scholarly journals Integrating mathematical models with experimental data to investigate the within-host dynamics of bacterial infections

2019 ◽  
Vol 77 (8) ◽  
Author(s):  
Myrto Vlazaki ◽  
John Huber ◽  
Olivier Restif
Keyword(s):  
Experimental Data ◽  
Mathematical Models ◽  
Bacterial Infections ◽  
Vaccine Development ◽  
Bacterial Colonization ◽  
Experimental Techniques ◽  
Efficient Design ◽  
Mortality And Morbidity ◽  
Bacterial Dynamics

ABSTRACT Bacterial infections still constitute a major cause of mortality and morbidity worldwide. The unavailability of therapeutics, antimicrobial resistance and the chronicity of infections due to incomplete clearance contribute to this phenomenon. Despite the progress in antimicrobial and vaccine development, knowledge about the effect that therapeutics have on the host–bacteria interactions remains incomplete. Insights into the characteristics of bacterial colonization and migration between tissues and the relationship between replication and host- or therapeutically induced killing can enable efficient design of treatment approaches. Recently, innovative experimental techniques have generated data enabling the qualitative characterization of aspects of bacterial dynamics. Here, we argue that mathematical modeling as an adjunct to experimental data can enrich the biological insight that these data provide. However, due to limited interdisciplinary training, efforts to combine the two remain limited. To promote this dialogue, we provide a categorization of modeling approaches highlighting their relationship to data generated by a range of experimental techniques in the area of in vivo bacterial dynamics. We outline common biological themes explored using mathematical models with case studies across all pathogen classes. Finally, this review advocates multidisciplinary integration to improve our mechanistic understanding of bacterial infections and guide the use of existing or new therapies.

scholarly journals Modeling Amantadine Treatment of Inuenza A Virus In Vitro

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
James J. McSharry ◽  
George L. Drusano ◽  
Jack T. Nguyen ◽  
Gregory T. Went ◽  
...  
Keyword(s):  
Experimental Data ◽  
Viral Infection ◽  
Mathematical Models ◽  
Influenza A ◽  
Mdck Cells ◽  
Rapid Development ◽  
Human Model ◽  
Parameter Estimates

We analyzed the dynamics of an influenza A/Albany/1/98 (H3N2) viral infection, using a set of mathematical models highlighting the differences between in vivo and in vitro infection. For example, we found that including virion loss due to cell entry was critical for the in vitro model but not for the in vivo model. Experiments were performed on influenza virus-infected MDCK cells in vitro inside a hollow-fiber (HF) system, which was used to continuously deliver the drug amantadine. The HF system captures the dynamics of an influenza infection, and is a controlled environment for producing experimental data which lend themselves well to mathematical modeling. The parameter estimates obtained from fitting our mathematical models to the HF experimental data are consistent with those obtained earlier for a primary infection in a human model. We found that influenza A/Albany/1/98 (H3N2) virions under normal experimental conditions at 37°C rapidly lose infectivity with a half-life of ~ 6.6 ± 0.2 h, and that the lifespan of productively infected MDCK cells is ~ 13 h. Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is ~ 74%, and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.

scholarly journals Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Xiang Liu ◽  
Ali Zaid ◽  
Joseph R. Freitas ◽  
Nigel A. McMillan ◽  
Suresh Mahalingam ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Infectious Clone ◽  
Basic Research ◽  
Clinical Disease ◽  
Lung Pathology ◽  
Reverse Genetic ◽  
Preclinical Development ◽  
Mortality And Morbidity ◽  
Infectious Clones

ABSTRACT Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit’s value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.

scholarly journals Finafloxacin, a Novel Fluoroquinolone, Reduces the Clinical Signs of Infection and Pathology in a Mouse Model of Q Fever

2021 ◽  
Vol 12 ◽  
Author(s):  
M. Gill Hartley ◽  
Isobel H. Norville ◽  
Mark I. Richards ◽  
Kay B. Barnes ◽  
Kevin R. Bewley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bacterial Infections ◽  
Standard Treatment ◽  
Q Fever ◽  
Bacterial Colonization ◽  
Clinical Signs ◽  
Histopathological Analysis ◽  
Antibiotic Efficacy ◽  
First Time

Finafloxacin is a novel fluoroquinolone with optimal antibacterial activity in low pH environments, therefore offering a therapeutic advantage over some traditional antibiotics, in treating bacterial infections associated with acidic foci. Coxiella burnetii, the causative agent of Q fever, is a bacterium which resides and replicates in acidic intracellular parasitic vacuoles. The efficacy of finafloxacin was evaluated in vivo using the A/J mouse model of inhalational Q fever and was compared to doxycycline, the standard treatment for this infection and ciprofloxacin, a comparator fluoroquinolone. Finafloxacin reduced the severity of the clinical signs of infection and weight loss associated with Q fever, but did not reduce the level of bacterial colonization in tissues compared to doxycycline or ciprofloxacin. However, histopathological analysis suggested that treatment with finafloxacin reduced tissue damage associated with C. burnetii infection. In addition, we report for the first time, the use of viable counts on axenic media to evaluate antibiotic efficacy in vivo.

scholarly journals Modeling Amantadine Treatment of Inuenza A Virus In Vitro

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
James J. McSharry ◽  
George L. Drusano ◽  
Jack T. Nguyen ◽  
Gregory T. Went ◽  
...  
Keyword(s):  
Experimental Data ◽  
Viral Infection ◽  
Mathematical Models ◽  
Influenza A ◽  
Mdck Cells ◽  
Rapid Development ◽  
Human Model ◽  
Parameter Estimates

We analyzed the dynamics of an influenza A/Albany/1/98 (H3N2) viral infection, using a set of mathematical models highlighting the differences between in vivo and in vitro infection. For example, we found that including virion loss due to cell entry was critical for the in vitro model but not for the in vivo model. Experiments were performed on influenza virus-infected MDCK cells in vitro inside a hollow-fiber (HF) system, which was used to continuously deliver the drug amantadine. The HF system captures the dynamics of an influenza infection, and is a controlled environment for producing experimental data which lend themselves well to mathematical modeling. The parameter estimates obtained from fitting our mathematical models to the HF experimental data are consistent with those obtained earlier for a primary infection in a human model. We found that influenza A/Albany/1/98 (H3N2) virions under normal experimental conditions at 37°C rapidly lose infectivity with a half-life of ~ 6.6 ± 0.2 h, and that the lifespan of productively infected MDCK cells is ~ 13 h. Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is ~ 74%, and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.

scholarly journals An experimental design tool to optimize inference precision in data-driven mathematical models of bacterial infections in vivo

2020 ◽  
Vol 17 (173) ◽  
pp. 20200717
Author(s):  
Myrto Vlazaki ◽  
David J. Price ◽  
Olivier Restif
Keyword(s):  
Experimental Design ◽  
Mathematical Models ◽  
High Precision ◽  
Bacterial Infections ◽  
Parameter Estimate ◽  
Fixed Number ◽  
Inoculum Size ◽  
Design Tool ◽  
Detailed Knowledge

The management of bacterial diseases calls for a detailed knowledge about the dynamic changes in host–bacteria interactions. Biological insights are gained by integrating experimental data with mechanistic mathematical models to infer experimentally unobservable quantities. This inter-disciplinary field would benefit from experiments with maximal information content yielding high-precision inference. Here, we present a computationally efficient tool for optimizing experimental design in terms of parameter inference in studies using isogenic-tagged strains. We study the effect of three experimental design factors: number of biological replicates, sampling timepoint selection and number of copies per tagged strain. We conduct a simulation study to establish the relationship between our optimality criterion and the size of parameter estimate confidence intervals, and showcase its application in a range of biological scenarios reflecting different dynamics patterns observed in experimental infections. We show that in low-variance systems with low killing and replication rates, predicting high-precision experimental designs is consistently achieved; higher replicate sizes and strategic timepoint selection yield more precise estimates. Finally, we address the question of resource allocation under constraints; given a fixed number of host animals and a constraint on total inoculum size per host, infections with fewer strains at higher copies per strain lead to higher-precision inference.

Integrating experimental data and mathematical models in simulation of physical systems

AIAA Journal ◽  
1997 ◽  
Vol 35 ◽  
pp. 1787-1790
Author(s):  
Boris A. Zeldin ◽  
Andrew J. Meade
Keyword(s):  
Experimental Data ◽  
Mathematical Models ◽  
Physical Systems

Ethanol Extract Of Centella Asiatica (L.) Urban Leaves Effectively Inhibit Streptococcus pyogenes and Pseudomonas aeruginosa by Invitro Test

2020 ◽  
Vol 2 (2) ◽  
pp. 69-76
Author(s):  
Dini Aulia Azmi ◽  
Nurlailah Nurlailah ◽  
Ratih Dewi Dwiyanti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Streptococcus Pyogenes ◽  
Bacterial Infections ◽  
Herbal Medicines ◽  
Centella Asiatica ◽  
Ethanol Extract ◽  
Dilution Method ◽  
Initial Stage ◽  
Independent Variable

Streptococcus pyogenes and Pseudomonas aeruginosa are some of the causes of infectious diseases. Centella asiatica (L.) Urban has many benefits for humans, including overcoming fever, anti-bacterial, and anti-inflammatory. This study aims to determine the inhibition of Centella asiatica (L.) Urban leaves ethanol extract on the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. This research is the initial stage of the development of herbal medicines to treat Streptococcus pyogenes and Pseudomonas aeruginosa infections. The independent variable was the concentration of ethanol extract of Centella asiatica (L.) Urban leaves and the dependent variable was the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. The anti-bacterial activity test was carried out by the liquid dilution method. The concentrations used are 20%, 40%, 60%, 80%. 100% The results showed that the minimum inhibitory concentration (MIC) against Streptococcus pyogenes: 40% and Pseudomonas aeruginosa: 40%. Minimum bactericidal concentration (MBC) results for Streptococcus pyogenes: 60% and Pseudomonas aeruginosa: 60%. So it can be concluded that there is inhibition of the ethanol extract of Centella asiatica (L.) Urban leaves on the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. Centella Asiatica (L.) Urban extract has potential as herbal medicine against bacterial infections but requires further research to determine its effect in vivo.

Garlic Extract (Allium sativum L.) Effectively Inhibits Staphylococcus aureus and Escherichia coli by Invitro Test

2020 ◽  
Vol 2 (2) ◽  
pp. 61-68
Author(s):  
Agnina Listya Anggraini ◽  
Ratih Dewi Dwiyanti ◽  
Anny Thuraidah
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Allium Sativum ◽  
Antibacterial Properties ◽  
Herbal Medicines ◽  
Garlic Extract ◽  
Dilution Method ◽  
Initial Stage

Infection is a disease caused by the presence of pathogenic microbes, including Staphylococcus aureus and Escherichia coli. Garlic (Allium sativum L.) has chemical contents such as allicin, alkaloids, flavonoids, saponins, tannins, and steroids, which can function as an antibacterial against Staphylococcus aureus and Escherichia coli. This study aims to determine the antibacterial properties of garlic extract powder against Staphylococcus aureus and Escherichia coli. This research is the initial stage of the development of herbal medicines to treat Staphylococcus aureus and Escherichia coli infections. The antibacterial activity test was carried out by the liquid dilution method. The concentrations used were 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL and 70 mg/mL. The results showed that the Minimum Inhibitory Concentration (MIC) against Staphylococcus aureus and Escherichia coli was 40 mg/mL and 50 mg / mL. Minimum Bactericidal Concentration (MBC) results for Staphylococcus aureus and Escherichia coli are 50 mg/mL and 70 mg/mL. Based on the Simple Linear Regression test, the R2 value of Staphylococcus aureus and Escherichia coli is 0.545 and 0.785, so it can be concluded that there is an effect of garlic extract powder on the growth of Staphylococcus aureus and Escherichia coli by 54.5% and 78.5%. Garlic (Allium sativum L.) extract powder has potential as herbal medicine against bacterial infections but requires further research to determine its effect in vivo.

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