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Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

ABSTRACT: Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 10⁶ cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacterial infections. A mathematical model for the in vitro dynamics of bacteria and the kinetics of neutrophil-mediated phagocytosis and digestion was developed, which was extended to in vivo studies in immune-competent and immune-compromised mice. Neutrophil-mediated bacterial killing was described by two first-order processes-phagocytosis and digestion-scaled by neutrophil concentration, where 50% of the maximum was achieved at neutrophil counts of 1.19 × 10⁶ cells/mL (phagocytosis) and 6.55 × 10⁶ cells/mL (digestion). The process efficiencies diminished as the phagocytosed bacteria to total neutrophils ratio increased (with 50% reduction at a ratio of 3.41). Neutrophil in vivo dynamics were captured through the characterization of myelosuppressive drug effects and postinoculation neutrophil influx into lungs and by system differences (27% bacterial growth and 9.3% maximum capacity, compared with in vitro estimates). Predictions showed how the therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5 × 10⁶ cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 10⁹ colony forming units/g lung). The model-based characterization of neutrophil-mediated bacterial killing simultaneously predicted data across in vitro and in vivo studies and may be used to inform the capacity of host-response at the individual level.

SUBMITTER: Thorsted A

PROVIDER: S-EPMC10725272 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

Thorsted Anders A Pham Anh Duc AD Friberg Lena E LE Nielsen Elisabet I EI

CPT: pharmacometrics & systems pharmacology 20231016 12

Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 10<sup>6</sup> cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacter ...[more]

PMID: 37700716

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Dataset Information

Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

Publications

Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

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