infection. The Murrieta Mesa SMART Team (Students Modeling A Research Topic) modeled PGT128 using 3D printing technology. PGT128 binds to glycans, which are sugars on the viral surface of the HIV envelope protein gp120. The gp120 molecule has a binding site that modulates attachment to the CD4 receptor on human CD4 T cells. Binding of gp120 to these cells leads to membrane fusion between the human cell and HIV. It is this initial infection that ultimately causes AIDS. The function of the PGT128 antibody is to coat gp120 by binding to two glycans on the HIV glycan shield. A glycan shield refers to sugars that protect glycoproteins from recognition by the human immune system. After PGT128 infiltrates the HIV glycan coat, it interacts with a specific part of gp120, the V3 loop, thus preventing membrane fusion and HIV infection. The antibody is thought to be able to bind two separate gp120 molecules via a cross linking mechanism. PGT128 is known to be a broad neutralizer, which means that the antibody can deactivate many different strains of HIV. Since PGT128 is able to neutralize 72% of circulating viruses, there is the possibility a vaccine can be generated for HIV. Supported by a grant from the HHMI Pre‐ College program.
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