A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics during Influenza

Amber Smith, Amanda P. Smith

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

Original languageEnglish (US)
Article number38703
JournalScientific Reports
Volume6
DOIs
StatePublished - Dec 15 2016

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Influenza A virus
Alveolar Macrophages
Virus Diseases
Coinfection
Human Influenza
Viruses
Bacteria
Therapeutic Uses
Growth
Bacterial Infections
Morbidity
Phenotype
Mortality

All Science Journal Classification (ASJC) codes

  • General

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A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics during Influenza. / Smith, Amber; Smith, Amanda P.

In: Scientific Reports, Vol. 6, 38703, 15.12.2016.

Research output: Contribution to journalArticle

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