Biology subjects

Laurie, K.

Publications and source records attributed to Laurie, K..

3 recordsLinked to original sources

bioRxiv2026

Epistasis facilitates the long-term antigenic evolution of the influenza B virus hemagglutinin

The antigenic drift of viral glycoproteins must be balanced by purifying selection pressure to maintain functionality. Understanding these evolutionary processes is key to predicting and combating viral evolution but is primarily based on influenza A(H3N2), which may limit generalisability. By characterising the influenza B virus haemagglutinin (HA) over 8 decades of circulation in humans, we found continuous genetic diversification, punctuated with antigenic changes that did not follow a linear path in antigenic space. Antigenic change is primarily underpinned by re-occurring mutations and deletions at positions 136, 150, 162-165, 197 and 203. These residues form complex epistatic networks that modulate the antigenic impact of mutation recycling. They also generate permissive backbones on which immune escape can emerge with limited replicative fitness cost. Our study identifies critical similarities and differences with A(H3N2) evolution and demonstrates the role of epistasis in balancing antigenic novelty with viral fitness. Our findings and genetic, antigenic and phenotypic datasets support the development of genotype-to-phenotype prediction tools, but such predictions need to capture the complex outcomes of epistasis.

microbiology↗

bioRxiv2020

Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

Thrombosis has been one of the complications of the Coronavirus disease of 2019 (COVID-19), often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms by which some of these variants may contribute to disease are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches. Author summaryIncreased blood clotting, especially in the lungs, is a common complication of COVID-19. Infectious diseases cause inflammation which in turn can contribute to increased blood clotting. However, the extent of clot formation that is seen in the lungs of COVID-19 patients suggests that there may be a more direct link. We identified three human proteins that are involved indirectly in the blood clotting cascade and have been shown to interact with proteins of SARS virus, which is closely related to the novel coronavirus. We examined computationally the interaction of these human proteins with the viral proteins. We looked for genetic variants of these proteins and examined how these variants are distributed across populations. We investigated whether variants of these genes could impact severity of COVID-19. Further investigation around these variants may provide clues for the pathogenesis of COVID-19 particularly in minority groups.

bioinformatics↗

bioRxiv2018

Characterising antibody kinetics from multiple influenza infection and vaccination events in ferrets

The strength and breadth of an individuals antibody repertoire are important predictors of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody mediated immune response, quantitative understanding remains limited. We developed a set of mathematical models describing short-term antibody kinetics following influenza infection or vaccination and fit them to haemagglutination inhibition (HI) titres from 5 groups of ferrets which were exposed to different combinations of trivalent inactivated influenza vaccine (TIV with or without adjuvant), priming inoculation with A/H3N2 and post-vaccination inoculation with A/H1N1. Based on the parameter estimates of the best supported model, we describe a number of key immunological features. We found quantifiable differences in the degree of homologous and cross-reactive antibody boosting elicited by different exposure types. Infection and adjuvanted vaccination generally resulted in strong, broadly reactive responses whereas unadjuvanted vaccination resulted in a weak, narrow response. We found that the order of exposure mattered: priming with A/H3N2 improved subsequent vaccine response, and the second dose of adjuvanted vaccination resulted in substantially greater antibody boosting than the first. Although there was considerable uncertainty in our estimates of antibody waning parameters, our results suggest that both short and long term waning were present and would be identifiable with a larger set of experiments. These results highlight the potential use of repeat exposure animal models in revealing short-term, strain-specific immune dynamics of influenza.\n\nAuthor summaryDespite most individuals having some preexisting immunity from past influenza infections and vaccinations, a significant proportion of the human population is infected with influenza each year. Predicting how an individuals antibody profile will change following exposure is therefore useful for evaluating which populations are at greatest risk and how effective vaccination strategies might be. However, interpretation of antibody data from humans is complicated by immunological interactions between all previous, unobserved exposures in an individuals life. We developed a mathematical model to describe short-term antibody kinetics that are important in building an individuals immune profile but are difficult to observe in human populations. We validated this model using antibody data from ferrets with known, varied infection and vaccination histories. We were able to quantify the independent contributions of various exposures and immunological mechanisms in generating observed antibody titres. These results suggest that data from experimental systems may be included in models of human antibody dynamics, which may improve predictions of vaccination strategy effectiveness and how population susceptibility changes over time.

immunology↗