General Host Defense Research Articles

Particulate matter impairs immune system function by up-regulating inflammatory pathways and decreasing pathogen response gene expression

Airborne particulate matter produced by industrial sources and automobiles has been linked to increased susceptibility to infectious diseases and it is known to be recognized by cells of the immune system. The molecular mechanisms and changes in gene expression profiles induced in immune cells by PM have not been fully mapped out or systematically integrated. Here, we use RNA-seq to analyze mRNA profiles of human peripheral blood mononuclear cells after exposure to coarse particulate matter (PM10). Our analyses showed that PM10 was able to reprogram the expression of 1,196 genes in immune cells, including activation of a proinflammatory state with an increase in cytokines and chemokines. Activation of the IL-36 signaling pathway and upregulation of chemokines involved in neutrophil and monocyte recruitment suggest mechanisms for inflammation upon PM exposure, while NK cell-recruiting chemokines are repressed. PM exposure also increases transcription factors associated with inflammatory pathways (e.g., JUN, RELB, NFKB2, etc.) and reduces expression of RNases and pathogen response genes CAMP, DEFAs, AZU1, APOBEC3A and LYZ. Our analysis across gene regulatory and signaling pathways suggests that PM plays a role in the dysregulation of immune cell functions, relevant for antiviral responses and general host defense against pathogens.

Chronic obstructive pulmonary disease and the risk for ventilator-associated pneumonia

To discuss recent data on the relationship between chronic obstructive pulmonary disease (COPD) and ventilator-associated pneumonia (VAP). Despite increased use of noninvasive ventilation, a large proportion of COPD patients still require invasive mechanical ventilation. Intubated COPD patients are at increased risk for VAP compared with patients without COPD. VAP is associated with increased mortality and duration of mechanical ventilation in these patients. Specific risk factors for VAP in this population include prolonged duration of invasive mechanical ventilation, high incidence of microaspiration and bacterial colonization, and altered local and general host defense mechanisms. Skeletal and diaphragmatic muscle weakness resulting from malnutrition, inflammation, and systemic corticosteroids is the main cause for prolonged mechanical ventilation. Increased risk for microaspiration of contaminated secretions is related to gastro-esophageal reflux, and altered interaction between breathing and deglutition. Defective mucociliary clearance contributes to a high incidence of respiratory tract colonization in these patients. Further, increasing evidence suggests that COPD is associated with immunosuppression promoting pulmonary infection. COPD is a risk factor for VAP. Future studies should focus on specific preventive measures in this population.

Autophagy Controls an Intrinsic Host Defense to Bacteria by Promoting Epithelial Cell Survival: A Murine Model

Cell death is a critical host response to regulate the fate of bacterial infections, innate immune responses, and ultimately, disease outcome. Shigella spp. invade and colonize gut epithelium in human and nonhuman primates but adult mice are naturally resistant to intra-gastric Shigella infection. In this study, however, we found Shigella could invade the terminal ileum of the mouse small intestine by 1 hour after infection and be rapidly cleared within 24 h. These early phase events occurred shortly after oral infection resulting in epithelial shedding, degranulation of Paneth cells, and cell death in the intestine. During this process, autophagy proceeded without any signs of inflammation. In contrast, blocking autophagy in epithelial cells enhanced host cell death, leading to tissue destruction and to inflammation, suggesting that autophagic flow relieves cellular stress associated with host cell death and inflammation. Herein we propose a new concept of “epithelial barrier turnover” as a general intrinsic host defense mechanism that increases survival of host cells and inhibits inflammation against enteric bacterial infections, which is regulated by autophagy.

The interaction of Theobroma cacao and Moniliophthora perniciosa, the causal agent of witches’ broom disease, during parthenocarpy

Witches’ broom disease of Theobroma cacao L. is caused by the hemibiotrophic basidiomycete Moniliophthora perniciosa. Infection of flower cushions by M. perniciosa results in parthenocarpy. Healthy and parthenocarpic immature cacao pods were obtained from seven cacao clones. Microscopic observations of parthenocarpic pods from two clones confirmed that fruits lack viable seed. Septate mycelia colonized parthenocarpic pods, but were absent from healthy pods. Parthenocarpic pods had increased concentrations of leucine, methionine, serine, phenylalanine, and valine. Major transport metabolites sucrose and asparagine were decreased by 63 and 40 %, respectively, during parthenocarpy. M. perniciosa expressed sequence tags (ESTs) related to detoxification (MpSOD2 and MpCTA1) and nutrient acquisition (MpAS, MpAK, MpATG8, MpPLY, and MpPME) were induced in parthenocarpic pods. Most M. perniciosa ESTs related to plant hormone biosynthesis were repressed (MpGAox, MpCPS, MpDES, MpGGPPS, and MpCAO) in parthenocarpic pods. RT-qPCR analysis was conducted for 54 defense-related cacao ESTs and 93 hormone-related cacao ESTs. Specific cacao ESTs related to plant defense were induced (TcPR5, TcChi4, TcThau-ICS) while others were repressed (TcPR1, TcPR6, TcP12, and TcChiB). Cacao ESTs related to GA biosynthesis (TcGA20OX1B) were repressed in parthenocarpic pods. Cacao ESTs putatively related to maintaining cytokinin (TcCKX3 and TcCKX5) and IAA (TcGH3.17a, TcGH3.1, TcARF18) homeostasis were induced in parthenocarpic pods, suggesting an attempt to regulate cytokinin and auxin concentrations. In conclusion, M. perniciosa expresses specific sets of transcripts targeting nutrient acquisition and survival while altering the host physiology without causing significant necrosis resulting in parthenocarpy. Only a general host defense response is elicited.

Quantitative resistance of potato to Pectobacterium atrosepticum and Phytophthora infestans: integrating PAMP-triggered response and pathogen growth.

While the mechanisms underlying quantitative resistance of plants to pathogens are still not fully elucidated, the Pathogen-Associated Molecular Patterns (PAMPs)-triggered response model suggests that such resistance depends on a dynamic interplay between the plant and the pathogen. In this model, the pathogens themselves or elicitors they produce would induce general defense pathways, which in turn limit pathogen growth and host colonisation. It therefore suggests that quantitative resistance is directly linked to a common set of general host defense mechanisms, but experimental evidence is still inconclusive. We tested the PAMP-triggered model using two pathogens (Pectobacterium atrosepticum and Phytophthora infestans) differing by their infectious processes and five potato cultivars spanning a range of resistance levels to each pathogen. Phenylalanine ammonia-lyase (PAL) activity, used as a defense marker, and accumulation of phenolics were measured in tuber slices challenged with lipopolysaccharides from P. atrosepticum or a concentrated culture filtrate from P. infestans. PAL activity increased following treatment with the filtrate but not with lipopolysaccharides, and varied among cultivars. It was positively related to tuber resistance to P. atrosepticum, but negatively related to tuber resistance to P. infestans. It was also positively related to the accumulation of total phenolics. Chlorogenic acid, the main phenolic accumulated, inhibited growth of both pathogens in vitro, showing that PAL induction caused active defense against each of them. Tuber slices in which PAL activity had been induced before inoculation showed increased resistance to P. atrosepticum, but not to P. infestans. Our results show that inducing a general defense mechanism does not necessarily result in quantitative resistance. As such, they invalidate the hypothesis that the PAMP-triggered model alone can explain quantitative resistance. We thus designed a more complex model integrating physiological host response and a key pathogen life history trait, pathogen growth, to explain the differences between the two pathosystems.

Corticosteroids in Dentistry

Glucocorticosteroids are used extensively in dentistry for their anti-inflammatory and immunosuppressive effects. Most of the diseases for which steroids are used are characterized by inflammation, which appears secondary to a hypersensitivity reaction against auto components. Glucocorticoids do not interfere with the primary disease mechanisms but they are used because of their anti-inflammatory and immunosuppressive effects. It seems reasonable to profit from steroids as palliatives in acute phases of the diseases and/or as long-term suppressors of the general host defense. The article deals with the use of corticosteroids in the treatment of the various conditions and diseases affecting oral cavity.

An Interferon-α-Induced Tethering Mechanism Inhibits HIV-1 and Ebola Virus Particle Release but Is Counteracted by the HIV-1 Vpu Protein

Type 1 interferon (IFN) inhibits the release of HIV-1 virus particles via poorly defined mechanisms. Here, we show that IFNalpha induces retention of viral particles on the surface of fibroblasts, T cells, or primary lymphocytes infected with HIV-1 lacking the Vpu protein. Retained particles are tethered to cell surfaces, can be endocytosed, appear fully assembled, exhibit mature morphology, and can be detached by protease. Strikingly, expression of the HIV-1 Vpu protein attenuates the ability of human cells to adhere to, and thereby retain, nascent HIV-1 particles upon IFNalpha treatment. Vpu also counteracts the IFNalpha-induced retention of virus-like particles assembled from the Ebola virus matrix protein. Furthermore, levels of IFNalpha that suppress replication of Vpu-defective HIV-1 have little effect on wild-type HIV-1. Thus, we propose that HIV-1 expresses Vpu to counteract an IFNalpha-induced, general host defense that inhibits dissemination of enveloped virions from the surface of infected cells.

Postoperative surgical site infections in cardiac surgery —an overview of preventive measures

Postoperative surgical site infections are a major cause of postoperative morbidity and mortality in cardiac surgery. A surgical site infection occurs when the contaminating pathogens overcome the host defense systems and an infectious process begins. Bacteria may enter the operating site either by direct contamination from the patient's skin or internal organs, through the hands and instruments of the surgical staff or by bacteria-carrying particles that float around in the operating theatre and may land in the wound. The ability to withstand the contaminating bacteria depends on both local and systemic host defense. Successful preventive strategies are multiple and must include: 1) Minimizing the bacterial contamination of the surgical site (skin preparation, operating room ventilation, scrubbing, double gloving, etc.), 2) Minimizing the consequences of virulent contaminating bacteria by antibiotic prophylaxis (adequate dose, sort, timing, duration), 3) Minimizing injury to local host defense (atraumatic surgery, no excessive electrocautery, meticulous hemostasis, etc.), and 4) Optimizing general host defense (nutrition, tobacco smoking, weight loss, etc.). Compliance with these preventive procedures must be enforced through regular reviews of performance. Non-compliance with hygiene routines is often due to ignorance and poor planning. Education of personnel in these issues is a continuous process.

Tamm-Horsfall Protein Acts as a General Host-Defense Factor against Bacterial Cystitis

Aims: Tamm-Horsfall protein (THP) is urine’s most abundant protein, but its biological function has remained elusive. Recently, THP-deficient (THP^–/–) mice were shown to have difficulty clearing Escherichia coli from the urinary bladder. It has remained unclear if interaction between THP and E. coli is specific for E. coli or if THP has a versatile ability to clear a variety of bacteria from the bladder, and act as a broad host-defense mechanism against urinary tract infection (UTI). In this study, we examined the role of THP as a protective factor against UTI caused by bacteria other than E. coli, namely Klebsiella pneumoniae and Staphylococcus saprophyticus by determining if the THP^–/– mouse has difficulty clearing these bacteria from its bladder. Methods: THP gene knockout mice were generated by the technique of homologous recombination. K. pneumoniae and S. saprophyticus were introduced transurethrally, in separate experiments, into the bladders of the THP^–/– and genetically similar wild-type (THP^+/+) mice. Urine was collected at periodic intervals and cultured to quantitate the degree of bacteriuria. Bladders were surgically removed and examined histomorphometrically to determine the intensity of inflammation. Results: Results showed that both with K. pneumoniae and with S. saprophyticus, the THP^–/– mice had more severe bacteriuria in comparison with THP^+/+ mice. The inflammatory changes in the bladder were also markedly more intense in THP^–/– mice with each of the bacterial species. Conclusions: These findings support the hypothesis that THP helps eliminate K. pneumoniae and S. saprophyticus from the urinary tract and acts as a general host-defense factor against UTI.

Targeting of Scavenger Receptor Class B Type I by Synthetic Amphipathic α-Helical-containing Peptides Blocks Lipopolysaccharide (LPS) Uptake and LPS-induced Pro-inflammatory Cytokine Responses in THP-1 Monocyte Cells

Human scavenger receptor class B type I, CLA-1, mediates lipopolysaccharide (LPS) binding and internalization (Vishnyakova, T. G., Bocharov, A. V., Baranova, I. N., Chen, Z., Remaley, A. T., Csako, G., Eggerman, T. L., and Patterson, A. P. (2003) J. Biol. Chem. 278, 22771-22780). Because one of the recognition motifs in SR-B1 ligands is the anionic amphipathic alpha-helix, we analyzed the effects of model amphipathic alpha-helical-containing peptides on LPS uptake and LPS-stimulated cytokine production. The L-37pA model peptide, containing two class A amphipathic helices, bound with high affinity (K(d) = 0.94 microg/ml) to CLA-1-expressing HeLa cells with a 10-fold increased capacity when compared with mock transfected HeLa cells. Both LPS and L-37pA colocalized with anti-CLA-1 antibody and directly bound CLA-1 as determined by cross-linking. SR-BI/CLA-1 ligands such as HDL, apoA-I, and L-37pA efficiently competed against iodinated L-37pA. Bacterial LPS, lipoteichoic acid, and hsp60 also competed against iodinated L-37pA. Model peptides blocked uptake of iodinated LPS in both mock transfected and CLA-1-overexpressing HeLa cells. Bound and internalized Alexa-L-37pA and BODIPY-LPS colocalized at the cell surface and perinuclear compartment. Both ligands were predominantly transported to the Golgi complex, colocalizing with the Golgi markers bovine serum albumin-ceramide, anti-Golgin97 antibody, and cholera toxin subunit B. A 100-fold excess of L-37pA nearly eliminated BODIPY-LPS binding and internalization. L-37pA and its d-amino acid analogue, D-37pA peptide were similarly effective in blocking LPS, Gram-positive bacterial wall component lipoteichoic acid and bacterial heat shock protein Gro-EL-stimulated cytokine secretion in THP-1 cells. In the same culture media used for the cytokine stimulation study, neither L-37pA nor D-37pA affected the Limulus amebocyte lysate activity of LPS, indicating that LPS uptake and cytokine stimulation were blocked independently of LPS neutralization. These results demonstrate that amphipathic helices of exchangeable apolipoproteins may represent a general host defense mechanism against inflammation.

Colonization and seasonality of goby (Gobiidae, Teleostei) parasites from the southwestern Baltic Sea

A comparative parasitology study of gobiid fishes from two sites on the western Baltic Sea was done to get information on the quality of the respective environments. The parameters used were the infracommunity, the species numbers and abundance with respect to the size classes of the hosts, and the abundance with respect to the seasons. The hosts, Gobius niger, Gobiusculus flavescens, Pomatoschistus minutus, and P. pictus, were caught at Blank Eck (Kiel Bight) and Dahmeshöved (Lübeck Bight) during 1992 and 1993. The infracommunities of Dahmeshöved attained higher rates of prevalence of helminth parasites than did those of Blank Eck, as was valid in all host specimens harboring one or two parasite species. The group bearing three parasite species was present in Dahmeshöved but absent in Blank Eck. Parasite species numbers, which were similar in the two sites, increased from the smallest to the largest hosts but changed with growth. With one exception, this result is also valid for the abundance, which clearly differed between the hosts and between the sites. Whereas species numbers as well as abundance rates were low in spring, they increased in summer. The results reveal that the composition of infracommunities depends on the local parasite fauna and on the strength of general host defense mechanisms, whereas that of the component community is dependent on the susceptibility of hosts to single parasite species and on the density of intermediate parasite stages. This is also the reason for the stronger infestation of hosts from Dahmeshöved as opposed to those from Blank Eck, where the degree of eutrophication is lower and, therefore, fewer herbivorous intermediate hosts can exist.

Variations in the VPg Protein Allow a Potyvirus to OvercomevaGene Resistance in Tobacco

Thevagene is used in commercial Burley tobacco cultivars including cv TN 86 to confer resistance to tobacco vein mottling virus (TVMV) and, to some extent, other potyviruses. A naturally occurring strain of TVMV (TVMV-S), which overcomes this resistance, was isolated from TN 86 plants. To investigate the mechanism by which TVMV-S overcomesvagene resistance, a cDNA clone encompassing the complete genome of TVMV-S was produced. Using chimeric transcripts combining regions of TVMV-S and regions of the wild-type strain (TVMV-WT) to which TN 86 is resistant, it was demonstrated that a domain within the VPg protein is responsible for overcomingvaresistance in TN 86. DNA sequence analysis revealed six amino acid differences between the two strains of TVMV within this domain. Inclusion of sequences for four of the TVMV-S VPg amino acids was sufficient to confer the resistance-overcoming phenotype to all corresponding transcripts. Coinoculation experiments suggested that the resistance of TN 86 to TVMV-WT was not due to the induction of a general host defense response. The results are compatible with the hypothesis that VPg must assume an appropriate configuration in order to interact with appropriate host components and facilitate systemic virus movement.

Peritoneal Dialysis in Liver Disorders

The purposes of this paper is to review the specific role of peritoneal dialysis (PD) in patients with liver disorders. We will pay attention to the confluence of liver diseases and situations for which chronic dialysis treatment is required. Hemodialysis (HD) and peritoneal membranes are safe barriers against the passage of the hepatitis C virus; consequently, while peritoneal effluent or HD ultrafiltrate drained from hepatitis B patients/carriers is infective, that from hepatitis C patients does not appear to present this risk. An important issue is horizontal transmission, which appears to occur with both viruses in HD units, and which is absent in peritoneal dialysis units. The incidence of hepatitis C among continuous ambulatory peritoneal dialysis (CAPD) patients is quite low, while it may reach almost 50%-60% of HD patients in some units. While hepatitis C transmission mechanisms are not completely understood and a vaccine is not available, PD provides some degree of protection when compared with HD, for and-stage renal disease patients. In summary, our experience and that of others, with a total of 19 PD-treated chronic liver disease patients, supports CAPD as the treatment of choice for cirrhotic patients with ascites who require chronic dialysis. Data on peritoneal diffusion of low molecular weight substances revealed a marked increase in most patients. The ultrafiltration capacity was clearly augmented with respect to noncirrhotic patients, making the use of hypertonic bags unnecessary. Hemodynamic tolerance was excellent. Complications and death were mainly related to liver disease complications. Spontaneous bacterial peritonitis (SBP), caused by gram-negative germs, is the most important complication directly related to ascites and may have some points in common with PD-related peritonitis. However, and in contrast to most PD peritonitis, two pathogenetic mechanisms have been suggested for SBP: (1) translocation of bacteria from the gut to the mesenteric lymph nodes, and (2) bacteremia in these patients is secondary to the general abnormal host defense mechanisms. Local factors such as intrahepatic shunting and the impairment of bactericidal activity in ascitic fluid favor the bacteria ascites. The hypothesis of a direct transmural contamination from bowel to ascitic fluid has been relegated to secondary bacterial peritonitis. Would cirrhotic patients with temporal or permanent renal function compromise benefit from peritoneal catheter placement and other PD practices to perform repetitive small ascitic drainages at home? Perhaps the time has arrived when hepatologists and PD nephrologists begin to work shoulder to shoulder in this particular field, as we have a common problem, the peritoneal cavity filled with fluid.

Rapid increase in plasma IL-6 after hemorrhage, and posthemorrhage reduction of the IL-6 response to LPS, in conscious rats: interrelation with plasma corticosterone levels.

To study whether hemorrhage stimulates interleukin-6 (IL-6) production in conscious rats, 30% of the total blood was withdrawn over 3 min through an indwelling venous catheter and the shedblood was reinfused 1 h later. Plasma adrenocorticotropic hormone (ACTH), corticosterone and IL-6 concentration rapidly increased. Plasma ACTH levels peaked at 10 min and corticosterone and IL-6 peaked at 60 min; all started to decrease after reinfusion. In adrenalectomized (ADX) rats with or without a corticosterone pellet implant, there was an inverse relationship between IL-6 and corticosterone concentrations, greatest in ADX rats and lowest in ADX rats in which plasma corticosterone was elevated by crushing the implanted pellet. However, the ADX rats in which plasma corticosterone was maintained at normal or slightly elevated levels showed greater IL-6 responses to hemorrhage and elevated basal plasma IL-6 levels compared to sham-operated control rats. Twenty-four hours after hemorrhage/reinfusion, ACTH, corticosterone, and IL-6 responses to i.v. injection of lipopolysaccharide (LPS) were all reduced compared to the non-hemorrhaged animals, indicating that hemorrhage impaired general host defense. Although very high plasma corticosterone concentrations markedly suppressed the IL-6 response to LPS, in ADX rats in which plasma corticosterone was maintained at slightly higher levels than normal, the reduced IL-6 response to LPS in the posthemorrhage period was not reversed, but enhanced. Thus corticosterone has biphasic effects on the IL-6 response to hemorrhage and the response to LPS during the posthemorrhage period, which has important clinical implications with regard to the optimal dose of glucocorticoid for maintaining the host defense response.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticosteroids and oral medicine.

The article deals with the use of glucocorticosteroids in the treatment of the oral manifestations of Systemic Lupus Erythematosus (SLE), Discoid Lupus Erythematosus (DLE), Rheumatoid Arthritis (RA) in the temporomandibular joint, Pemphigus Vulgaris, Pemphigoid, Erythema Multiforme Exudativum (EME), Lichen Planus (LP), and Recurrent Aphthous Ulcerations (RAU). The benefit from steroids is discussed on the basis of current knowledge of etiology and pathogenesis of the various disorders. All of them are characterized by inflammation which appears secondary to a hypersensitivity reaction against autocomponents. Glucocorticoids do not interfere with the primary disease mechanisms. But it is concluded from the literature, that because of anti-inflammatory and immunosuppressive effects of the hormones, it seems reasonable to profit from steroids as palliatives in acute phases of the diseases and/or as long-term suppressors of the general host defense.