Purser, L. | bioRxiv Science

bioRxiv2022

Broadly neutralizing antibodies target the coronavirus fusion peptide

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2 cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2 cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence SummaryRare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

immunology↗

bioRxiv2022

Air pollution induces Staphylococcus aureus USA300 respiratory tract colonisation mediated by specific bacterial genetic responses dependent on the global virulence gene regulators Agr and Sae

Exposure to particulate matter (PM), a major component of air pollution, is associated with exacerbation of chronic respiratory disease, and infectious diseases such as community acquired pneumonia. Although PM can cause adverse health effects through direct damage to host cells, our previous study showed that PM can also impact bacterial behaviour by promoting in vivo colonisation. In this study we describe the genetic mechanisms involved in the bacterial response to exposure to black carbon (BC), a constituent of PM found in most sources of air pollution. We show that Staphylococcus aureus strain USA300 LAC grown in BC prior to inoculation showed increased murine respiratory tract colonisation and pulmonary invasion in vivo, as well as adhesion and invasion of human epithelial cells in vitro. Global transcriptional analysis showed that BC has a widespread effect on S. aureus transcriptional responses, altering the regulation of the major virulence gene regulators Sae and Agr and causing increased expression of genes encoding toxins, proteases, and immune evasion factors. Together these data describe a previously unrecognised causative mechanism of air pollution-associated infection, in that exposure to BC can increase bacterial colonisation and virulence factor expression by acting directly on the bacterium rather than via the host. Originality-Significance StatementThis study shows that exposure to air pollution results in a global change in gene expression in bacteria. Specifically, our data show that in the important human pathogen Staphylococcus aureus, exposure to a major constituent of air pollution, black carbon (BC) results in widespread changes in global gene expression, altering the expression of key virulence determinants. Furthermore, S. aureus that are exposed to BC prior to inoculation show increased colonisation of the murine nasopharynx and lungs in vivo, and increased adhesion and invasion in lung epithelial cells in vitro. These findings indicate that air pollution has a significant and direct impact on bacteria, altering their behaviour and their potential to colonise and invade during infection. While many studies have taken a host-focussed approach to studying the impact of air pollution on human health, this study takes a pathogen-focussed approach to further the understanding of these fundamental interactions to identify new causative mechanisms of the detrimental effects of air pollution. This is critical for understanding the adverse health effects caused by exposure to air pollution, the single largest environmental risk to human health in the world.

microbiology↗