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

Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5·10 6 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 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 -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 1.19·10 6 cells/mL (phagocytosis) and 6.55·10 6 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 characterization of myelosuppressive drug effects and post-inoculation neutrophil influx into lungs, and by system differences (27% bacterial growth and 9.3% maximum velocity, compared to in vitro estimates). Predictions showed how therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5·10 6 cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 10 9 CFU/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.