Evidence for bistable bacteria-neutrophil interaction and its clinical implications
Roy Malka, … , Eliezer Shochat, Vered Rom-Kedar
Roy Malka, … , Eliezer Shochat, Vered Rom-Kedar
Published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):3002-3011. https://doi.org/10.1172/JCI59832.
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Research Article

Evidence for bistable bacteria-neutrophil interaction and its clinical implications

Abstract

Neutropenia, which may develop as a consequence of chemotherapy, increases the risk of bacterial infection. Similarly, increased risk of bacterial infection appears in disorders of phagocytic functions, such as the genetic disorder chronic granulomatous disease. To elucidate the organizing principles behind these distinct immunodeficiency conditions, we investigated the interaction between in vitro bacteria and human neutrophils by experiments and mathematical modeling. The model and the experiments showed that the in vitro bacterial dynamics exhibit bistability for a certain range of neutrophil concentration and function. Thus, there is a critical bacterial concentration above which infection develops, and below which neutrophils defeat the bacteria. Whereas with normal neutrophil concentration and function, an infection may develop when the initial bacterial concentration is very high, under neutropenic conditions or when there is neutrophil dysfunction, the critical bacterial concentration can be lower, within the clinically relevant range. We conclude that critical bacterial concentration has clinically relevant implications. The individual maximum bearable bacterial concentration depended on neutrophil concentration, phagocytic activity, and patient barrier integrity; thus, the resulting maximal bearable bacterial concentration may vary by orders of magnitude between patients. Understanding the interplay between neutrophils and bacteria may enhance the development of new therapeutic approaches to bacterial infections.

Authors

Roy Malka, Baruch Wolach, Ronit Gavrieli, Eliezer Shochat, Vered Rom-Kedar

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Figure 4

Evolution of infection in hypothetical patients during a 21-day cycle of chemotherapy-induced neutropenia.

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Evolution of infection in hypothetical patients during a 21-day cycle of...
(A) Hypothetical N with no G-CSF support (untreated) and with 10 daily injections (treated). Thresholds for neutropenia (1,000 × 103 neutrophils/ml) and severe neutropenia (500 × 103 neutrophils/ml) are shown by dashed and solid red lines, respectively. (B–D) Bacterial dynamics for 3 hypothetical patients with increasing bacterial influx (s). Hypothetical patients P1-treated and P4-treated received G-CSF support and thus had mild neutropenia. Their neutrophil functionality parameters are taken to be those of volunteers P1 and P4, respectively (see Table 2). Hypothetical patient P1-untreated did not receive G-CSF support and thus had severe neutropenia. His neutrophil functionality parameters are taken to be those of volunteer P1. (B) P1-treated could bear the 300-CFU/ml/h load, whereas for P4-treated and P1-untreated, this small s led to the development of acute infection. (C) With a more than 350-fold increase in s, P1-treated still succeeded in overcoming the infection. (D) With s increased 400-fold, all hypothetical patients developed an infection, regardless of G-CSF support.