Efficacy of post exposure administration of doxycycline in a murine model of inhalational melioidosis.
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ABSTRACT:
SUBMITTER: Gelhaus HC
PROVIDER: S-EPMC3556592 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:Doxycycline post-exposure prophylaxis (PEP) holds the potential to mitigate increasing rates of syphilis among sexual minority men (SMM) in the US yet has received limited attention. Since evaluation of this intervention in actual populations is not currently feasible, we used agent-based models (ABM) to assess the population-level impact of this strategy. We adapted ABM of HIV and HPV transmission, representing a population of 10,230 SMM in Philadelphia, Pennsylvania, US. Parameter inputs were derived from the literature, and ABM outputs during the pre-intervention period were calibrated to local surveillance data. Intervention scenarios varied doxycycline uptake by 20, 40, 60, 80 and 100%, while assuming continued condom use and syphilis screening and treatment. Under each intervention scenario, we incorporated treatment adherence at the following levels: 0, 20, 40, 60, 80 and 100%. Long-term population impact of prophylactic doxycycline was measured using the cumulative incidence over the 10-year period and the percentage of infections prevented attributable to doxycycline at year 10. An uptake scenario of 20% with an adherence level of 80% would reduce the cumulative incidence of infections by 10% over the next decade, translating to 57 fewer cases per 1000 SMM. At year 10, under the same uptake and adherence level, 22% of infections would be prevented due to doxycycline PEP in the instances where condoms were not used or failed. Findings suggest that doxycycline PEP will have a modest impact on syphilis incidence when assuming a reasonable level of uptake and adherence. Doxycycline PEP may be most appropriate as a secondary prevention measure to condoms and enhanced syphilis screening for reducing infections among SMM.
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Project description:Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication.
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Project description:Burkholderia pseudomallei, the etiologic agent of melioidosis, causes severe disease in humans and animals. Diagnosis and treatment of melioidosis can be challenging and no licensed vaccines currently exist. Several studies have shown that this pathogen expresses a variety of structurally conserved protective antigens that include cell-surface polysaccharides and cell-associated/-secreted proteins. Based on this, such antigens have become important components of the subunit vaccine candidates that we are currently developing. In the present study, the 6-deoxyheptan capsular polysaccharide (CPS) from B. pseudomallei was purified, chemically activated and covalently linked to recombinant CRM197 diphtheria toxin mutant (CRM197) to produce CPS-CRM197. Additionally, tandem nickel-cobalt affinity chromatography was used to prepare highly purified recombinant B. pseudomallei Hcp1 and TssM proteins. Immunization of C57BL/6 mice with CPS-CRM197 produced high-titer IgG and opsonizing antibody responses against the CPS component of the glycoconjugate while immunization with Hcp1 and TssM produced high titer IgG and robust IFN-? secreting T cell responses against the proteins. Extending upon these studies, we found that when vaccinated with a combination of CPS-CRM197 plus Hcp1, 100% of the mice survived a lethal inhalational challenge of B. pseudomallei Remarkably, 70% of the survivors had no culturable bacteria in their lungs, livers or spleens indicating that the vaccine formulation had generated sterilizing immune responses. Collectively, these studies help to better establish surrogates of antigen-induced immunity against B. pseudomallei as well as provide valuable insights towards the development of a safe, affordable and effective melioidosis vaccine.
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Project description:Acute lung injury is an inflammatory condition developed after severe sepsis in response to excessive secretion of pro-inflammatory cytokines. Doxycycline is widely reported to possess immunomodulatory activity through inhibition of various inflammatory pathways. Considering the broad spectrum of anti-inflammatory activity, protective effect of doxycycline was evaluated in clinically relevant murine polymicrobial sepsis model induced by caecal ligation and puncture (CLP). In this model, sepsis is accompanied with infection and therefore ceftriaxone at sub-protective dose was combined to retard the bacterial growth. Three hours after CLP challenge, mice were administered vehicle, ceftriaxone (100 mg/kg subcutaneously) alone and in combination with immunomodulatory dose of doxycycline (50 mg/kg, intraperitoneal) and survival were monitored for 5 days. Bacterial count in blood and peritoneal fluid along with cytokines [interleukin (IL)-6, IL-1?, tumour necrosis factor (TNF)-?] and myeloperoxidase (MPO) in plasma and lung homogenate were measured at 18 h post-CLP. Plasma glutathione (GSH) was also determined. Doxycycline in presence of ceftriaxone improved survival of septic mice by significantly reducing the plasma and lung pro-inflammatory cytokines and MPO levels. It also increased plasma GSH levels. Doxycycline did not improve antibacterial effect of ceftriaxone in combination, suggesting that the protective effect of doxycycline was due to its immunomodulatory activity. Doxycycline in the presence of ceftriaxone demonstrated improved survival of septic mice by modulating the immune response.
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Project description:Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.
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Project description:Pre-session administration of d-cycloserine (DCS) has been found to augment exposure therapy outcomes in a variety of anxiety disorders. To be able to enhance learning only for successful exposure sessions, it would be beneficial to have the option of administering DCS after rather than before the session, a strategy encouraged by pre-clinical work. We believe the present study is the first published report on the efficacy of post-session administration of DCS in humans.Adults (N = 29) with a DSM-IV diagnosis of acrophobia were randomized to receive two sessions of virtual reality exposure therapy (VRE) in combination with placebo or 50 mg of DCS. Instead of administering the pill prior to each of the sessions, as has been done in extant work, we administered the pill immediately following each session. Measures of acrophobia severity were collected at baseline, at each treatment session, 1-week post-treatment, and at 1-month follow-up.Mixed-effects repeated-measures ANOVAs and GLMMs revealed significant improvement in all outcome measures over time, but no between-group differences were observed. At post-treatment, 63.5% of patients in the placebo condition vs. 60.0% of those in the DCS condition were in remission. At 1-month follow up, 63.4% of those in the placebo condition vs. 66.6% of those in the DCS condition were in remission.These findings do not support the application of post-session DCS administration for augmenting the efficacy of exposure-based treatments. Possible reasons for these findings are discussed.The Trial is registered at ClinicalTrials.gov (NCT01102803).
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Project description:Nucleotide-binding oligomerization domain 2 (NOD2) is a cytosolic pathogen recognition receptor that regulates susceptibility to a variety of infections and chronic diseases. Burkholderia pseudomallei, a facultative intracellular bacterium, causes the tropical infection melioidosis. We hypothesized that NOD2 may participate in host defense in melioidosis. We performed a series of in vitro assays and in vivo experiments and analyzed the association of human genetic variation with infection to delineate the contribution of NOD2 to the host response to B. pseudomallei. We found that transfection with NOD2 mediated NF-κB activation induced by B. pseudomallei stimulation of HEK293 cells. After low-dose inoculation with aerosolized B. pseudomallei, Nod2-deficient mice showed impaired clinical responses and permitted greater bacterial replication in the lung and dissemination to the spleen compared with wild-type mice. IL-6 and KC levels were higher in the lungs of Nod2-deficient mice. In a cohort of 1562 Thai subjects, a common genetic polymorphism in the NOD2 region, rs7194886, was associated with melioidosis, and this effect was most pronounced in women. rs7194886 was not associated with differences in cytokine production induced by whole-blood stimulation with the NOD2 ligand, muramyl dipeptide, or B. pseudomallei. To our knowledge, these findings are the first to characterize the role of NOD2 in host defense in mammalian melioidosis.
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Project description:BackgroundPreclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches.MethodsdKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals.FindingsNucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy.InterpretationOur results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype.FundingThis work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Project description:Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu.A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide+intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5.Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P<.01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P<.05), decreased microglial activation (P<.05), and decreased fetal neurotoxicity (P<.05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P<.05). Injected MSCs were localized to placenta.Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice.
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Project description:Particulate matter (PM) exposure has been associated with intestinal disorders. Therefore, there is an urgent need to understand the precise molecular mechanism involved and explore potential prevention strategies. In this study, inhaled PM is shown to activate inflammatory pathways in murine colon. In a panel study, it is found that ambient PM levels are significantly associated with elevated number of fecal white blood cells in healthy subjects. Acting as a promoter, PM exposure accelerates chemical carcinogenesis-induced colonic tumor formation in a murine model. Mechanistically, RNA-seq assays suggest activation of phosphoinositide 3-kinase (PI3K)/AKT cascades in chronically PM-exposed human colon mucosal epithelial cells. Ablation of up-stream driver fibroblast growth factor receptor 4 (FGFR4) effectively inhibits inflammation and neoplasia in PM-exposed murine colons. Notably, dietary curcumin supplement is shown to protect against PM-induced colonic injuries in mice. Collectively, these findings identify that PM exposure accelerates colonic tumorigenesis in a PI3K/AKT-dependent manner and suggests potential nutrient supplement for prevention.
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