Biology subjects

Horsnell, W. G.

Publications and source records attributed to Horsnell, W. G..

2 recordsLinked to original sources

bioRxiv2024

Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologous Salmonella challenge

Lipopolysaccharide O-antigen is an immunodominant target of protective antibodies. Variation in O-antigen structures limits antibody-mediated cross-protection between closely-related pathogens including Salmonella Typhimurium (STm) and S. Enteritidis (SEn). Bacterial outer membrane vesicles (OMV) are vaccine platforms presenting surface antigens in their natural conformations. To assess how O-antigen lengths impact antibody responses and control of homologous or heterologous infection, mice were immunized with STm-OMV containing wild-type O-antigen unit repeats (wt-OMV), [≤]1 O-antigen unit (wzy-OMV), or no O-antigen units (wbaP-OMV) respectively and challenged with either STm or SEn. Unexpectedly, anti-STm LPS IgG and protection to STm were comparable after immunization with either wt-OMV or wzy-OMV. Anti-porin responses were elevated after immunization with wzy-OMV and wbaP-OMV. A single immunization with any OMV induced minimal cross-protection against SEn, except in blood. In contrast, boosting with O-antigen-expressing OMV enhanced control of SEn infections by >10-fold. These results suggest that i) Antibody to single or variable-length O-antigen units are comparably protective against Salmonella; ii) Antigens other than immunodominant O-antigens may be targets of cross-reactive antibodies that moderate bacterial burdens; iii) Boosting can enhance the level of cross-protection against related Salmonella serovars and iv) High tissue burdens of Salmonella can be present in the absence of detectable bacteraemia.

immunology↗

bioRxiv2024

Discrete and conserved inflammatory signatures drive thrombosis in different organs after Salmonella infection

Inflammation-induced thrombosis is a common consequence of bacterial and viral infections, such as those caused by Salmonella Typhimurium (STm) and SARS-CoV-2. The identification of multi-organ thrombosis and the chronological differences in its induction and resolution raises significant challenges for successfully targeting multi-organ infection-associated thrombosis. Here, we identified specific pathways and effector cells driving thrombosis in the spleen and liver following STm infection. Thrombosis in the spleen is independent of IFN-{gamma} or the platelet C-type lectin-like receptor CLEC-2, while both molecules were previously identified as key drivers of thrombosis in the liver. Furthermore, we identified platelets, monocytes, and neutrophils as core constituents of thrombi in both organs. Depleting neutrophils or monocytic cells independently abrogated thrombus formation. Nevertheless, blocking TNF, which is expressed by both myeloid cell types, diminished both thrombosis and inflammation which correlates with reduced endothelial expression of E-selectin and leukocyte infiltration. Moreover, tissue factor and P-selectin glycoprotein ligand 1 inhibition impair thrombosis in both spleen and liver, identifying multiple common checkpoints to target multi-organ thrombosis. Therefore, organ-specific, and broad mechanisms driving thrombosis potentially allow tailored treatments based on the clinical need and to define the most adequate strategy to target both thrombosis and inflammation associated with systemic infections.

immunology↗