Evidence for bistable bacteria-neutrophil interaction and its clinical implications
Roy Malka, Baruch Wolach, Ronit Gavrieli, Eliezer Shochat, Vered Rom-Kedar
Roy Malka, Baruch Wolach, Ronit Gavrieli, Eliezer Shochat, Vered Rom-Kedar
View: Text | PDF
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

×

Figure 2

Sign diagrams.

Options: View larger image (or click on image) Download as PowerPoint
Sign diagrams. At each initial experimental data point [B(0),N], we indi...
At each initial experimental data point [B(0),N], we indicate whether the final bacterial population in each of the 2 duplicates after 60 minutes has a larger or smaller value than the initial one (+ or O, respectively). As each initial data point corresponds to 2 experiments (duplicates; see Methods), 2 symbols are plotted for each point. Points with 2 different signs appear near the BNC, where small experimental deviations between the duplicates may lead to opposite outcomes. (A) A slanted line (here in log scale) divided the symbols better than a vertical line (n = 78). (B) S. epidermidis data (n = 34), adopted from ref. 10. (C and D) Addition of the BNC (black curve), determined from the fitted mathematical model of Equation 3 and Table 2 (the dashed BNC curve of Figure 1D in a logarithmic plot). The entire data set (n = 86) is presented in C, and the single subject P1 (n = 22) in D, with the extent of increase/decrease (i.e., magnitude of Y = log[B(60 minutes),N/B(0)]) shown by color. As expected, near the BNC, the rates were close to 0 (greenish symbols).