Competition and dispersal in predator-prey waves

Dispersing predators and prey can exhibit complex spatio-temporal wave-like patterns if the interactions between them cause oscillatory dynamics. We study the effect of these predator-prey density waves on the competition between prey populations and between predator populations with different dispersal strategies. We first describe 1- and 2-dimensional simulations of both discrete and continuous predator-prey models. The results suggest that any population that diffuses faster, disperses farther, or is more likely to disperse will exclude slower diffusing, shorter dispersing, or less likely dispersing populations, everything else being equal. It also appears that it does not matter whether time, space, or state are discrete or continuous, nor what the exact interactions between the predators and prey are. So long as waves exist the competition between populations occurs in a similar fashion. We derive a theory that qualitatively explains the observed behaviour and calculate approximate analytical solutions that describe, to a reasonable extent, these behaviours. Predictions about the cost of dispersal are tested. If strong enough, cost can reverse the populations' relative competitive strengths or lead to coexistence because of the effect of spiral wave cores. The theory is also able to explain previous results of simulations of coexistence in host-parasitoid models (Comins, H. N., and Massell, M. P., 1996, J. Theor. Biol. 183, 19-28).     

Application of polymerase chain reaction (PCR) and TaqMan PCR techniques to the detection and identification of Rhodococcus coprophilus in faecal samples.

Rhodococcus coprophilus, a natural inhabitant of herbivore faeces, has been suggested as a good indicator of animal (as opposed to human) faecal contamination of aquatic environments. However, conventional detection methods limit its use for this as they require up to 21 days to obtain a result. In this paper an optimised method for extracting R. coprophilus DNA from faecal samples is described. PCR and 5'-nuclease (TaqMan) PCR methods were developed to allow the detection and enumeration of R. coprophilus in faecal samples within 2-3 days. Both PCR methods targeted the 16S rRNA gene, producing an amplicon of 443 bp which was specific for R. coprophilus. Sixty cells were required to produce an amplification product by conventional PCR, while as little as one cell was required for the TaqMan PCR method. The latter approach gave a linear quantitative response over at least four log units with both bacterial cells and DNA. Successful amplification by PCR was achieved using DNA extracted from cow, sheep, horse and deer faeces but was negative for samples from humans, pig, possum, duck and rabbit. These PCR methods enhance the feasibility of using R. coprophilus to distinguish faecal pollution of farmed herbivores from human pollution.     

Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation

The role played by resident macrophages (Mphi) in the initiation of peritoneal inflammation is currently unclear. We have used a conditional Mphi ablation strategy to determine the role of resident peritoneal Mphi in the regulation of neutrophil (PMN) recruitment in experimental peritonitis. We developed a novel conditional Mphi ablation transgenic mouse (designated CD11bDTR) based upon CD11b promoter-mediated expression of the human diphtheria toxin (DT) receptor. The murine DT receptor binds DT poorly such that expression of the human receptor confers toxin sensitivity. Intraperitoneal injection of minute (nanogram) doses of DT results in rapid and marked ablation of F4/80-positive Mphi populations in the peritoneum as well as the kidney, and ovary. In experimental peritonitis, resident Mphi ablation resulted in a dramatic attenuation of PMN infiltration that was rescued by the adoptive transfer of resident nontransgenic Mphi. Attenuation of PMN infiltration was associated with diminished CXC chemokine production at 1 h. These studies indicate a key role for resident peritoneal Mphi in sensing perturbation to the peritoneal microenvironment and regulating PMN infiltration.     

Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion

Macrophage interactions with apoptotic cells can suppress inflammatory responses, but cell death by apoptosis may also trigger inflammation. We now report that murine macrophages exposed to the combination of apoptotic cells and archetypal ligands for Toll-like receptors (TLRs) 2, 4, and 9 mount cytokine responses that differ importantly from those elicited by either class of stimulus alone. TLR ligands induced early and sustained secretion of TNF-alpha, macrophage-inflammatory protein (MIP) 1alpha and MIP-2 with later secretion of IL-10, IL-12, and TGF-beta1; apoptotic cells alone stimulated late TGF-beta1 secretion only. The combination of apoptotic cells and TLR ligands enhanced early secretion of TNF-alpha, MIP-1alpha, and MIP-2 and increased late TGF-beta1 secretion, while suppressing late TNF-alpha, IL-10, and Il-12 by mechanisms which could nevertheless be overridden by IFN-gamma. We propose that this combinatorial macrophage cytokine response to apoptotic cells and TLR ligands may contribute to recruitment and activation of innate immune defense when cell death occurs at infected inflamed sites while promoting later resolution with diminished engagement of adaptive immunity.     

Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death

Caspase-directed apoptosis usually fragments cells, releasing nonfunctional, prothrombogenic, membrane-bound apoptotic bodies marked for rapid engulfment by macrophages. Blood platelets are functional anucleate cells generated by specialized fragmentation of their progenitors, megakaryocytes (MKs), but committed to a constitutive caspase-independent death. Constitutive formation of the proplatelet-bearing MK was recently reported to be caspase-dependent, apparently involving mitochondrial release of cytochrome c, a known pro-apoptogenic factor. We extend those studies and report that activation of caspases in MKs, either constitutively or after Fas ligation, yields platelets that are functionally responsive and evade immediate phagocytic clearance, and retain mitochondrial transmembrane potential until constitutive platelet death ensues. Furthermore, the exclusion from the platelet progeny of caspase-9 present in the progenitor accounts for failure of mitochondrial release of cytochrome c to activate caspase-3 during platelet death. Thus, progenitor cell death by apoptosis can result in birth of multiple functional anucleate daughter cells.     

Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation

Dendritic cells (DCs) are the sentinels of the immune system, able to interact with both naive and memory T cells. The recent observation that DCs can ingest cells dying by apoptosis has raised the possibility that DCs may, in fact, present self-derived Ags, initiating both autoimmunity and tumor-specific responses, especially if associated with appropriate danger signals. Although the process of ingestion of apoptotic cells has not been shown to induce DC maturation, the exact fate of these phagocytosing DCs remains unclear. In this paper we demonstrate that DCs that ingest apoptotic cells are able to produce TNF-alpha but have a diminished ability to produce IL-12 in response to external stimuli, a property that corresponds to a failure to up-regulate CD86. By single-cell analysis we demonstrate that these inhibitory effects are restricted to those DCs that have engulfed apoptotic cells, with bystander DCs remaining unaffected. These changes were independent of the production of anti-inflammatory cytokines TGF-beta1 and IL-10 and corresponded with a diminished capacity to stimulate naive T cells. Thus, the ingestion of apoptotic cells is not an immunologically null event but is capable of modulating DC maturation. These results have important implications for our understanding of the role of clearance of dying cells by DCs not only in the normal resolution of inflammation but also in control of subsequent immune responses to apoptotic cell-derived Ags.     

Mathematical modelling of nitric oxide regulation of rete peg formation in psoriasis.

Recent experiments have shown that in patients with psoriasis, highly elevated levels of nitric oxide (NO) are released at the surface of psoriatic plaques. Nitric oxide is a central biological regulator of many aspects of physiology, and it is a natural possibility that the high nitric oxide levels in psoriasis play a causal role in the onset of the disease. Here, we use mathematical modelling to investigate this possibility. We begin by discussing a simple model consisting of a single equation for nitric oxide concentration, which enables nitric oxide secretion rates in the basal epidermis to be calculated from the observed NO release rates at the skin surface. Using this key parameter value, we then develop an extended model that tests the hypothesis that nitric oxide regulates the formation of the extended rete pegs seen in psoriatic plaques. This occurs via the peroxynitrite-dependent activation of the collagenase MMP-8, which is produced by neutrophils present at high levels in psoriatic plaques. The plausibility of the hypothesis is demonstrated and specific testable quantitative predictions about the roles of the various cell types and signalling molecules are made.     

Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux

ATP-binding cassette A1 (ABCA1) is a key mediator of cholesterol and phospholipid efflux to apolipoprotein particles. We show that ABCA1 is a constitutively phosphorylated protein in both RAW macrophages and in a human embryonic kidney cell line expressing ABCA1. Furthermore, we demonstrate that phosphorylation of ABCA1 is mediated by protein kinase A (PKA) or a PKA-like kinase in vivo. Through site-directed mutagenesis studies of consensus PKA phosphorylation sites and in vitro PKA kinase assays, we show that Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ApoA-I-dependent phospholipid efflux was decreased significantly by mutation of Ser-2054 alone and Ser-1042/Ser-2054 but was not significantly impaired with Ser-1042 alone. The mechanism by which ABCA1 phosphorylation affected ApoA-I-dependent phospholipid efflux did not involve either alterations in ApoA-I binding or changes in ABCA1 protein stability. These studies demonstrate a novel serine (Ser-2054) on the ABCA1 protein crucial for PKA phosphorylation and for regulation of ABCA1 transporter activity.     

A blast from the past: clearance of apoptotic cells regulates immune responses

Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.