Mechanistic modeling of Mycobacterium tuberculosis infection in murine models for drug and vaccine efficacy studies

Nan Zhang, Natasha Strydom, Sandeep Tyagi, Heena Soni, Rokeya Tasneen, Eric L. Nuermberger, Rada M. Savic

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Tuberculosis (TB) drug, regimen, and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics is essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection over time in BALB/c and athymic nude mice, which consisted of bacterial replication, bacterial death, and adaptive immune effects. The adaptive immune effect was best described by a sigmoidal function on both bacterial load and incubation time. Applications to demonstrate the utility of this baseline model showed (i) the important influence of the adaptive immune response on pyrazinamide (PZA) drug efficacy, (ii) a persistent adaptive immune effect in mice relapsing after chemotherapy cessation, and (iii) the protective effect of vaccines after M. tuberculosis challenge. These findings demonstrate the utility of our model for describing M. tuberculosis infection and corresponding adaptive immune dynamics for evaluating the efficacy of TB drugs, regimens, and vaccines.

Original languageEnglish (US)
Article numbere01727-19
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number3
DOIs
StatePublished - 2020

Keywords

  • Adaptive immunity
  • Drug discovery and development
  • Mechanistic modeling
  • Mouse model
  • Mycobacterium tuberculosis
  • Pyrazinamide
  • TB disease
  • Vaccine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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