Bistability and Bacterial Infections

Bacterial infections occur when the natural host defenses are overwhelmed by invading bacteria. The main component of the host defense is impaired when neutrophil count or function is too low, putting the host at great risk of developing an acute infection. In people with intact immune systems, neutrophil count increases during bacterial infection. However, there are two important clinical cases in which they remain constant: a) in patients with neutropenic-associated conditions, such as those undergoing chemotherapy at the nadir (the minimum clinically observable neutrophil level); b) in ex vivo examination of the patient's neutrophil bactericidal activity. Here we study bacterial population dynamics under fixed neutrophil levels by mathematical modelling. We show that under reasonable biological assumptions, there are only two possible scenarios: 1) Bacterial behavior is monostable: it always converges to a stable equilibrium of bacterial concentration which only depends, in a gradual manner, on the neutrophil level (and not on the initial bacterial level). We call such a behavior type I dynamics. 2) The bacterial dynamics is bistable for some range of neutrophil levels. We call such a behavior type II dynamics. In the bistable case (type II), one equilibrium corresponds to a healthy state whereas the other corresponds to a fulminant bacterial infection. We demonstrate that published data of in vitro Staphylococcus epidermidis bactericidal experiments are inconsistent with both the type I dynamics and the commonly used linear model and are consistent with type II dynamics. We argue that type II dynamics is a plausible mechanism for the development of a fulminant infection

Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wound

Oscillatory hyperpolarizations and resting membrane potentials of mouse fibroblast and macrophage cell lines.

L cells (a mouse fibroblast cell line) and macrophages have been reported to exhibit slow oscillatory hyperpolarizations and relatively low membrane potentials, when measured with glass micro-electrodes. This paper describes the role of micro-electrode-induced leakage in these oscillations for L cells and a mouse macrophage cell line (P388D1). Both L cells and macrophages showed fast negative-going peak-shaped potential transients upon micro-electrode entry. This shows that the micro-electrode introduces a leakage conductance across the membrane. The peak values of these fast transients were less negative for L cells (-17 mV) than for macrophages (-39 mV), although their sustained resting membrane potentials were about equal (-13 mV). This indicates that the pre-impaled membrane potential of macrophages is more negative than that of L cells. Ionophoretic injection of Ca2+ into the P388D1 macrophages showed the existence of a Ca2+ -dependent hyperpolarizing conductance presumed to be involved in the oscillatory hyperpolarizations of L cells and macrophages. Cells increased in size by X-ray irradiation to reduce membrane input resistances were still found to be susceptible to micro-electrode-induced leakage. Impalement transients upon entry of a second electrode during a hyperpolarization evoked by a first electrode, were often step-shaped instead of peak-shaped due to the high membrane conductance associated with hyperpolarization. Since peak-shaped impalement transients were always seen with the first impalement both in oscillating and non-oscillating cells, oscillatory hyperpolarizations cannot be regarded as spontaneously occurring in the unperturbed cells but are induced by micro-electrode penetration. Since the hyperpolarizing response can be evoked by ionophoretic injection of Ca2+, and oscillatory as well as single hyperpolarizing responses are absent in a Ca2+ -free medium, it is concluded that the Ca2+ needed intracellularly to activate the hyperpolarizing responses enters the cell via the leakage pathway introduced by the measuring electrode