The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: Modeling Human Enterovirus 71 Infection for Vaccine and Therapeutics Development
Authors: Xingdong Yang and Lijuan Yuan*
Affiliation: Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, 24060, USA; E-mails: email@example.com (L.Y.); firstname.lastname@example.org (X.Y.)
Abstract: Human enterovirus 71 (EV71) is a re-emerging viral pathogen and a major public health issue in Asia-Pacific countries. It commonly causes hand, foot, and mouth diseases (HFMD) in young children but shows an increasing trend in recent years of causing severe or fatal neurological and respiratory diseases. Vaccines and antiviral drugs for EV71 are being actively pursued, with the most advanced vaccines entering phase II and III clinical trials. However, existing animal models for EV71 infection have limitations in their applications in vaccine and antiviral drug research. For example, mice models are limited by the inherent difference between human and mouse pathophysiology and resistance to infection and disease in mice older than 2 weeks. Monkey models are restricted by the ethical concerns and cost. Future development in modeling systems for EV71 infection, such as novel animal models (e.g. pigs and hamsters), humanized animal models (with transgenic EV71 receptors, human immune system, or human gut flora), as well as models based on new advances in biomedical science (in silico modeling, iPSCs, 3D cell culture, and microfluidics devices), will result in better understanding of EV71 infection and immunity, thus accelerating the development of safe and effective vaccines and antiviral drugs.
Keywords: Human Enterovirus 71 (EV71); Vaccines; Antiviral drugs; Modeling systems
Type of Paper: Article
Title: Strategies to Prevent Antibiotic Resistance
Author: Anthony Coates
Affiliation: Medical Microbiology, Centre for Infection, Department of Cellular and Molecular Medicine, St George's University of London, London SW17 ORE, UK; E-Mail: email@example.com
Abstract: Since the development of antibiotics over 60 years ago, they have become an integral part of healthcare practice worldwide. Recently this has come under jeopardy, with the emergence of wide-spread antibiotic resistance, which is one of the major problems now facing modern medicine. Previously, the development of new antibiotics kept us one step ahead of the problem of resistance; however only two new classes of antibiotics have reached the market in the last thirty years and antibiotic resistance to those is developing rapidly. This article examines antibiotics and the way we use them and will summarise some of the strategies we can identify to prevent resistance. For example the mechanisms of antibiotic action, whether they are used in combinations or as single therapy and the pharmacokinetics and pharmacodynamics of antibiotics all have implications on the development of resistance. Better understanding of those can help us to use antibiotics in ways that will generate less resistance. In addition patient concordance with antibiotic therapy and infection control both have large effects on resistance development and as such are important areas of focus for resistance prevention. Also public health policies have a major role to play.
Type of Paper: Article
Title: Novel Imaging Techniques to Monitor Therapeutic Treatments Against Burkholderia Respiratory Infections
Authors: Alfredo G. Torres
Affiliation: UTMB Health, Department of Microbiology and Immunology, Department of Pathology, Sealy Center for Vaccine Development, 301 University Blvd MRB 3.142E, Galveston, Tx 77555-1070, USA; E-Mail: firstname.lastname@example.org
Abstract: Burkholderia mallei and B. pseudomallei are two intracellular pathogens causing glanders and melioidosis, respectively, and which are classified as Category B select agents, due to their biothreat potential and lack of effective therapeutic treatment. We previously showed that intranasal treatment of mice with CpG oligodeoxynucleotides confers protection against acute meliodosis, due to the recruitment of inflammatory monocytes and neutrophils. Recently, we have monitored neutrophil recruitment to the lungs in response to CpG treatment using in vivo whole body imaging technique and demonstrate protection in the murine glanders model. We have observed that CpG administration reduced the robust production of chemokines and pro-inflammatory cytokines in lungs, which is a hallmark of the infection in non-treated animals. Lungs of infected control animals were infiltrated with neutrophils, as compared to CpG-treated animals. A stable luminescent reporter B. mallei strain was initially detected in the nose of infected animals and progressed to the lungs and spleen over the course of infection. CpG-treatment 48 h pre-infection resulted in increased recruitment of neutrophils (visualized by near infrared fluorescent imaging) to the lungs and reduction of bioluminescent bacteria, correlating with decrease bacterial burden in target organs and protection against acute murine glanders. We have developed optimized in vivo imaging methods to monitor disease progression and to evaluate efficacy of therapeutic treatment/vaccination during Burkholderia infections. Further, protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, real time in vivo imaging and co-localization of neutrophils and bacteria in the lungs.
Type of Paper: Review
Title: Heterologous Immunity: What Can We Learn from Viral Co-Infections?
Authors: Shalini Sharma and Paul G. Thomas
Affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis TN 38105, USA; E-mail: Paul.Thomas@STJUDE.ORG
Abstract: Immunity to previously encountered viruses can alter responses to unrelated pathogens, a finding well-supported by studies in animal model systems. This heterologous immunity appears to be relatively common, and may indeed be beneficial by boosting protective responses. In other instances, heterologous reactivity can result in severe immunopathology, This review discusses the current literature on viral co-infection models and the key features that define heterologous immune modulation, including alterations in CD8/CD4+ counts, an increase or decrease in viral load, changes in drug resistance patterns and disease progression. We focus mainly on the setting of persistent viral infections. The difficulties of studying these complex systems in humans are discussed, with special reference to the variations in HLA haplotypes and uncertainties over infection history. Nevertheless, epidemiological analyses in humans and the data from mouse co-infection models can be interpreted to aid in the design of therapeutics and vaccination strategies.
Type of Paper: Review
Title: Humanized Mouse Models of Epstein-Barr Virus Infection and Associated Diseases
Author: Shigeyoshi Fujiwara
Affiliation: Department of Infectious Diseases, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan; E-mail: email@example.com
Abstract: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of adult population in the world. EBV is associated with a variety of diseases including transient lymphoproliferation (infectious mononucleosis), neoplasms (Burkitt lymphoma, Hodgkin lymphoma, posttransplant lymphoproliferative disease, etc.), hyperinflammatory conditions like hemophagocytic lymphohistiocytosis, and autoimmunity (rheumatoid arthritis (RA), multiple sclerosis, etc.). EBV infects only humans naturally and limited species of new-world monkeys in experimental settings. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, with their hematoimmune system replaced by that of human equivalent, carry human B lymphocytes, the major target of EBV, and human T lymphocytes, a central player in immune responses to the virus, as well as other major components of the immune system including NK cells, macrophages, and dendritic cells. Thus many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytc lymphohistiocytosis, erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. We describe recent achievements in the field of humanized mouse models of EBV infection and show how these mice have been useful in elucidating the pathogenesis of EBV-associated diseases and how they can be applied for the development of novel therapeutics.
Type of Paper: Review
Title: Immune Response to Human Metapneumovirus Infection: Lessons from Animal Models
Authors: Ma. Del Rocío Baños-Lara, Lindsey J. Harvey, and Antonieta Guerrero-Plata
Affiliation: Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research. Louisiana State University, Baton Rouge, LA. USA
Abstract: Human Metapneumovirus (hMPV), a single-stranded RNA paramyxovirus, represents a serious respiratory pathogen in young children, elderly, and immunocompromised individuals. Since its detection in 2001, considerable research progress has been made towards our knowledge of the pathogenesis of this virus. However, there is no effective vaccine or treatment for hMPV. The study of the innate and adaptive immune response elicited by hMPV is critical for the design of an effective counteraction of the infection. In that regard, studies in several rodent animal models (mice, cotton rats, hamsters, and ferrets) as well as non-human primates have provided critical information regarding the immunity to hMPV. In this review, we discuss the different animal models that have contributed to a better understanding of the hMPV-induced immune response and pathogenesis.
Type of Paper: Review
Title: Host-Viral Interactions: Role of PRRs in Human Pneumovirus Infections
Authors: Deepthi Kolli, Thangam Sudha Velayutham and Antonella Casola
Affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
Abstract: 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.
Keywords: PRRs; RSV; hMPV; innate immunity
Type of Paper: Article
Title: Mycobacterium tuberculosis in the Guinea Pig Model of Infection
Authors: Karen M. Dobos
Affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, 1682 Campus Delivery, Colorado State University, Fort Collins, CO 80523–1682, USA; E-Mail: Karen.Dobos@Colostate.Edu
Abstract: Mycobacterium tuberculosis (Mtb) currently infects approximately 2 billion people worldwide, most of whom are in a state of latency and are not contagious, although are at risk for reactivation. The only vaccine available for use in humans against tuberculosis (TB) is a live attenuated strain of the closely related M bovis, Bacille Calmette-Guerin (BCG). A shortfall of BCG is that it is unable to protect against adult pulmonary TB, and is unable to prevent reactivation of latent tuberculosis. Vaccine focus has thus turned to developing subunit vaccines which contain a single antigen and is delivered with an adjuvant to either boost previously administered BCG, or to be given as a stand-alone subunit vaccine. One such antigen from Mtb is the small heat shock protein and molecular chaperone, HspX. This protein has been implicated as a latency associated antigen because it is highly up-regulated in times of stress and hypoxia, is required for growth within macrophages, and is preferentially recognized by sera latently infected patients. When given as a vaccine in the mouse, the native form of the protein isolated from Mtb was protective, but the recombinant HspX expressed and purified from E coli was not protective; in contrast, recombinant HspX incubated with, and purified from Mtb lysate, regained its ability to protect mice from challenge. Thus, HspX mediated protection may be based on its ability to properly chaperone other molecules in vivo. In this report, vaccination studies with these three HspX protein constructs were performed in guinea pigs experimentally infected with Mtb. In these studies, none of the HspX formulations were protective when animals were challenged with WT Mtb. Interestingly, some protective effect was observed with the HspX constructs when animals were challenged with a strain of Mtb lacking the HspX gene (ΔHspX, strain X4-19). This supports the conjecture that the protective effect of HspX is related to its function. In addition to these vaccine studies, the virulence of Mtb X4-19 in the guinea pig model of infection was compared to the wild type strain; X4-19 exhibits a loss of virulence phenotype in the guinea pig model. Quantitative PCR and whole genome sequencing analysis identified several proteins, in addition to HspX, with reduced expression and/or single nucleotide polymorphisms that may contribute to this phenotype. Taken together, the data suggests physiological differences in the establishment of Mtb infection between the mouse and guinea pig models of disease that affects the potential of specific vaccines to elicit a protective immune response.
Type of Paper: Review
Title: Experimental Models of Bacterial Vaginosis: Past, Present, and Future
Authors: Amanda Lewis
Affiliation: Washington University in St. Louis School of Medicine, USA; E-Mail: firstname.lastname@example.org
Abstract: Bacterial vaginosis (BV) is a common vaginal condition that is characterized by the absence/loss of ‘beneficial’ lactobacilli and an overgrowth of diverse mixtures of ‘BV-associated bacteria’, mostly fastidious anaerobes. Reproductive age and pregnant women with BV are at increased risk of secondary infections, infectious complications of surgery, uterine infections during pregnancy, and preterm birth. There have been significant hurdles in the development of experimental models for BV, in part due to the polymicrobial nature of the condition, taken together with the fact that the bacterial species associated with BV are difficult to grow and are so far mostly genetically intractable. Here we review experimental approaches that have been used to gain insights into this polymicrobial dysbiosis, including (1) co-culture-based in vitro models, (2) biochemical/enzymatic approaches, (3) systems approaches, and (4) animal infection models. These experimental systems have revealed insights into synergistic and antagonistic bacterial interactions, vaginal mucus degradation, and epithelial cell cytotoxicity and exfoliation. However, many important questions remain. The development of robust physiologically relevant model systems is an essential component of ongoing and future BV research. A better understanding of BV at the molecular, cellular, and mucosal levels can translate into new ideas for prevention of upper reproductive tract infections by BV-associated bacteria during pregnancy.