Identifiability investigation of within-host models of acute virus infection.

Uncertainty in parameter estimates from fitting within-host models to empirical data limits the model's ability to uncover mechanisms of infection, disease progression, and to guide pharmaceutical interventions. Understanding the effect of model structure and data availability on model predictions is important for informing model development and experimental design. To address sources of uncertainty in parameter estimation, we use four mathematical models of influenza A infection with increased degrees of biological realism. We test the ability of each model to reveal its parameters in the presence of unlimited data by performing structural identifiability analyses. We then refine the results by predicting practical identifiability of parameters under daily influenza A virus titers alone or together with daily adaptive immune cell data. Using these approaches, we present insight into the sources of uncertainty in parameter estimation and provide guidelines for the types of model assumptions, optimal experimental design, and biological information needed for improved predictions.

The effect of model structure and data availability on Usutu virus dynamics at three biological scales.

Understanding the epidemiology of emerging pathogens, such as Usutu virus (USUV) infections, requires systems investigation at each scale involved in the host-virus transmission cycle, from individual bird infections, to bird-to-vector transmissions, and to USUV incidence in bird and vector populations. For new pathogens field data are sparse, and predictions can be aided by the use of laboratory-type inoculation and transmission experiments combined with dynamical mathematical modelling. In this study, we investigated the dynamics of two strains of USUV by constructing mathematical models for the within-host scale, bird-to-vector transmission scale and vector-borne epidemiological scale. We used individual within-host infectious virus data and per cent mosquito infection data to predict USUV incidence in birds and mosquitoes. We addressed the dependence of predictions on model structure, data uncertainty and experimental design. We found that uncertainty in predictions at one scale change predicted results at another scale. We proposed in silico experiments that showed that sampling every 12 hours ensures practical identifiability of the within-host scale model. At the same time, we showed that practical identifiability of the transmission scale functions can only be improved under unrealistically high sampling regimes. Instead, we proposed optimal experimental designs and suggested the types of experiments that can ensure identifiability at the transmission scale and, hence, induce robustness in predictions at the epidemiological scale.

Modeling within-host and aerosol dynamics of SARS-CoV-2: The relationship with infectiousness.

The relationship between transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the amount of virus present in the proximity of a susceptible host is not understood. Here, we developed a within-host and aerosol mathematical model and used it to determine the relationship between viral kinetics in the upper respiratory track, viral kinetics in the aerosols, and new transmissions in golden hamsters challenged with SARS-CoV-2. We determined that infectious virus shedding early in infection correlates with transmission events, shedding of infectious virus diminishes late in the infection, and high viral RNA levels late in the infection are a poor indicator of transmission. We further showed that viral infectiousness increases in a density dependent manner with viral RNA and that their relative ratio is time-dependent. Such information is useful for designing interventions.

Modeling the dynamics of Usutu virus infection in birds.

Usutu virus is an emerging zoonotic flavivirus causing high avian mortality rates and occasional severe neurological disorders in humans. Several virus strains are co-circulating and the differences in their characteristics and avian pathogenesis levels are still unknown. In this study, we use within-host mathematical models to characterize the mechanisms responsible for virus expansion and clearance in juvenile chickens challenged with four Usutu virus strains. We find heterogeneity between the virus strains, with the time between cell infection and viral production varying between 16 h and 23 h, the infected cell lifespan varying between 48 min and 9.5 h, and the basic reproductive number R0 varying between 12.05 and 19.49. The strains with high basic reproductive number have short infected cell lifespan, indicative of immune responses. The virus strains with low basic reproductive number have lower viral peaks and longer lasting viremia, due to lower infection rates and high infected cell lifespan. We discuss how the host and virus heterogeneities may differently impact the public health threat presented by these virus strains.

Pathogenesis and shedding of Usutu virus in juvenile chickens.

Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus that causes severe neuroinvasive disease in humans and has been implicated in the loss of breeding bird populations in Europe. USUV is maintained in an enzootic cycle between ornithophilic mosquitos and wild birds. As a member of the Japanese encephalitis serocomplex, USUV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both neuroinvasive arboviruses endemic in wild bird populations in the United States. An avian model for USUV is essential to understanding zoonotic transmission. Here we describe the first avian models of USUV infection with the development of viremia. Juvenile commercial ISA Brown chickens were susceptible to infection by multiple USUV strains with evidence of cardiac lesions. Juvenile chickens from two chicken lines selected for high (HAS) or low (LAS) antibody production against sheep red blood cells showed markedly different responses to USUV infection. Morbidity and mortality were observed in the LAS chickens, but not HAS chickens. LAS chickens had significantly higher viral titers in blood and other tissues, as well as oral secretions, and significantly lower development of neutralizing antibody responses compared to HAS chickens. Mathematical modelling of virus-host interactions showed that the viral clearance rate is a stronger mitigating factor for USUV viremia than neutralizing antibody response in this avian model. These chicken models provide a tool for further understanding USUV pathogenesis in birds and evaluating transmission dynamics between avian hosts and mosquito vectors.