The impact of cell regeneration on the dynamics of viral coinfection

Pinky, Lubna; Dobrovolny, Hana M.

doi:10.1063/1.4985276

Cited by 13 publications

(14 citation statements)

References 68 publications

(103 reference statements)

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“…The models suggested that chronic illness is possible only with one viral species. Coexistence of multiple viruses in chronic conditions is unlikely to occur if the regeneration model is considered (465).…”

Section: Mathematical Models Of Viral Coinfectionsmentioning

confidence: 99%

Virological and Immunological Outcomes of Coinfections

et al. 2018

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SUMMARYCoinfections involving viruses are being recognized to influence the disease pattern that occurs relative to that with single infection. Classically, we usually think of a clinical syndrome as the consequence of infection by a single virus that is isolated from clinical specimens. However, this biased laboratory approach omits detection of additional agents that could be contributing to the clinical outcome, including novel agents not usually considered pathogens. The presence of an additional agent may also interfere with the targeted isolation of a known virus. Viral interference, a phenomenon where one virus competitively suppresses replication of other coinfecting viruses, is the most common outcome of viral coinfections. In addition, coinfections can modulate virus virulence and cell death, thereby altering disease severity and epidemiology. Immunity to primary virus infection can also modulate immune responses to subsequent secondary infections. In this review, various virological mechanisms that determine viral persistence/exclusion during coinfections are discussed, and insights into the isolation/detection of multiple viruses are provided. We also discuss features of heterologous infections that impact the pattern of immune responsiveness that develops.

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Section: Mathematical Models Of Viral Coinfectionsmentioning

confidence: 99%

Virological and Immunological Outcomes of Coinfections

et al. 2018

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“…In this paper, we have shown that superinfection can result in chronic coinfection if cell regeneration is also considered in the model. Our previous work showed that while cell regeneration is necessary for producing chronic infection, it is not sufficient for chronic coinfections ( Pinky and Dobrovolny, 2017 ). This work shows that superinfection alone is also not sufficient for chronic coinfections.…”

Section: Discussionmentioning

confidence: 66%

“…Previously, we tested the mechanism of target cell replenishment in the basic coinfection model ( Pinky and Dobrovolny, 2016 ) and confirmed that addition of a renewable supply of cells was necessary for chronic infection. However, that model could not produce long-lasting infections with both viruses ( Pinky and Dobrovolny, 2017 ). The basic coinfection model did not consider superinfection mechanism, so here we aim to determine whether allowing single cells to be infected by both viruses (superinfection) can lead to chronic coinfection.…”

Section: Resultsmentioning

confidence: 99%

“…As some studies have shown that coinfection is associated with long-lasting disease ( Aberle et al, 2005;Choi et al, 2015;Costa et al, 2014;Martin et al, 2013;Mazur et al, 2017 ), we extend our model to be more biologically relevant and at the same time to examine possible mechanisms for chronic disease conditions. Our previous study exploring the effect of cell regeneration in coinfection models indicated that cell regeneration alone could lead to chronic infection, but only with a single virus ( Pinky and Dobrovolny, 2017 ). Here, we will explore the phenomenon of superinfection, where a single cell can be infected by both types of viruses at the same time, both with and without constant regeneration of cells and cell death.…”

Section: Methodsmentioning

confidence: 99%

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Superinfection and cell regeneration can lead to chronic viral coinfections

Pinky

González-Parra

Dobrovolny

2019

Journal of Theoretical Biology

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a b s t r a c tMolecular diagnostic techniques have revealed that approximately 43% of the patients hospitalized with influenza-like illness are infected by more than one viral pathogen, sometimes leading to long-lasting infections. It is not clear how the heterologous viruses interact within the respiratory tract of the infected host to lengthen the duration of what are usually short, self-limiting infections. We develop a mathematical model which allows for single cells to be infected simultaneously with two different respiratory viruses (superinfection) to investigate the possibility of chronic coinfections. We find that a model with superinfection and cell regeneration has a stable chronic coinfection fixed point, while superinfection without cell regeneration produces only acute infections. This analysis suggests that both superinfection and cell regeneration are required to sustain chronic coinfection via this mechanism since coinfection is maintained by superinfected cells that allow slow-growing infections a chance to infect cells and continue replicating. This model provides a possible mechanism for chronic coinfection independent of any viral interactions via the immune response.

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“…Among them, Pinilla et al [24] and Petrie et al [25] used their models to study competitive mixed-infection experiments of pandemic A/H1N1 influenza with its H275Y mutant strain and Simeonov et al [26] considered a spatiotemporal model to explain in vitro cellular susceptibility due to the simultaneous presence of RSV A2 and RSV B. Pinky and Dobrovolny [27] proposed a two virus coinfection model to investigate viral interference observed in an experimental study of IAV-RSV coinfection (Shinjoh et al [28]) where they concluded that distinct viruses interact through resource competition. In further investigations [29,30], they used the model to quantify the impact of resource availability, finding the possibility of chronic single infection if constant cellular regeneration was considered and chronic coinfection if both cellular regeneration and superinfection were considered. However, the majority of the two virus models studied so far have focused on the deterministic approach that reproduces the average behavior of infection kinetics.…”

Section: Introductionmentioning

confidence: 99%

Effect of stochasticity on coinfection dynamics of respiratory viruses

2019

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Background Respiratory viral infections are a leading cause of mortality worldwide. As many as 40% of patients hospitalized with influenza-like illness are reported to be infected with more than one type of virus. However, it is not clear whether these infections are more severe than single viral infections. Mathematical models can be used to help us understand the dynamics of respiratory viral coinfections and their impact on the severity of the illness. Most models of viral infections use ordinary differential equations (ODE) that reproduce the average behavior of the infection, however, they might be inaccurate in predicting certain events because of the stochastic nature of viral replication cycle. Stochastic simulations of single virus infections have shown that there is an extinction probability that depends on the size of the initial viral inoculum and parameters that describe virus-cell interactions. Thus the coinfection dynamics predicted by the ODE might be difficult to observe in reality. Results In this work, a continuous-time Markov chain (CTMC) model is formulated to investigate probabilistic outcomes of coinfections. This CTMC model is based on our previous coinfection model, expressed in terms of a system of ordinary differential equations. Using the Gillespie method for stochastic simulation, we examine whether stochastic effects early in the infection can alter which virus dominates the infection. Conclusions We derive extinction probabilities for each virus individually as well as for the infection as a whole. We find that unlike the prediction of the ODE model, for similar initial growth rates stochasticity allows for a slower growing virus to out-compete a faster growing virus. Electronic supplementary material The online version of this article (10.1186/s12859-019-2793-6) contains supplementary material, which is available to authorized users.

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The impact of cell regeneration on the dynamics of viral coinfection

Cited by 13 publications

References 68 publications

Virological and Immunological Outcomes of Coinfections

Virological and Immunological Outcomes of Coinfections

Superinfection and cell regeneration can lead to chronic viral coinfections

Effect of stochasticity on coinfection dynamics of respiratory viruses

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