Biology subjects

Norris, M. J.

Publications and source records attributed to Norris, M. J..

3 recordsLinked to original sources

bioRxiv2024

A surface lipoprotein on Pasteurella multocida binds complement factor I to promote immune evasion.

Pasteurella multocida is the leading cause of wound infections in humans following animals bites or scratches. This bacterium is also commonly found in the respiratory tract of many mammals and can cause serious diseases resulting in the brutal rapid death of infected animals, especially cattle. To prevent these infections in cattle, a subunit-based vaccine utilizing the surface lipoprotein PmSLP was developed and showed remarkable protection with a single dose administration. Here, we report that PmSLP binds host complement factor I (FI) and facilitates cleavage of complement components C3b and C4b independently of any cofactors (e.g FH, C4BP), thereby allowing the pathogen to evade host defence. Cryo-EM structure of PmSLP bound to FI reveals that PmSLP stimulates FI enzymatic activity by stabilizing the catalytic domain. This is the first time that a bacterial protein has been shown to directly activate FI independent of complement cofactors and target all arms of the complement cascade.

microbiology↗

bioRxiv2024

A noncanonical glycoprotein H complex enhances cytomegalovirus entry

Human cytomegalovirus (HCMV) causes severe birth defects, lifelong health complications, and $4 billion in annual costs in the United States alone. A major challenge in vaccine design is the incomplete understanding of the diverse protein complexes the virus uses to infect cells. In Herpesviridae, the gH/gL glycoprotein heterodimer is expected to be a basal element of virion cell entry machinery. For HCMV, gH/gL forms a "trimer" with gO and a "pentamer" with UL128, UL130, and UL131A, with each complex binding distinct receptors to enter varied cell types. Here, we reveal a third glycoprotein complex, abundant in HCMV virions, which significantly enhances infection of endothelial cells. In this "3-mer" complex, gH, without gL, associates with UL116 and UL141, an immunoevasin previously known to function in an intracellular role. Cryo-EM reveals the virion-surface 3-mer is structurally unique among Herpesviridae gH complexes, with gH-only scaffolding, UL141-mediated dimerization and a heavily glycosylated UL116 cap. Given that antibodies directed at gH and UL141 each can restrict HCMV replication, our work highlights this virion surface complex as a new target for vaccines and antiviral therapies.

microbiology↗

bioRxiv2021

Molecular assembly of measles and Nipah virus: specific lipid binding drives conformational change and matrix polymerization

Measles virus, Nipah virus, and multiple other paramyxoviruses cause disease outbreaks in humans and animals worldwide. The paramyxovirus matrix (M) protein mediates virion assembly and budding from host cell membranes. M is thus a key target for antivirals, but few high-resolution structures of paramyxovirus M are available, and we lack the clear understanding of how viral M proteins interact with membrane lipids to mediate viral assembly and egress needed to guide antiviral design. Here, we reveal that M proteins associate with phosphatidylserine and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) at the plasma membrane. Using X-ray crystallography, electron microscopy, and molecular dynamics we demonstrate that PI(4,5)P2 binding induces conformational and electrostatic changes in the M protein surface that trigger membrane deformation, matrix layer polymerization, and virion assembly.

microbiology↗