Biology subjects

Grenfell, B.

Publications and source records attributed to Grenfell, B..

9 recordsLinked to original sources

bioRxiv2026

Defective Viral Genomes Reveal History-dependent Self-regulation of Type I Interferon Dynamics

Type I interferons (IFN) help clear a viral infection, but IFN levels can then decline to reset the antiviral state and avoid innate immune dysregulation. Such dysregulation can occur following infection with highly pathogenic and pandemic RNA viruses, such as H5N1 influenza A viruses or SARS-CoV-2. In spite of the strong innate immune response that these viruses induce, pandemic viruses replicate and spread successfully, suggesting that they can circumvent the effects of IFN. Innate immune activation is triggered when host cells detect viral RNA, especially defective viral genomes (DVGs). A strong IFN response (e.g. to DVGs or a highly immunogenic wild-type infection) must then decline through negative feedback involving the IFN receptor. How DVGs modulate this feedback remains poorly understood. To quantify positive and negative IFN regulation, we first performed in vitro experiments combining different doses of viral RNA and exogenous IFN, and measured subsequent IFN expression. We next developed an in vivo Bayesian computational model that captures the impact of influenza virus DVGs on both positive and negative IFN feedback. Competition between DVGs and virus is also considered. Finally, we calibrated this model on published in vitro and in vivo influenza virus infection data. Our model suggests that the cumulative IFN exposure of a host cell, rather than the instantaneous IFN level, shapes further IFN induction; this gives DVGs a dual role: beyond triggering IFN induction, they can also lower it through negative feedback. Our model further predicts that these effects are important locally, shaping the spatial dynamics of the response, allowing suppression of innate immune responses in neighbouring, uninfected cells. Through this model, we can explain two important biological observations: i) IFN levels can decline while virus and DVG levels continue to rise in tissue culture and mouse infections; and ii) pandemic viruses that produce high levels of immunogenic RNA molecules can successfully replicate through local innate immune suppression. Overall, we propose that heterogeneity within viral populations (including DVGs and other noncanonical viral RNAs) can modulate positive and negative feedback loops and shape infection outcomes. More broadly, our work may support studies into the therapeutic use of these viral RNA populations.

microbiology↗

bioRxiv2026

Unifying coexistence theory for ecological communities and pathogen strain competition

Predicting the outcome of species or pathogen strain competition is a fundamental aim in both community ecology and infectious disease dynamics. Recent work revealed major challenges in predicting strain co-circulation from ecological coexistence theory due to overcompensatory competition among pathogens for susceptible resources, which can prevent the re-invasion of other competing strains. This resource overcompensation is ubiquitous across host-pathogen systems, but not apparent in simple Lotka-Volterra competition system, highlighting fundamental differences between pathogen strain and species competition. To address this gap, we begin by deriving classical models of pathogen strain and species competition from a resource-consumer model. This generalization illustrates that the relative time scale between resource and consumer dynamics limits the degree of resource overcompensation and therefore dictates the outcome of stochastic competition. Moreover, by introducing a mathematical framework for quantifying pairwise and higher-order terms from general competition systems, we show that a simple, ecological competition model can accurately predict the equilibrium dynamics of strain competition. A case study of rotavirus strain competition reveals that the ability to predict the outcome of strain competition from ecological theory depends on the underlying cross immunity structure. This work synthesizes coexistence theory across two fields by providing a unifying framework for predicting the outcome of complex ecological competition.

ecology↗

bioRxiv2025

Spatio-temporal modelling of in vitro viral infection: the impact of defective interfering particles on type I interferon response

Defective interfering particles (DIPs) are incomplete viral genomes that modulate infection by competing with wild-type viruses and activating innate immunity. How DIPs interact with type I interferon (IFN) in spatially structured environments remains unclear. Focusing initially on influenza A, we developed a spatially explicit, stochastic model of in vitro viral infection integrating virus and DIP replication, IFN signalling, and alternative dispersal modes. We find that: (1) our model captures the ring-like and patchy plaque morphologies observed experimentally; (2) IFN production peaks at an intermediate DIP ratio, reflecting a trade-off between early immune activation and sufficient co-infection; and (3) even a small fraction of long-range spread of virus and DIPs escape containment despite longer IFN ranges; this causes stronger antiviral responses but earlier peaks in lysis at similar levels of cell loss. The model is available as an interactive platform: https://shiny-spatial-infection-app-production.up.railway.app/.

systems biology↗

bioRxiv2025

Susceptible host dynamics explain pathogen resilience to perturbations

Interventions to slow the spread of SARS-CoV-2 significantly disrupted the transmission of other pathogens. As interventions lifted, whether and when human pathogens would eventually return to their pre-pandemic dynamics remains to be answered. Here, we present a framework for estimating pathogen resilience based on how fast epidemic patterns return to their pre-pandemic dynamics. By analyzing time series data from Hong Kong, Canada, Korea, and the US, we quantify the resilience of common respiratory pathogens and further predict when each pathogen will eventually return to its pre-pandemic dynamics. Our predictions are able to distinguish which pathogens should have returned already, and deviations from these predictions reveal long-term impacts of pandemic perturbations. We find a faster rate of susceptible replenishment underlies pathogen resilience and sensitivity to both large and small perturbations. Overall, our analysis highlights the persistent nature of common respiratory pathogens compared to vaccine-preventable infections, such as measles. Significance StatementCOVID-19 interventions slowed the transmission of many respiratory pathogens in different ways, raising questions about the mechanisms driving the variation in responses to interventions. To address this gap, we characterized the sensitivity of pathogen transmission to perturbations by quantifying how fast each pathogen returned to its pre-pandemic circulation patterns. We analyzed data from Hong Kong, Canada, Korea, and the US, and showed that common respiratory pathogens are far less sensitive to perturbations than measles, a vaccine-preventable infection. Finally, we showed that the speed of replenishment of the susceptible population--for example, through waning immunity--largely determines this sensitivity, suggesting that the persistence of common respiratory pathogens is likely driven by rapid susceptible replenishment.

ecology↗

bioRxiv2025

Drought dynamics explain once in a century yellow fever virus outbreak in Brazil with implications for climate change

While excess rainfall is associated with mosquito-borne disease because it sup-ports mosquito breeding, drought may also counterintuitively increase disease transmission by altering mosquito and host behavior. This phenomenon is important to understand because climate change is projected to increase both extreme rainfall and drought. In this study, we investigated the extent to which seasonally-driven mosquito and primate behavior drove the first yellow fever virus (YFV) epidemic in an urban area in Brazil in nearly a century, coinciding with an equally rare drought, and to assess the role of interventions in ending the outbreak. We hypothesized that drought triggered the outbreak by driving the forest mosquitoes and non-human primates towards the city in search of water and that the mosquitoes were biting more frequently to avoid desiccation. A dynamical YFV model supports these hypotheses, showing that both behavioral changes were needed to explain the outbreak timing and incidence. Fur-ther, a combination of vector control, conservation measures, and vaccination contributed to ending the outbreak, with the strongest effects from vaccination. Together, these results suggest that drought, likely to become more frequent in this region in the coming decades, can significantly influence mosquito-borne disease transmission, and that sustained control will require multiple interventions.

ecology↗

bioRxiv2024

A unified theory for predicting pathogen mutual invasibility and co-circulation

A key aim in the dynamics and control of infectious diseases is predicting competitive outcomes of pathogen interactions. Observed pathogen community structure indicates both considerable coexistence of related variants and spectacular instances of replacement, notably in seasonal influenza and SARS-CoV-2. However, an overall comparative quantitative framework for invasion and coexistence remains elusive. Inspired by modern ecological coexistence theory, we address this gap by developing pathogen invasion theory (PIT) and test the resulting framework against empirical systems. PIT predicts near-universal mutual invasibility across major pathogen systems, including seasonal influenza strains and SARS-CoV-2 variants. Predicting co-circulation from mutual invasibility further depends on the extent of overcompensatory susceptible depletion dynamics. Our analyses highlight the central role of immuno-epidemiological factors in determining pathogen coexistence and community structure.

ecology↗

bioRxiv2020

Interpreting pathogen genetic diversity during measles epidemics

While measles remains endemic in parts of the world, efforts to eliminate measles transmission continue, and viral sequence data may shed light on progress towards these goals. Genetic diversity has been used as a proxy for disease prevalence; however, seasonally-driven disease dynamics are typically characterized by deep population bottlenecks between epidemics, which severely disrupt the genetic signal. Here, we simulate measles metapopulation dynamics, and show that it is the population bottleneck, rather than epidemic size, which plays the largest role in observed pathogen diversity. While high levels of vaccination greatly reduces measles diversity, paradoxically, diversity increases with intermediate levels of vaccination, despite reducing incidence. We examined diversity and incidence using published data to compare our simulated outcomes with real observations, finding a significant relationship between harmonic mean incidence and genetic diversity. Our study demonstrates that caution should be taken when interpreting pathogen diversity, particularly for short-term, local dynamics.

evolutionary biology↗

bioRxiv2019

Comparison of alternative models of human movement and the spread of disease

Predictive models for the spatial spread of infectious diseases has received much attention in recent years as tools for the management of infectious diseas outbreaks. Prominently, various versions of the so-called gravity model, borrowed from transportation theory, have been used. However, the original literature suggests that the model has some potential misspecifications inasmuch as it fails to capture higher-order interactions among population centers. The fields of economics, geography and network sciences holds alternative formulations for the spatial coupling within and among conurbations. These includes Stouffers rank model, Fotheringhams competing destinations model and the radiation model of Simini et al. Since the spread of infectious disease reflects mobility through the filter of age-specific susceptibility and infectivity and since, moreover, disease may alter spatial behavior, it is essential to confront with epidemiological data on spread. To study their relative merit we, accordingly, fit variants of these models to the uniquely detailed dataset of prevaccination measles in the 954 cities and towns of England and Wales over the years 1944-65 and compare them using a consistent likelihood framework. We find that while the gravity model is a reasonable first approximation, both Stouffers rank model, an extended version of the radiation model and the Fotheringham competing destinations model provide significantly better fits, Stouffers model being the best. Through a new method of spatially disaggregated likelihoods we identify areas of relatively poorer fit, and show that it is indeed in densely-populated conurbations that higher order spatial interactions are most important. Our main conclusion is that it is premature to narrow in on a single class of models for predicting spatial spread of infectious disease. The supplemental materials contain all code for reproducing the results and applying the methods to other data sets. Author summaryThe ability to predict how infectious disease will spread is of great importance in the face of the numerous emergent and re-emergent pathogens that currently threatening human well-being. We identified a variety of alternative models that predict human mobility as as a function of population distribution across a landscape. These consider some models that account for pair-wise interactions between population centers, as well as some that allow for higher-order interactions. We trained the models using a uniquely rich spatiotemporal data set on pre-vaccination measles in England and wales (1944-65), which comprises more than a million records from 954 cities and towns. Likelihood rankings of the different models reveal strong evidence for higher-order interactions in the form of competition among cities as destinations for travelers and, thus, dilution of spatial transmission. The currently most commonly used so-called gravity models were far from the best in capturing spatial disease dynamics.

ecology↗

bioRxiv2019

Within-host dynamics of virulent viruses in bat reservoirs for emerging zoonotic disease

Bats host virulent zoonotic viruses without experiencing disease. A mechanistic understanding of the impact of bats virus hosting capacities, including uniquely constitutive immune pathways, on cellular-scale viral dynamics is needed to elucidate zoonotic emergence. We carried out virus infectivity assays on bat cell lines expressing induced and constitutive immune phenotypes, then developed a theoretical model of our in vitro system, which we fit to empirical data. Best fit models recapitulated expected immune phenotypes for representative cell lines, supporting robust antiviral defenses in bat cells that correlated with higher estimates for within-host viral propagation rates. In general, heightened immune responses limit pathogen-induced cellular morbidity, which can facilitate the establishment of rapidly-propagating persistent infections within-host. Rapidly-replicating viruses that have evolved with bat immune systems will likely cause enhanced virulence following emergence into secondary hosts with immune systems that diverge from those unique to bats.

ecology↗