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Biomedical subjects

David H Dockrell

Publications and source records attributed to David H Dockrell.

14 recordsLinked to original sources
PubMed2006

Streptococcus pneumoniae: the role of apoptosis in host defense and pathogenesis.

Programmed cell death or apoptosis is a recognised feature of infection with Streptococcus pneumoniae, and is observed during pneumococcal meningitis and pneumonia. The cholesterol-dependent cytolysin, pneumolysin, is a major trigger of apoptosis in the brain in association with pneumococcal production of hydrogen peroxide. Pneumococcal cell wall is also an important stimulus for apoptosis. Microbial factors and host factors combine in causing apoptosis in the brain, with hippocampal neurons being particularly susceptible. In pulmonary infection epithelial cell apoptosis contributes to tissue injury but macrophage apoptosis may benefit the host, aiding microbial killing and downregulating the inflammatory response. During sepsis lymphocyte apoptosis may be harmful to the host while dendritic cell apoptosis may limit the generation of an adaptive immune response during infection. Apoptosis induction may be harmful or potentially beneficial during pneumococcal infection and understanding its function in each setting is essential to allow specific therapeutic intervention.

Animals↗
PubMed2006

Regulation of phagocyte lifespan in the lung during bacterial infection.

The innate-immune response to infection is critically dependent on the antimicrobial actions of macrophages and neutrophils. Host and pathogen have evolved strategies to regulate immune-cell antimicrobial functions via alterations in cell death. Modulation of phagocyte death by bacteria is an important pathogenic mechanism. Host benefits of phagocyte apoptosis also exist, and understanding the mechanisms and consequences of apoptosis is essential before we can devise strategies to modulate this element of the innate-immune response to the host's benefit. This is of particular importance in an organ such as the lung, in which the balance between the need to recruit phagocytes to maintain bacterial sterility and the requirement to clear recruited cells from the alveolar units to preserve physiologic gas exchange must be finely tuned to ensure survival during bacterial infection. Apoptosis clearly plays a critical role in reconciling these physiological requirements.

Animals↗
PubMed2006

Granulocyte apoptosis in the pathogenesis and resolution of lung disease.

Apoptosis, programmed cell death, of neutrophil and eosinophil granulocytes is a potential control point in the physiological resolution of innate immune responses. There is also increasing evidence that cellular processes of apoptosis can be dysregulated by pathogens as a mechanism of immune evasion and that delayed apoptosis, resulting in prolonged inflammatory cell survival, is important in persistence of tissue inflammation. The identification of cell-type specific pathways to apoptosis may allow the design of novel anti-inflammatory therapies or agents to augment the innate immune responses to infection. This review will explore the physiological roles of granulocyte apoptosis and their importance in infectious and non-infectious lung disease.

Apoptosis↗
PubMed2005

Pyocyanin production by Pseudomonas aeruginosa induces neutrophil apoptosis and impairs neutrophil-mediated host defenses in vivo.

Clearance of neutrophils from inflamed sites is critical for resolution of inflammation, but pathogen-driven neutrophil apoptosis can impair host defenses. We previously showed that pyocyanin, a phenazine toxic metabolite produced by Pseudomonas aeruginosa, accelerates neutrophil apoptosis in vitro. We compared wild-type and pyocyanin-deficient strains of P. aeruginosa in a murine model of acute pneumonia. Intratracheal instillation of either strain of P. aeruginosa caused a rapid increase in bronchoalveolar lavage neutrophil counts up to 18 h after infection. In wild-type infection, neutrophil numbers then declined steadily, whereas neutrophil numbers increased up to 48 h in mice infected with pyocyanin-deficient P. aeruginosa. In keeping with these differences, pyocyanin production was associated with reduced bacterial clearance from the lungs. Neutrophil apoptosis was increased in mice infected with wild-type compared with the phenazine-deficient strain or two further strains that lack pyocyanin production, but produce other phenazines. Concentrations of potent neutrophil chemokines (MIP-2, KC) and cytokines (IL-6, IL-1beta) were significantly lower in wild-type compared with phenazine-deficient strain-infected mice at 18 h. We conclude that pyocyanin production by P. aeruginosa suppresses the acute inflammatory response by pathogen-driven acceleration of neutrophil apoptosis and by reducing local inflammation, and that this is advantageous for bacterial survival.

Animals↗
PubMed2005

Gamma interferon enhances internalization and early nonoxidative killing of Salmonella enterica serovar Typhimurium by human macrophages and modifies cytokine responses.

Gamma interferon (IFN-gamma) is a critical cytokine in host defense against salmonella infections, but its role in phagocytic killing of intracellular Salmonella spp. has been investigated mainly in animal rather than human cells. We measured the effect of recombinant IFN-gamma (rIFN-gamma) priming on bacterial internalization, intracellular killing, oxidative burst, and cytokine release during phagocytosis of Salmonella enterica serovar Typhimurium by human monocyte-derived macrophages (MDM). Eleven-day-old MDM, primed for 72 h with rIFN-gamma (100 ng/ml) exhibited an increased proportion of cells with associated bacteria (31% versus 26%, P = 0.036) and a 67% increase in internalized bacteria per cell compared to unprimed cells (P = 0.025). Retrieval of viable bacteria following internalization was reduced 3.6-fold in 72-h primed versus unprimed MDM (interquartile range, 3.1 to 6.4) at 0.5 h due to enhanced early intracellular killing, and this difference was maintained up to 24 h. In contrast, cells primed for only 24 h exhibited no increase in early killing. MDM were competent to produce an early oxidative burst when stimulated with phorbol myristate acetate, which was fully abrogated by the respiratory burst inhibitor diphenyleneiodonium chloride (DPI), but infection of MDM with S. enterica serovar Typhimurium did not cause an increase in the early respiratory burst under unprimed or primed conditions, and DPI had no effect on the early killing of bacteria by primed or unprimed MDM. During 24 h following infection, rIFN-gamma-primed MDM released more interleukin-12 (IL-12) and less IL-10 relative to unprimed cells. We conclude that 72-h priming with rIFN-gamma increases the efficiency of internalization and nonoxidative early intracellular killing of S. enterica serovar Typhimurium by human macrophages and modifies subsequent cytokine release.

Adult↗
PubMed2005

Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance.

Macrophages are critical effectors of bacterial clearance and must retain viability, despite exposure to toxic bacterial products, until key antimicrobial functions are performed. Subsequently, host-mediated macrophage apoptosis aids resolution of infection. The ability of macrophages to make this transition from resistance to susceptibility to apoptosis is important for effective host innate immune responses. We investigated the role of Mcl-1, an essential regulator of macrophage lifespan, in this switch from viability to apoptosis, using the model of pneumococcal-associated macrophage apoptosis. Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours. Subsequently, macrophages reduce expression of full-length Mcl-1 and upregulate a 34-kDa isoform of Mcl-1 corresponding to a novel BH3-only splice variant, Mcl-1(Exon-1). Change in expression of Mcl-1 protein is associated with mitochondrial membrane permeabilization, which is characterized by loss of mitochondrial inner transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor. Following pneumococcal infection, macrophages expressing full-length human Mcl-1 as a transgene exhibit a delay in apoptosis and in bacterial killing. Mcl-1 transgenic mice clear pneumococci from the lung less efficiently than nontransgenic mice. Dynamic changes in Mcl-1 expression determine macrophage viability as well as antibacterial host defense.

Alternative Splicing↗
PubMed2004

Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection.

Macrophages are resistant to constitutive apoptosis, but infectious stimuli can induce either microbial or host-mediated macrophage apoptosis. Phagocytosis and killing of opsonized pneumococci by macrophages are potent stimuli for host-mediated apoptosis, but the link between pneumococcal killing and apoptosis induction remains undefined. We now show phagocytosis of pneumococci by differentiated human monocyte-derived macrophages (MDM) results in up-regulation of inducible nitric oxide synthase (iNOS) and increased production of NO and reactive nitrogen species. NO accumulation in macrophages initiates an apoptotic program that involves NO-dependent mitochondrial membrane permeabilization, Mcl-1 down-regulation, and caspase activation and results in nuclear condensation and fragmentation. An inhibitor of mitochondrial permeability transition, bongkrekic acid, decreases pneumococcal-associated macrophage apoptosis. Conversely, inhibition of NO production using iNOS inhibitors decreases bacterial killing and shifts the cell death program from apoptosis to necrosis. Pneumolysin contributes to both NO production and apoptosis induction. After initial microbial killing, NO accumulation switches the macrophage phenotype from an activated cell to a cell susceptible to apoptosis. These results illustrate important roles for NO in the integration of host defense and regulation of inflammation in human macrophages.

Adult↗
PubMed2003

Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection.

The role of alveolar macrophages (AM) in host defense against pulmonary infection has been difficult to establish using in vivo models. This may reflect a reliance on models of fulminant infection. To establish a unique model of resolving infection, with which to address the function of AM, C57BL/6 mice received low-dose intratracheal administration of pneumococci. Administration of low doses of pneumococci produced a resolving model of pulmonary infection characterized by clearance of bacteria without features of pneumonia. AM depletion in this model significantly increased bacterial outgrowth in the lung. Interestingly, a significant increase in the number of apoptotic AM was noted with the low-dose infection as compared with mock infection. Caspase inhibition in this model decreased AM apoptosis and increased the number of bacteremic mice, indicating a novel role for caspase activation in pulmonary innate defense against pneumococci. These results suggest that AM play a key role in clearance of bacteria from the lung during subclinical infection and that induction of AM apoptosis contributes to the microbiologic host defense against pneumococci.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Streptococcus pneumoniae-associated human macrophage apoptosis after bacterial internalization via complement and Fcgamma receptors correlates with intracellular bacterial load.

Opsonization enhances Streptococcus pneumoniae-induced human monocyte-derived macrophage (MDM) apoptosis. Both depletion of complement and immunoglobulin from opsonizing serum and blockade of the macrophages CR1, CR3, FcgammaRII, and FcgammaRIII partially decreased MDM apoptosis after S. pneumoniae phagocytosis, and these effects correlated with reduced numbers of internalized bacteria. Chloramphenicol inhibition of protein synthesis by opsonized S. pneumoniae down-regulated subsequent MDM apoptosis. Phagocytosis of an unencapsulated mutant of S. pneumoniae resulted in increased MDM apoptosis, in association with enhanced internalization. Caspase inhibition was associated with decreased killing of bacteria. Enhanced induction of apoptosis by opsonized S. pneumoniae is the result of increased intracellular burden of bacteria, rather than of a specific pattern of engagement of complement receptor or FcgammaR. A dynamic interaction between live intracellular bacteria and the host cell is necessary for induction of apoptosis in MDMs, and induction of apoptosis contributes to the host defense against S. pneumoniae.

Apoptosis↗
PubMed2003

Acceleration of human neutrophil apoptosis by TRAIL.

Neutrophil granulocytes have a short lifespan, with their survival limited by a constitutive program of apoptosis. Acceleration of neutrophil apoptosis following ligation of the Fas death receptor is well-documented and TNF-alpha also has a transient proapoptotic effect. We have studied the role of the death receptor ligand TRAIL in human neutrophils. We identified the presence of mRNAs for TRAIL, TRAIL-R2, and TRAIL-R3, and cell surface expression of TRAIL-R2 and -R3 in neutrophil populations. Neutrophil apoptosis is specifically accelerated by exposure to a leucine zipper-tagged form of TRAIL, which mimics cell surface TRAIL. Using blocking Abs to TRAIL receptors, specifically TRAIL-R2, and a TRAIL-R1:FcR fusion protein, we have excluded a role for TRAIL in regulating constitutive neutrophil apoptosis. No additional proapoptotic effect of leucine zipper TRAIL was identified following TRAIL treatment of neutrophils in the presence of gliotoxin, an inhibitor of NF-kappaB, suggesting TRAIL does not activate NF-kappaB in human neutrophils. TRAIL treatment of human neutrophils did not induce a chemotactic response. The susceptibility of neutrophils to TRAIL-mediated apoptosis suggests a role for TRAIL in the regulation of inflammation and may provide a mechanism for clearance of neutrophils from sites of inflammation.

Apoptosis↗
PubMed2002

The burden of invasive pneumococcal disease and the potential for reduction by immunisation.

Streptococcus pneumoniae causes invasive disease world-wide and in all age groups. The reported incidence varies geographically and is increased in certain population groups. The incidence is highest in children less than 2 years and is also increased in the elderly. Mortality remains substantial even in the developed world despite appropriate antimicrobial therapy. The emergence of penicillin-resistant pneumococci highlights the importance of immunisation as a means to prevent disease. This review discusses the burden of invasive pneumococcal disease, identifies high-risk patients and analyses evidence for vaccine efficacy and cost-effectiveness.

Cost-Benefit Analysis↗
PubMed2002

Group G streptococcal bacteraemia: an opportunistic infection associated with immune senescence.

The number of cases of group G streptococcal bacteraemia reported worldwide is increasing. Twenty-six cases of group G streptococcal bacteraemia were identified during a 70-month period at a single university teaching hospital in Sheffield, UK. These cases represented 20% of all bacteraemias due to beta-hemolytic Streptococci, a higher proportion than previously reported. The median age of these cases was 72 y and although medical comorbidities were common only cutaneous ulceration was clearly linked to the presenting syndromes. The skin was the source of infection in 16 cases (62%) and the most frequent clinical presentations were cellulitis in 13 cases (50%) and endovascular infection in 5 (19%). Eight (31%) of the cases died during the period of follow-up but only 2 deaths were related to the streptococcal infection. Immunosenescence represents the major risk factor for group G streptococcal infection in this population and comorbidities, including carcinoma, may be markers of the senescent immune system rather than direct contributing factors to group G streptococcal bacteraemia.

Adult↗