Inter-α inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection.

Human inter-α inhibitor proteins are endogenous human plasma proteins that function as serine protease inhibitors. Inter-α inhibitor proteins can block the systemic release of proteases in sepsis and block furin-mediated assembly of protective antigen, an essential stop in the intracellular delivery of the anthrax exotoxins, lethal toxin and edema toxin. Inter-α inhibitor proteins administered on hour or up to 24 h after spore challenge with Bacillus anthracis Sterne strain protected mice from lethality if administered with antimicrobial therapy (P < 0.001). These human plasma proteins possess combined actions against anthrax as general inhibitors of excess serine proteases in sepsis and specific inhibitors of anthrax toxin assembly. Inter-α inhibitor proteins could represent a novel adjuvant therapy for the treatment of established anthrax infection.

Penicillium marneffei infection in HIV-infected travelers.

Disseminated Penicillium marneffei infection is the third most common AIDS-defining illness in parts of Southeast Asia. A review of the literature now shows that penicilliosis may represent an emergent opportunistic infection in HIV-positive travelers to endemic regions as well.

WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock.

OBJECTIVE: To determine the effect of an estrogen receptor-beta selective agent in experimental models of systemic infection and sepsis. DESIGN: WAY-202196, a nonsteroidal selective estrogen receptor-beta agonist, was tested in the murine listeriosis model, the neutropenic rat Pseudomonas aeruginosa infection, and the mouse cecal ligation and puncture sepsis models. SETTING: University-affiliated biomedical research laboratory. SUBJECTS: BALB/c mice and Sprague-Dawley rats. INTERVENTIONS: WAY-202196 or control (vehicle) was administered orally in doses ranging from 1.5 to 50 mg/kg at various time points in the three experimental model systems. MEASUREMENTS AND MAIN RESULTS: Susceptibility of mice treated with a single oral dose of up to 50 mg/kg WAY-202196 did not differ from those treated with vehicle alone after systemic challenge by Listeria monocytogenes, suggesting a lack of generalized immunosuppression. In the neutropenic rat model, daily administration of WAY-202196 (50 mg/kg) significantly increased survival against an otherwise lethal challenge of P. aeruginosa 12.4.4 compared with the control group (83% vs. 25% survival; p < 0.05). Preservation of intestinal mucosal weight and prevention of histopathologic changes were also observed with the administration of WAY-202196. Similar results were obtained in a cecal ligation and puncture model, in which multiple oral doses of WAY-202196 (50 mg/kg) improved survival (83% vs. 0%; p < 0.05), preserved intestinal epithelial integrity, and significantly reduced systemic bacteremia and peritoneal interleukin-6 and tumor necrosis factor levels. The estrogen receptor-beta agonist provided a comparable level of protection in both male and female animals. CONCLUSION: These results indicate that oral administration of WAY-202196 preserved gastrointestinal barrier function and improved outcome in experimental models of systemic infection and inflammation. WAY-202196 and similar agents may prove useful clinically as a novel treatment strategy for the treatment or prevention of severe sepsis.

Engineering mucosal RNA interference in vivo.

Mucosal surfaces serve as a gateway to disease. Here, we demonstrate that RNA interference can be used to manipulate mucosal gene expression in vivo. Using a murine model, we show that direct application of liposome-complexed siRNA mediates gene-specific silencing in cervicovaginal and rectal mucosa. A single vaginal or rectal administration of siRNA targeting hematopoietic or somatic cell gene products reduced corresponding mRNA levels by up to 90%. Using a murine model of inflammatory bowel disease, we found that the rectal application of siRNA targeting TNF-alpha led to relative mucosal resistance to experimental colitis. Liposomal siRNA formulations proved nontoxic, did not elicit a nonspecific interferon response, and provide a means for genetic engineering of mucosal surfaces in vivo.

Role of Toll-like receptors in infection and immunity: clinical implications.

The remarkable discovery of the Toll-like receptors (TLRs) over the past 5 years has opened up an entirely new era in the understanding of the molecular events that initiate the inflammatory response. These type 1 transmembrane receptors are expressed on a large number of immune cells as well as epithelial cells and play an essential role in the activation of the innate immune response to microbial pathogens. They impact on adaptive immune reactions and contribute to the initiation and maintenance of the inflammatory response to a multitude of potential microbial pathogens through recognition of pathogen-associated molecular patterns. TLRs also interact with a variety of endogenous human ligands and influence the activity of a wide range of tissues and cell processes. Among the common and important processes in which TLRs play a role are asthma, acute respiratory distress syndrome, cardiac ischaemia, coronary artery disease, ventricular remodelling, vascular collapse, inflammatory bowel disease, acute tubular necrosis, psoriasis, rheumatoid arthritis, pre-term birth, fertility, cancer angiogenesis and transplant rejection. From this strikingly diverse list, many important opportunities for disease modification through TLR manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated, and the current status of these treatment strategies is reviewed in this article.

The activity of pathway-selective estrogen receptor ligands in experimental septic shock.

Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-kappaB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.

Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication.

Inter-alpha-inhibitor protein (IalphaIp) functions as an endogenous serine protease inhibitor in human plasma, and IalphaIp levels diminish rapidly during acute inflammatory states. One potential target for IalphaIp is furin, a cell-associated serine endopeptidase essential for the activation of protective antigen and the formation of anthrax lethal toxin (LT). IalphaIp blocks furin activity in vitro and provides significant protection against cytotoxicity for murine peritoneal macrophages exposed to up to 500 ng/ml LT. A monoclonal antibody (MAb), 69.31, that specifically blocks the enzymatic activity of IalphaIp eliminates its protective effect against LT-induced cytotoxicity. IalphaIp (30 mg/kg of body weight) administered to BALB/c mice 1 hour prior to an intravenous LT challenge resulted in 71% survival after 7 days compared with no survivors among the control animals (P < 0.001). We conclude that human IalphaIp may be an effective preventative or therapeutic agent against anthrax intoxication.

Chloroquine enhances survival in Bacillus anthracis intoxication.

The intentional release of anthrax in the United States in 2001 resulted in 11 cases of inhalational disease, with an attendant mortality rate of 45%. Current therapeutic options for anthrax are limited; antimicrobials target only replicating organisms, thus allowing bacterial toxins to cause unchecked, devastating physiological derangements in the host. Novel approaches that target the cytotoxic effects of anthrax exotoxins are needed. Chloroquine (CQ), a commonly used antimalarial agent, endows anthrax-intoxicated murine peritoneal macrophages with a 50% and 35% marginal survival advantage at 2 and 4 h, respectively, over that of untreated control cells. The cell rescue is dose dependent and, at lower concentrations, results in delayed cell death. We subsequently studied the effect of CQ in BALB/c mice challenged with anthrax lethal toxin. CQ-treated mice demonstrated reduced tissue injury, as assessed by histopathological examination of the spleen and by peripheral blood differential cell count ratios. CQ significantly enhanced survival and may augment current treatment and prophylaxis options for this otherwise lethal infection.

Infection and fever in the elderly.

The elderly make more frequent use of general podiatric medical services than the younger population. It is therefore important for podiatric physicians to become familiar with the general principles of infectious disease as applied to an elderly population, which is susceptible to a wider spectrum of disease with more subtle and unusual clinical signs and symptoms. This article reviews the diagnosis and evaluation of suspected infection, appropriate laboratory testing, patterns of specific infectious disease syndromes, and antibiotic use in the elderly.

The Toll-like receptors and their role in septic shock.

The Toll-like receptors (TLRs) are a class of pattern recognition molecules with unique functions in the innate and the acquired immune systems. The innate immune response has evolved as the immediate host defence system in response to foreign structures and it also serves to prime the adaptive immune response. As such, the TLRs set the tone and pace of the inflammatory response that follows initial contact with a microbial pathogen over the course of the following minutes, hours and days. Sepsis, a leading cause of death in critically ill patients worldwide, is defined as 'the systemic inflammatory response syndrome that occurs during infection' [1]; that is, sepsis is the orchestration of the events controlled by the gene products triggered by signals transduced through the TLRs. Through analysis of the human genome, ten TLRs have been identified, and several of them have been characterised with respect to their associated ligands. Following engagement of the cognate ligand to the ectodomain of each TLR, the assembly of intracellular homo- or heterodimers or multimers induces cell signalling. The receptors are variably expressed on different types of cells, such as neutrophils, dendritic cells, lymphocytes, endothelial cells etc. and can be up- and downregulated, blocked or triggered by mimetic substances. By controlling or modifying TLR responses, the trajectory of the entire septic process may be modified. This review covers the events responsible for TLR activation in detail, with an emphasis on possible points of pharmacological intervention.