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1. Quantifying relative virulence: when μ max fails and AUC alone just is not enough

   https://doi.org/10.1099/jgv.0.001515  

   Ceballos, Ruben Michael; Stacy, Carson Len (January 2021, Journal of General Virology)

   null (Ed.)

   A challenge in virology is quantifying relative virulence ( V R ) between two (or more) viruses that exhibit different replication dynamics in a given susceptible host. Host growth curve analysis is often used to mathematically characterize virus–host interactions and to quantify the magnitude of detriment to host due to viral infection. Quantifying V R using canonical parameters, like maximum specific growth rate ( μ max ), can fail to provide reliable information regarding virulence. Although area-under-the-curve (AUC) calculations are more robust, they are sensitive to limit selection. Using empirical data from Sulfolobus Spindle-shaped Virus (SSV) infections, we introduce a novel, simple metric that has proven to be more robust than existing methods for assessing V R . This metric ( I SC ) accurately aligns biological phenomena with quantified metrics to determine V R . It also addresses a gap in virology by permitting comparisons between different non-lytic virus infections or non-lytic versus lytic virus infections on a given host in single-virus/single-host infections. 

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2. Virulence evolution during a naturally occurring parasite outbreak

   https://doi.org/10.1007/s10682-022-10169-6  

   Gowler, Camden D.; Essington, Haley; O’Brien, Bruce; Shaw, Clara L.; Bilich, Rebecca W.; Clay, Patrick A.; Duffy, Meghan A. (January 2022, Evolutionary Ecology)

   Virulence, the degree to which a pathogen harms its host, is an important but poorly understood aspect of host-pathogen interactions. Virulence is not static, instead depending on ecological context and potentially evolving rapidly. For instance, at the start of an epidemic, when susceptible hosts are plentiful, pathogens may evolve increased virulence if this maximizes their intrinsic growth rate. However, if host density declines during an epidemic, theory predicts evolution of reduced virulence. Although well-studied theoretically, there is still little empirical evidence for virulence evolution in epidemics, especially in natural settings with native host and pathogen species. Here, we used a combination of field observations and lab assays in the Daphnia - Pasteuria model system to look for evidence of virulence evolution in nature. We monitored a large, naturally occurring outbreak of Pasteuria ramosa in Daphnia dentifera , where infection prevalence peaked at ~ 40% of the population infected and host density declined precipitously during the outbreak. In controlled infections in the lab, lifespan and reproduction of infected hosts was lower than that of unexposed control hosts and of hosts that were exposed but not infected. We did not detect any significant changes in host resistance or parasite infectivity, nor did we find evidence for shifts in parasite virulence (quantified by host lifespan and number of clutches produced by hosts). However, over the epidemic, the parasite evolved to produce significantly fewer spores in infected hosts. While this finding was unexpected, it might reflect previously quantified tradeoffs: parasites in high mortality (e.g., high predation) environments shift from vegetative growth to spore production sooner in infections, reducing spore yield. Future studies that track evolution of parasite spore yield in more populations, and that link those changes with genetic changes and with predation rates, will yield better insight into the drivers of parasite evolution in the wild. 

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3. Risk of death during acute infection is accelerating across diverse host-pathogen systems and consistent with multiple models of host-pathogen interaction

   https://doi.org/10.1128/msphere.00953-24  

   O'Sullivan, Tim; Karakoç, Canan; Wollein_Waldetoft, Kristofer; Brown, Sam P (May 2025, mSphere)

   Buchler, Nicolas E (Ed.)

   ABSTRACT Infectious diseases remain a major cause of global mortality, yet basic questions concerning the relationship between within-host processes governing pathogen burden (pathogen replication, immune responses) and population-scale (epidemiological) patterns of mortality remain obscure. We use a structured literature review to leverage the extensive biomedical data generated by controlled host infections to address the epidemiological question of whether infection-induced mortality is constant, accelerating, or follows some other pattern of change and to infer the within-host mechanistic basis of this pattern. We show that across diverse lethal infection models, the risk of death increases approximately exponentially in time since infection, in a manner phenomenologically similar to the dynamics of all-cause death. We further show that this pattern of accelerating risk is consistent with multiple alternate mechanisms of pathogen growth and host-pathogen interaction, underlining the limitations of current experimental approaches to connect within-host processes to epidemiological patterns. We review critical experimental questions that our work highlights, requiring additional non-invasive data on pathogen burden throughout the course of infection.IMPORTANCEHere, we ask a simple question: what are the dynamics of pathogen-induced death? Death is a central phenotype in both biomedical and epidemiological infectious disease biology, yet very little work has attempted to link the biomedical focus on pathogen dynamics within a host and the epidemiological focus on populations of infected hosts. To systematically characterize the dynamics of death in controlled animal infections, we analyzed 209 data sets spanning diverse lethal animal infection models. Across experimental models, we find robust support for an accelerating risk of death since the time of infection, contrasting with conventional epidemiological models that assume a constant elevated risk of death. Using math models, we show that multiple processes of growth and virulence are consistent with accelerating risk of death, and we end with a discussion of critical experiments to resolve how within-host biomedical processes map onto epidemiological patterns of disease. 

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4. An Adapted Optical Density-Based Microplate Assay for Characterizing Actinobacteriophage Infection

   https://doi.org/10.3791/65482  

   Christenson, Elijah I; Zhang, Qingyang; Plymale, Ruth (January 2023, Journal of Visualized Experiments)

   Bacteriophages are a key part of natural environments, and they have a powerful ability to shape bacterial populations. To understand how individual phages interact with slow-growing bacterial hosts such as actinomycetes, an easy and reliable method for quantifying long-term bacterial growth in the presence of phages is needed. Spectrophotometric microplate readers allow for high-throughput repeated measurements, but incubating a small volume for an extended time can present technical challenges. This procedure adapts a standard 96-well microplate to allow for the co-culturing of phages and bacteria without sub-sampling for 96 h, with the bacterial growth recorded every 8 h using spectrophotometric absorbance values. These optical density values are analyzed using R to yield infection metrics, including the percent growth inhibition, relative virulence, and the Stacy-Ceballos index. The methods outlined here provide an effective way to conduct and analyze extended- duration microplate growth curve experiments and includes modifications to reduce evaporation and lid condensation. These protocols facilitate microplate-based assays of interactions between slow-growing bacterial hosts and their bacteriophages. 

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5. Orthohantavirus Isolated in Reservoir Host Cells Displays Minimal Genetic Changes and Retains Wild-Type Infection Properties

   https://doi.org/10.3390/v12040457  

   Strandin, Tomas; Smura, Teemu; Ahola, Paula; Aaltonen, Kirsi; Sironen, Tarja; Hepojoki, Jussi; Eckerle, Isabella; Ulrich, Rainer G.; Vapalahti, Olli; Kipar, Anja; et al (April 2020, Viruses)

   Orthohantaviruses are globally emerging zoonotic pathogens. While the reservoir host role of several rodent species is well-established, detailed research on the mechanisms of host-othohantavirus interactions has been constrained by the lack of an experimental system that is able to effectively replicate natural infections in controlled settings. Here we report the isolation, and genetic and phenotypic characterization of a novel Puumala orthohantavirus (PUUV) in cells derived from its reservoir host, the bank vole. The isolation process resulted in cell culture infection that evaded antiviral responses, persisted cell passaging, and had minor viral genome alterations. Critically, experimental infections of bank voles with the new isolate resembled natural infections in terms of viral load and host cell distribution. When compared to an attenuated Vero E6 cell-adapted PUUV Kazan strain, the novel isolate demonstrated delayed virus-specific humoral responses. A lack of virus-specific antibodies was also observed during experimental infections with wild-type PUUV, suggesting that delayed seroconversion could be a general phenomenon during orthohantavirus infection in reservoir hosts. Our results demonstrate that orthohantavirus isolation on cells derived from a vole reservoir host retains wild-type infection properties and should be considered the method of choice for experimental infection models to replicate natural processes. 

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