Pathogens, Volume 2, Issue 2 (June 2013) – 10 articles , Pages 193-435

Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram-negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development. Full article

Tick-borne hemorrhagic fever viruses (TBHFV) are detected throughout the African and Eurasian continents and are an emerging or re-emerging threat to many nations. Due to the largely sporadic incidences of these severe diseases, information on human cases and research activities in general have been limited. In the past decade, however, novel TBHFVs have emerged and areas of endemicity have expanded. Therefore, the development of countermeasures is of utmost importance in combating TBHFV as elimination of vectors and interrupting enzootic cycles is all but impossible and ecologically questionable. As in vivo models are the only way to test efficacy and safety of countermeasures, understanding of the available animal models and the development and refinement of animal models is critical in negating the detrimental impact of TBHFVs on public and animal health. Full article

Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections. Full article

Primary infection with varicella zoster virus (VZV) results in varicella (chickenpox) followed by the establishment of latency in sensory ganglia. Declining T cell immunity due to aging or immune suppressive treatments can lead to VZV reactivation and the development of herpes zoster (HZ, shingles). HZ is often associated with significant morbidity and occasionally mortality in elderly and immune compromised patients. There are currently two FDA-approved vaccines for the prevention of VZV: Varivax^® (for varicella) and Zostavax^® (for HZ). Both vaccines contain the live-attenuated Oka strain of VZV. Although highly immunogenic, a two-dose regimen is required to achieve a 99% seroconversion rate. Zostavax vaccination reduces the incidence of HZ by 51% within a 3-year period, but a significant reduction in vaccine-induced immunity is observed within the first year after vaccination. Developing more efficacious vaccines and therapeutics requires a better understanding of the host response to VZV. These studies have been hampered by the scarcity of animal models that recapitulate all aspects of VZV infections in humans. In this review, we describe different animal models of VZV infection as well as an alternative animal model that leverages the infection of Old World macaques with the highly related simian varicella virus (SVV) and discuss their contributions to our understanding of pathogenesis and immunity during VZV infection. Full article

Common marmosets (Callithrix jacchus) developed high levels of viremia, clinical signs including fever, weight loss, a decrease in activity and hematuria upon inoculation with dengue virus (DENV). Presence of DENV genome in urine samples and pathological changes in kidneys were examined in the present study. Levels of DENV genome were determined in 228 urine samples from 20 primary DENV-inoculated marmosets and in 56 urine samples from four secondary DENV-inoculated marmosets. DENV genome was detected in 75% (15/20) of marmosets after primary DENV infection. No DENV genome was detected in urine samples from the marmosets with secondary infection with homologous DENV (0%, 0/4). Two marmosets demonstrated hematuria. Pathological analysis of the kidneys demonstrated non-suppressive interstitial nephritis with renal tubular regeneration. DENV antigen-positive cells were detected in kidneys. In human dengue virus infections, some patients present renal symptoms. The results indicate that marmosets recapitulate some aspects of the involvement of kidneys in human DENV infection, and suggest that marmosets are potentially useful for the studies of the pathogenesis of DENV infection, including kidneys. Full article

The influence of microorganisms growing as sessile communities in a large number of human infections has been extensively studied and recognized for 30–40 years, therefore warranting intense scientific and medical research. Nonetheless, mimicking the biofilm-life style of bacteria and biofilm-related infections has been an arduous task. Models used to study biofilms range from simple in vitro to complex in vivo models of tissues or device-related infections. These different models have progressively contributed to the current knowledge of biofilm physiology within the host context. While far from a complete understanding of the multiple elements controlling the dynamic interactions between the host and biofilms, we are nowadays witnessing the emergence of promising preventive or curative strategies to fight biofilm-related infections. This review undertakes a comprehensive analysis of the literature from a historic perspective commenting on the contribution of the different models and discussing future venues and new approaches that can be merged with more traditional techniques in order to model biofilm-infections and efficiently fight them. Full article

The Henipavirus genus contains two highly lethal viruses, the Hendra and Nipah viruses and one, recently discovered, apparently nonpathogenic member; Cedar virus. These three, negative-sense single-stranded RNA viruses, are hosted by fruit bats and use EphrinB2 receptors for entry into cells. The Hendra and Nipah viruses are zoonotic pathogens that emerged in the middle of 90s and have caused severe, and often fatal, neurologic and/or respiratory diseases in both humans and different animals; including spillover into equine and porcine species. Development of relevant models is critical for a better understanding of viral pathogenesis, generating new diagnostic tools, and assessing anti-viral therapeutics and vaccines. This review summarizes available data on several animal models where natural and/or experimental infection has been demonstrated; including pteroid bats, horses, pigs, cats, hamsters, guinea pigs, ferrets, and nonhuman primates. It recapitulates the principal features of viral pathogenesis in these animals and current knowledge on anti-viral immune responses. Lastly it describes the recently characterized murine animal model, which provides the possibility to use numerous and powerful tools available for mice to further decipher henipaviruses immunopathogenesis, prophylaxis, and treatment. The utility of different models to analyze important aspects of henipaviruses-induced disease in humans, potential routes of transmission, and therapeutic approaches are equally discussed. Full article

Acute respiratory tract infection (RTI) is a leading cause of morbidity and mortality worldwide and the majority of RTIs are caused by viruses, among which respiratory syncytial virus (RSV) and the closely related human metapneumovirus (hMPV) figure prominently. Host innate immune response has been implicated in recognition, protection and immune pathological mechanisms. Host-viral interactions are generally initiated via host recognition of pathogen-associated molecular patterns (PAMPs) of the virus. This recognition occurs through host pattern recognition receptors (PRRs) which are expressed on innate immune cells such as epithelial cells, dendritic cells, macrophages and neutrophils. Multiple PRR families, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), contribute significantly to viral detection, leading to induction of cytokines, chemokines and type I interferons (IFNs), which subsequently facilitate the eradication of the virus. This review focuses on the current literature on RSV and hMPV infection and the role of PRRs in establishing/mediating the infection in both in vitro and in vivo models. A better understanding of the complex interplay between these two viruses and host PRRs might lead to efficient prophylactic and therapeutic treatments, as well as the development of adequate vaccines. Full article

Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote “regenerative inflammation” and potentially cancer. Full article

Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund’s incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy. Full article