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 August 1, 2012; First 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 1

Bacteria versus neutrophils: 4 plausible behaviors.

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Bacteria versus neutrophils: 4 plausible behaviors. Red regions correspo...
Red regions correspond to experimental B and N concentrations that lead to an increase in the bacterial population (B locally wins); blue regions correspond to concentrations that lead to a decrease in the bacterial population (N locally wins). (A) Ratio-dependent models propose that the initial B/N ratio determines the result (6–8). (B) The neutrophil-threshold model proposes that a single neutrophil threshold exists, below which the bacterial population grows, and above which the bacterial population decreases (9, 10). (C) Monostable models propose that when the bacterial natural growth conditions are mild, the presence of neutrophils leads to a gradual decrease in the bacterial maximum capacity, down to extinction (11). (D) Bistable models propose that when the bacterial natural growth conditions are more favorable, the presence of neutrophils leads to bistable behavior (see Figure 1 in ref. 11). Here, we focused on the experimentally relevant region. The BNC (dashed and solid black curves) separates regions of bacterial growth from regions of bacterial decrease. Only in the bistable case (D) does the BNC have a positive slope, not conserving the B/N ratio.