Modify Host Responses Research Articles

Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression.

Most studies using murine disease models are conducted at housing temperatures (20 - 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 - 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted experiments to determine: (1) the inflammatory response to malarial agents injection in a peritonitis model and (2) disease progression in PbA-infected mice at TT compared to ST. In one study, acclimatized mice were injected intraperitoneally with native hemozoin (nHZ) or Leishmania at TT (28 - 31°C) or ST, and immune cells, cytokine, and extracellular vesicle (EV) profiles were determined from the peritoneal cavity (PEC) fluid. In another study, PbA-infected mice were monitored until end-point (i.e. experimental malaria score ≥4). We found that Leishmania injection resulted in decreased cell recruitment and higher phagocytosis of nHZ in mice housed at TT. We found 398 upregulated and 293 downregulated proinflammatory genes in mice injected with nHZ, at both temperatures. We report the presence of host-derived EVs never reported before in a murine parasitic murine model at both temperatures. We observed metabolic changes in mice housed at TT, but these did not result to noticeable changes in disease progression compared to ST. To our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. We found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations.

The coral microbiome: Towards an understanding of the molecular mechanisms of coral-microbiota interactions.

Corals live in a complex, multi-partite symbiosis with diverse microbes across kingdoms, some of which are implicated in vital functions, such as those related to resilience against climate change. However, knowledge gaps and technical challenges limit our understanding of the nature and functional significance of complex symbiotic relationships within corals. Here, we provide an overview of the complexity of the coral microbiome focusing on taxonomic diversity and functions of well-studied and cryptic microbes. Mining the coral literature indicate that while corals collectively harbor a third of all marine bacterial phyla, known bacterial symbionts and antagonists of corals represent a minute fraction of this diversity and that these taxa cluster into select genera, suggesting selective evolutionary mechanisms enabled these bacteria to gain a niche within the holobiont. Recent advances in coral microbiome research aimed at leveraging microbiome manipulation to increase coral's fitness to help mitigate heat stress-related mortality are discussed. Then, insights into the potential mechanisms through which microbiota can communicate with and modify host responses are examined by describing known recognition patterns, potential microbially-derived coral epigenome effector proteins and coral gene regulation. Finally, the power of omics tools used to study corals are highlighted with emphasis on an integrated host-microbiota multiomics framework to understand the underlying mechanisms during symbiosis and climate change-driven dysbiosis.

Effect of advanced-platelet rich-fibrin combined with rosuvastatin application after open flap debridement of infrabony pocket

Open flap debridement (OFD) is an invasive therapy for chronic periodontitis with pocket 5 mm or more. However, it is difficult to achieve regeneration and new attachment with this therapy. Periodontitis starts to add growth factors and local drugs delivery as host modulation therapy. Advanced-PRF (A-PRF) contains more growth factor than PRF which plays a role in promoting fibroblast proliferation, reepithelization, extracellular matrix production, and endothelial cell migration. 1.2% rosuvastatin gel (RSV) is a local delivery drug with a pleiotropic effect that can modify host response to promoting BMSCs, BMP-2, OPG, ALP, RANKL, and osteoblasts. This study aimed to examine the effect of the application of A-PRF+RSV in OFD therapy of which the parameters were probing depth (PD), relative attachment loss (RAL), and alveolar bone height. The study samples consisted of 24 periodontal pockets which were divided into 2 groups of 12 pockets each, namely A-PRF+RSV for group 1 and PRF+RSV for group 2. Clinical evaluations were carried out on baseline, day-30, and day-90 for PD and RAL, and on baseline and day -90 for alveolar bone height. Data of PD and RAL reduction were analyzed with non-parametric test Mann-Withney, while data of reduction of alveolar bone height were analyzed with parametric Independent-T test. Group 1 obtained a statistically more significant result in reducing PD, RAL, and alveolar bone height compared to group 2 (p<0.05) To conclude, the application of A-PRF and 1.2% rosuvastatin gel in OFD procedure promotes a higher PD and RAL reduction and alveolar bone height increase than the application of PRF coupled with 1.2% rosuvastatin gel.

Interactions between the intestinal microbiota and epigenome in individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable impairment of cognitive function and interpersonal relationships. Furthermore, some individuals with ASD have gastrointestinal disorders that have been correlated with impairments in intestinal microbiota. Gut microbiota are important not only for intestinal health, but also for many other functions including food digestion, energy production, immune system regulation, and, according to current data, behavior. Disruption of the indigenous microbiota, microbial dysbiosis (imbalance between microorganisms present in the gut), overgrowth of potentially pathogenic microorganisms, a less diverse microbiome, or lower levels of beneficial bacteria in children with ASD can affect behavior. Metabolome analysis in children with ASD has identified perturbations in multiple metabolic pathways that might be associated with cognitive functions. Recent studies have shown that the intestinal microbiome provides environmental signals that can modify host response to stimuli by modifying the host epigenome, which affects DNA methylation, histone modification, and non-coding RNAs. The most studied microbiota-produced epigenetic modifiers are short-chain fatty acids, although other products of intestinal microbiota might also cause epigenetic modifications in the host's DNA. Here we review evidence suggesting that epigenetic alterations caused by modification of gene expression play an important role in understanding ASD.

The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway.

The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP-AOP framework by organizing and integrating in vitro dose-response data and in vivo exposure-response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk-based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

Role of inherited thrombophilic profile on survival of patients with sepsis

The existence of various coagulation and/or fibrinolytic system disorders (such as inherited thrombophilia) in patients with sepsis could possibly modify host response to infection as well as patient outcome. The...

Host modulation therapeutics in periodontics: role as an adjunctive periodontal therapy.

Host Modulation Therapy (HMT) is a treatment concept that reduces tissue destruction and stabilizes or even regenerates inflammatory tissue by modifying host response factors. It has been used for treating osteoporosis and arthritis for several decades. However, its use in dentistry has only been recently reported. The objective of this article is to present a review of the various literatures available on HMT and also its role as adjunct therapy in periodontics. For identifying studies for this review, a PUBMED search was carried out in 2013 for all articles published till December 2012. The search was restricted to English language publications only. Longitudinal prospective and retrospective studies were included in the search. The key words used were: Host Modulation Therapy; Sub antimicrobial dose doxycycline and Non-Surgical Periodontal Therapy. The main outcomes sought were host modulation therapeutics in periodontics. Exclusion criteria included cross sectional studies, short case series as well as studies with short follow-up periods. There is a paucity of literature on HMT in periodontics although the only drug approved by United States Food and Drug Administration (FDA) is a subantimicrobial dose of doxycycline (SDD) with highly predictable results as a host modulating agent in periodontal diseases and also an effective adjunctive therapy in various diseases of periodontium. However, more randomized controlled trials are needed to obtain clinical guidelines on the usage of other host modulating agents as adjunct as well as definite therapy for periodontal diseases. SDD is an effective adjunct therapy when used in dosage of 20mg twice daily for minimum 3 months duration in various periodontal diseases with predictable clinical outcomes. It is also recommended that future clinical research on anti cytokine drugs, chemically modified tetracycline and other HMT agents should be conducted so that new drugs are available with highly predictable results.

Host Modulation in Rheumatoid Arthritis Patients with TNF Blockers Significantly Decreases Biochemical Parameters in Periodontitis

The aim of this study was to evaluate the effects of host modulation therapy on periodontal and biochemical parameters. Sixteen rheumatoid arthritis patients newly scheduled for anti-tumour necrosis factor (TNF) therapy were screened for 30 days. Periodontal parameters (clinical attachment level, probing pocket depth, bleeding on probing, plaque index and gingival index) as well as salivary and gingival crevicular fluid (GCF), interleukin (IL)-1β, IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels of the patients were evaluated at baseline and on the 30th day of therapy. GCF volume, IL-1β and IL-8 levels (p = 0.007, p = 0.017 and p = 0.009, respectively) of the periodontitis patients significantly decreased. Although there was a decrease in all these parameters in healthy patients, it was below statistical significance. Salivary IL-8 and MCP-1 levels significantly decreased in periodontitis patients (p = 0.028 and p = 0.013, respectively), but IL-1β levels remained unchanged. These results suggest that TNF blockers may significantly modify host response in terms of biochemical parameters of the periodontium and may mask significant associations such as those reported between periodontitis and rheumatoid arthritis.

Cigarette Smoking and Inflammation

Cigarette smoke (CS) causes considerable morbidity and mortality by inducing cancer, chronic lung and vascular diseases, and oral disease. Despite the well-recognized risks associated with smoking, the habit remains unacceptably prevalent. Several toxins present in CS have immunomodulatory effects. CS also contains trace amounts of microbial cell components, including bacterial lipopolysaccharide. These and other CS constituents induce chronic inflammation at mucosal surfaces and modify host responses to exogenous antigens. The effects of CS on immunity are far-reaching and complex; both pro-inflammatory and suppressive effects may be induced. The net effect of CS on immunity depends on many variables, including the dose and type of tobacco, the route and chronicity of exposure, and the presence of other factors at the time of immune cell stimulation, such as Toll receptor ligands or other inflammatory mediators. CS impairs innate defenses against pathogens, modulates antigen presentation, and promotes autoimmunity. CS also impairs immunity in the oral cavity and promotes gingival and periodontal disease and oral cancer. The recognition of specific mechanisms by which CS affects host immunity is an important step toward elucidating mechanisms of tobacco-induced disease and may identify novel therapeutic approaches for the management of diseases that afflict smokers. Abbreviations: AP-1, activator protein-1; CD, cluster of differentiation; COPD, chronic obstructive pulmonary disease; HLA, human leukocyte antigen; IFNγ, interferon gamma; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-B; RAGE, receptors for advanced glycation end-products; ROS, reactive oxidative species; RORγτ, retinoic acid receptor-related orphan receptor transcription factor; STAT, signal transducer and activator of transcription; T-bet, T-box transcription factor; Th, T-helper; TLR, Toll-like receptors; TNFα, Tumor necrosis factor alpha; and TSLP, thymic stromal lymphopoeitin.

Tetrahydrolipstatin Inhibition, Functional Analyses, and Three-dimensional Structure of a Lipase Essential for Mycobacterial Viability

The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG_6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG_6394, solved to 2.9 Å resolution, revealed an α/β hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG_6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria.

Host pathways for recognition: Establishing gastrointestinal microbiota as relevant in animal health and nutrition

It has long been recognized that gastrointestinal colonization by commensal microbiota is advantageous to the host. Relative to germ-free animals, microbiota adds digestive enzyme capability, creates nutrients (e.g. vitamins, volatile fatty acids) and excludes harmful pathogens. More recently, an appreciation for the much broader impacts of the commensal microbiota on host physiology has been established including developmental and regulatory impacts on adaptive immunity, innate immunity, nutrient digestion, absorption and metabolism. In mono-association experiments, many of these impacts are affected differently depending on the colonizing bacterial species. This suggests opportunity to modify host responses by altering intestinal microbial colonization patterns. Interestingly, new observations linking differences in intestinal microbial composition to obesity and diabetes support a role for intestinal microbiota in systemic host physiology. Host response pathways associated with these outcomes may have relevance to efficiency of nutrient utilization and/or the net rate of tissue deposition. Unfortunately, relatively little is understood about the mechanisms by which the microbiota induces host changes. With reference to the pig where possible, this review will examine identified and speculated host pathways through which microbial products are recognized and induce physiological responses. Pathways are categorized as host sampling of bacterial antigens, receptor mediated recognition of microbiota-associated molecular patterns (MAMPS), recognition of bioactive fermentation products, and microbial-origin effector molecules. We hypothesize that the relevance of the gastrointestinal microbiota in animal health and performance will be defined by elucidating the specific host response pathways. Knowledge of these pathways will, in turn, facilitate the development of targeted nutritional strategies.

A plant natriuretic peptide-like molecule of the pathogen Xanthomonas axonopodis pv. citri causes rapid changes in the proteome of its citrus host.

BackgroundPlant natriuretic peptides (PNPs) belong to a novel class of peptidic signaling molecules that share some structural similarity to the N-terminal domain of expansins and affect physiological processes such as water and ion homeostasis at nano-molar concentrations. The citrus pathogen Xanthomonas axonopodis pv. citri possesses a PNP-like peptide (XacPNP) uniquely present in this bacteria. Previously we observed that the expression of XacPNP is induced upon infection and that lesions produced in leaves infected with a XacPNP deletion mutant were more necrotic and lead to earlier bacterial cell death, suggesting that the plant-like bacterial PNP enables the plant pathogen to modify host responses in order to create conditions favorable to its own survival.ResultsHere we measured chlorophyll fluorescence parameters and water potential of citrus leaves infiltrated with recombinant purified XacPNP and demonstrate that the peptide improves the physiological conditions of the tissue. Importantly, the proteomic analysis revealed that these responses are mirrored by rapid changes in the host proteome that include the up-regulation of Rubisco activase, ATP synthase CF1 α subunit, maturase K, and α- and β-tubulin.ConclusionsWe demonstrate that XacPNP induces changes in host photosynthesis at the level of protein expression and in photosynthetic efficiency in particular. Our findings suggest that the biotrophic pathogen can use the plant-like hormone to modulate the host cellular environment and in particular host metabolism and that such modulations weaken host defence.

Xanthomonas axonopodis pv. citri uses a plant natriuretic peptide-like protein to modify host homeostasis.

Plant natriuretic peptides (PNPs) are a class of extracellular, systemically mobile molecules that elicit a number of plant responses important in homeostasis and growth. The bacterial citrus pathogen, Xanthomonas axonopodis pv. citri, also contains a gene encoding a PNP-like protein, XacPNP, that shares significant sequence similarity and identical domain organization with plant PNPs but has no homologues in other bacteria. We have expressed and purified XacPNP and demonstrated that the bacterial protein alters physiological responses including stomatal opening in plants. Although XacPNP is not expressed under standard nutrient rich culture conditions, it is strongly induced under conditions that mimic the nutrient poor intercellular apoplastic environment of leaves, as well as in infected tissue, suggesting that XacPNP transcription can respond to the host environment. To characterize the role of XacPNP during bacterial infection, we constructed a XacPNP deletion mutant. The lesions caused by this mutant were more necrotic than those observed with the wild-type, and bacterial cell death occurred earlier in the mutant. Moreover, when we expressed XacPNP in Xanthomonas axonopodis pv. vesicatoria, the transgenic bacteria caused less necrotic lesions in the host than the wild-type. In conclusion, we present evidence that a plant-like bacterial PNP can enable a plant pathogen to modify host responses to create conditions favorable to its own survival.

816. RNAi Applications for Respiratory Epithelia: Delivery and Efficacy

The airway epithelium is a common site of disease pathogenesis, including viral infections and primary diseases associated with inflammation. The delivery of RNAi to respiratory epithelia offers an approach to inhibit replication of RNA viruses and modify host responses to infection. To this end, we are using respiratory syncytial virus (RSV) as a model disease target. RSV is a major cause of respiratory disease in infants and immunocompromised adults. There is no approved vaccine for RSV, and medical treatment is supportive. The primary site of RSV replication is in the respiratory epithelium. As a proof of principle for RNAi delivery to the conducting airways of mice, we used gel-formulated adenoviral vectors to deliver short hairpin RNAs (shRNAs) against GFP or an irrelevant control to respiratory epithelia of GFP-transgenic mice. Vector transduced cells were visualized by expression of a reporter gene (dsRed or beta-galactosidase) to localize cells with putative RNAi activity. This approach achieved efficient transduction of the conducting airway epithelium. The efficiency of RNAi against GFP is measured by reduction of GFP in transduced cells. In a complementary approach, we are evaluating uptake of Cy3 labeled siRNA oligos in polarized human airway epithelial (HAE) cell culture and in mouse models. To inhibit RSV expression in vitro and in vivo, shRNAs were designed against the viral nucleocapsid (N) and large polymerase (L) genes of the RSV A2 strain and cloned into an expression vector behind a mU6 promoter. A misdirected control shRNA was produced by the same method to control for off-target effects of shRNA. Short hairpin expression vectors were screened for RNAi activity against renilla luciferase-viral gene fusions in co-transfection experiments, and functional constructs were identified. Subsequently, antiviral activity of effective shRNAs was measured in an in vitro infection model by reduction of viral RNA (Real Time-PCR) and viral protein (western blot). We will present our progress in these studies.

Recent developments in the identification of novel therapeutic targets for the treatment of patients with sepsis and septic shock.

The overall mortality in patients with sepsis is approximately 30%; this figure increases to 50% or higher in patients with septic shock, and sepsis continues to be seen as a major clinical challenge. The recent success of several important trials has fuelled interest in further therapeutic developments. Here, I review the many different strategies that are being investigated, focusing in particular on those that are in late pre-clinical or early clinical development. These can be broadly divided into three groups: strategies aimed at bacterial targets, strategies aimed at disorders of immune regulation in the host, and finally, other novel strategies based on modifying host response; which, if any, of these will prove successful in large clinical trials is unknown. Nevertheless, the fact that sepsis has finally proved tractable as a target for new drug development lends support to those who believe that at least some of the compounds identified in this paper will prove to have clinical benefit.

Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection.

There is evidence that TNF-alpha contributes to the pathogenesis of chronic viral hepatitis. The cellular effects of this cytokine are regulated by two specific receptors, and membranous shedding of these receptors reflects activation of the TNF system. We performed a study of TNF-alpha and functionally active soluble TNF-receptors (TNFR-p55 and -p75) in 105 patients with chronic HCV infection. In HCV RNA-positive patients a significant enhancement of TNF-alpha and both receptor types was observed compared with controls (TNF-alpha 83.8+/-91.7 pg/ml versus 18.8+/-8.4 pg/ml, P<0.001; TNFR-p55 1.4+/-0.4 ng/ml versus 0.9+/-0.2 ng/ml, P<0.0001; TNFR-p75 6.4+/-2.4 ng/ml versus 2.9+/-0.6 ng/ml, P<0.0001, respectively). The enhanced serum levels of TNF-alpha and TNFRs were reflected by a significant expression of TNFR-specific mRNA in peripheral mononuclear cells of HCV-infected patients (P<0.001). Serum aminotransferases correlated with soluble TNFR-p75 (P<0.001) but not with TNFR-p55 and TNF-alpha. We demonstrated an association of the degree of histological inflammation with both TNFRs (P<0.01). Furthermore, enhanced hepatocellular expression of TNF-alpha and TNFRs could be demonstrated by immunohistochemical staining in HCV-infected patients. Sixty-eight out of 105 patients were treated with interferon-alpha (IFN-alpha) (3x10(6)U x 3/week). Pretreatment levels of TNF-alpha and TNFRs did not differ between responders and non-responders. Our results demonstrate that TNF-alpha and TNFRs are enhanced in chronic HCV infection and reflect histological activity of the disease. This up-regulation of TNFRs might modify host response and potentially contribute to liver damage in chronic HCV infection.

Neuroimmunomodulation by opiates: relationship to HIV-1 infection and AIDS

Opiate addiction is a major risk factor for acquired immunodeficiency disease syndrome (AIDS). Since alkaloid opiates and endogenous opioid peptides have been shown to affect immune function, there is considerable interest in understanding whether opioids themselves play any direct or indirect role in modulating expression of HIV-1 and the development of AIDS in heroin addicts. This issue is difficult to address for two main reasons. The addictive liabilities of opiates prohibit direct controlled assessments of their effects in humans and epidemiological assessments of heroin addiction are compromised by the association of addiction with a variety of interdependent milieu cofactors, aside from opiates themselves, that have the independent potential to modulate immune function and viral expression. Accordingly, experimental evidence attained through in vitro and in vivo studies with animal models and human blood cells must supplement clinical observations to obtain the best possible estimate of the potential of opiates to modify host responses to HIV-1 infection and the development of AIDS. Reviewing current evidence from this perspective indicates that there is substantial support for the notion that opiates can affect both immunological and virological processes that dictate the pathogenesis of HIV-1 infections. However, the influence exerted by opiates appears to be conditionally dependent on the stage of opiate dependency. Thus, a well-maintained opiate dependency can be beneficial to host defense systems while poorly maintained dependencies can be quite disruptive. Such information has relevance, not only to the AIDS situation per se , but, also, to therapy of drug addiction and to the field of neuroimmunomodulation in general.

Enhancement of murine macrophage binding of and response to bacterial lipopolysaccharide (LPS) by LPS-binding protein

We have studied the effects of highly purified rabbit lipopolysaccharide (LPS)-binding protein (LBP) on the ability of murine bone marrow-derived macrophages to respond to bacterial LPS. Macrophage responses studied include the secretion of tumor necrosis factor alpha, production of arginine-derived nitrite (NO2-), and killing of an intracellular pathogen, Leishmania enriettii. Macrophages from either CBA or LPS-hyporesponsive C3H/HeJ mice exhibited significantly greater sensitivity to LPS in the presence of LBP. Furthermore, both CBA and C3H/HeJ macrophages demonstrated an LBP-dependent enhancement of LPS binding. These results suggest that C3H/HeJ macrophages are capable of binding LPS-LBP complexes and support the hypothesis that hyporesponsiveness in this strain involves a step subsequent to LPS binding. Furthermore, these findings provide additional evidence of the important role played by the acute-phase plasma protein LBP in modifying host response to LPS.

Fungal surfaces: effects of interactions with phagocytic cells.

Fungal surfaces undergo profound changes during morphogenesis that modify host responses. For example, inhaled spores or conidia of Rhizopus or Aspergillus lose their surface hydrophobic outer layers, initially swell, and then germinate to form mycelia that may invade tissues. These various fungal forms not only elicit differing response from host phagocytic cells but also differ in their susceptibilities to cellular microbicidal mechanisms. In addition, studies comparing neutrophil activation responses to opsonized and unopsonized Candida hyphae indicate that the presence or absence of antibody or complement on fungal surfaces determines distinct patterns of the early responses of neutrophils to stimulation, such as membrane depolarization, cytosolic increase in calcium, and phosphoinositide turnover. These initial events in the neutrophil activation sequence are followed by release of both fungicidal granule constituents and oxidants from the respiratory burst. The quantity and specificity of delivery of these toxic neutrophil products ultimately determine the relative efficiency of fungicidal activity versus inflammatory cytotoxicity to host cells.

Aspects of pathogenesis in a mouse model of infection by Corynebacterium pseudotuberculosis.

A new medium, nutrient tween 80 broth (NTB) was utilised to achieve improved cultivation of Corynebacterium pseudotuberculosis. Twenty four hour NTB cultures were used for cutaneous and intraperitoneal infection of mice. The intraperitoneal administration of heterologous protein, liquid paraffin or thioglycollate prior to intraperitoneal challenge caused enhanced multiplication of the organism although this could be prevented by modifying host response. Pretreatment of skin with thioglycollate enabled cutaneous infection to be consistently achieved. The progress of lesions in skin and viscera is described. Immunisation of the mice was effected by both intraperitoneal and cutaneous routes of inoculation, the latter being particularly useful because it did not lead to residual lesions of viscera. Immunity was expressed by a failure of organisms to localise at secondary sites although infection of primary sites in skin or peritoneal cavity occurred, apparently at a reduced level. The relevance of these findings to the natural disease of sheep is discussed.