Editor’s Choice Articles

The term “prion disease” encompasses a group of neurodegenerative diseases affecting both humans and animals. Currently, there is no effective therapy and all forms of prion disease are invariably fatal. Because of (a) the outbreak of bovine spongiform encephalopathy in cattle and variant Creutzfeldt–Jakob disease in humans; (b) the heated debate about the prion hypothesis; and (c) the availability of a natural prion disease in rodents, the understanding of the pathogenic process in prion disease is much more advanced compared to that of other neurodegenerative disorders, which inspired many attempts to develop therapeutic strategies against these fatal diseases. In this review, we focus on immunotherapy against prion disease. We explain our rationale for immunotherapy as a plausible therapeutic choice, review previous trials using either active or passive immunization, and discuss potential strategies for overcoming the hurdles in developing a successful immunotherapy. We propose that immunotherapy is a plausible and practical therapeutic strategy and advocate more studies in this area to develop effective measures to control and treat these devastating disorders. Full article

Lassa virus (LASV), the causative agent of Lassa fever, is estimated to be responsible for up to 300,000 new infections and 5000 deaths each year across Western Africa. The most recent 2018 and 2019 Nigerian outbreaks featured alarmingly high fatality rates of up to 25.4%. In addition to the severity and high fatality of the disease, a significant population of survivors suffer from long-term sequelae, such as sensorineural hearing loss, resulting in a huge socioeconomic burden in endemic regions. There are no Food and Drug Administration (FDA)-approved vaccines, and therapeutics remain extremely limited for Lassa fever. Development of countermeasures depends on relevant animal models that can develop a disease strongly mimicking the pathogenic features of Lassa fever in humans. The objective of this review is to evaluate the currently available animal models for LASV infection with an emphasis on their pathogenic and histologic characteristics as well as recent advances in the development of a suitable rodent model. This information may facilitate the development of an improved animal model for understanding disease pathogenesis of Lassa fever and for vaccine or antiviral testing. Full article

Coronaviruses (CoVs) are RNA viruses that have become a major public health concern since the Severe Acute Respiratory Syndrome-CoV (SARS-CoV) outbreak in 2002. The continuous evolution of coronaviruses was further highlighted with the emergence of the Middle East Respiratory Syndrome-CoV (MERS-CoV) outbreak in 2012. Currently, the world is concerned about the 2019 novel CoV (SARS-CoV-2) that was initially identified in the city of Wuhan, China in December 2019. Patients presented with severe viral pneumonia and respiratory illness. The number of cases has been mounting since then. As of late February 2020, tens of thousands of cases and several thousand deaths have been reported in China alone, in addition to thousands of cases in other countries. Although the fatality rate of SARS-CoV-2 is currently lower than SARS-CoV, the virus seems to be highly contagious based on the number of infected cases to date. In this review, we discuss structure, genome organization, entry of CoVs into target cells, and provide insights into past and present outbreaks. The future of human CoV outbreaks will not only depend on how the viruses will evolve, but will also depend on how we develop efficient prevention and treatment strategies to deal with this continuous threat. Full article

Aggregatibacter actinomycetemcomitans, the focus of this review, was initially proposed as a microbe directly related to a phenotypically distinct form of periodontitis called localized juvenile periodontitis. At the time, it seemed as if specific microbes were implicated as the cause of distinct forms of disease. Over the years, much has changed. The sense that specific microbes relate to distinct forms of disease has been challenged, as has the sense that distinct forms of periodontitis exist. This review consists of two components. The first part is presented as a detective story where we attempt to determine what role, if any, Aggregatibacter plays as a participant in disease. The second part describes landscape ecology in the context of how the host environment shapes the framework of local microbial dysbiosis. We then conjecture as to how the local host response may limit the damage caused by pathobionts. We propose that the host may overcome the constant barrage of a dysbiotic microbiota by confining it to a local tooth site. We conclude speculating that the host response can confine local damage by restricting bacteremic translocation of members of the oral microbiota to distant organs thus constraining morbidity and mortality of the host. Full article

Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has received an increasing amount of attention from virologists, clinicians, veterinarians, and epidemiologists over the past decade. The host range and animal reservoirs of HEV are rapidly expanding and a plethora of emerging HEV variants have been recently identified, some of which have the potential for interspecies infection. In this review, the detection of genetically diverse HEV variants, classified into and presumably associated with the species Orthohepevirus C, currently comprising HEV genotypes C1 and C2, by either serological or molecular approach is summarized. The distribution, genomic variability, and evolution of Orthohepevirus C are analyzed. Moreover, the potential risk of cross-species infection and zoonotic transmission of Orthohepevirus C are discussed. Full article

Porcine epidemic diarrhea virus (PEDV) is a highly virulent re-emerging enteric coronavirus that causes acute diarrhea, dehydration, and up to 100% mortality in neonatal suckling piglets. Despite this, a safe and effective PEDV vaccine against highly virulent strains is unavailable, making PEDV prevention and control challenging. Lactogenic immunity induced via the gut-mammary gland-secretory IgA (sIgA) axis, remains the most promising and effective way to protect suckling piglets from PEDV. Therefore, a successful PEDV vaccine must induce protective maternal IgA antibodies that passively transfer into colostrum and milk. Identifying variables that influence lymphocyte migration and IgA secretion during gestation and lactation is imperative for designing maternal immunization strategies that generate the highest amount of lactogenic immune protection against PEDV in suckling piglets. Because pregnancy-associated immune alterations influence viral pathogenesis and adaptive immune responses in many different species, a better understanding of host immune responses to PEDV in pregnant swine may translate into improved maternal immunization strategies against enteric pathogens for multiple species. In this review, we discuss the role of host factors during pregnancy on antiviral immunity and their implications for generating protective lactogenic immunity in suckling neonates. Full article

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer. Full article

The outbreaks of viral encephalopathy and retinopathy (VER), caused by nervous necrosis virus (NNV), represent one of the main infectious threats for marine aquaculture worldwide. Since the first description of the disease at the end of the 1980s, a considerable amount of research has gone into understanding the mechanisms involved in fish infection, developing reliable diagnostic methods, and control measures, and several comprehensive reviews have been published to date. This review focuses on host–virus interaction and epidemiological aspects, comprising viral distribution and transmission as well as the continuously increasing host range (177 susceptible marine species and epizootic outbreaks reported in 62 of them), with special emphasis on genotypes and the effect of global warming on NNV infection, but also including the latest findings in the NNV life cycle and virulence as well as diagnostic methods and VER disease control. Full article

Epstein–Barr virus (EBV) and Helicobacter pylori (H. pylori) are two pathogens associated with the development of various human cancers. The coexistence of both microorganisms in gastric cancer specimens has been increasingly reported, suggesting that crosstalk of both pathogens may be implicated in the carcinogenesis process. Considering that chronic inflammation is an initial step in the development of several cancers, including gastric cancer, we conducted a systematic review to comprehensively evaluate publications in which EBV and H. pylori co-infection has been documented in patients with non-malignant gastroduodenal disorders (NMGDs), including gastritis, peptic ulcer disease (PUD), and dyspepsia. We searched the PubMed database up to August 2019, as well as publication references and, among the nine studies that met the inclusion criteria, we identified six studies assessing EBV infection directly in gastric tissues (total 949 patients) and three studies in which EBV infection status was determined by serological methods (total 662 patients). Due to the substantial methodological and clinical heterogeneity among studies identified, we could not conduct a meta-analysis. The overall prevalence of EBV + H. pylori co-infection in NMGDs was 34% (range 1.8% to 60%). A higher co-infection rate (EBV + H. pylori) was reported in studies in which EBV was documented by serological methods in comparison with studies in which EBV infection was directly assessed in gastric specimens. The majority of these studies were conducted in Latin-America and India, with most of them comparing NMGDs with gastric cancer, but there were no studies comparing the co-infection rate in NMGDs with that in asymptomatic individuals. In comparison with gastritis caused by only one of these pathogens, EBV + H. pylori co-infection was associated with increased severity of gastric inflammation. In conclusion, only relatively small studies testing EBV and H. pylori co-infection in NMGDs have been published to date and the variable report results are likely influenced by geographic factors and detection methods. Full article

Infectious pancreatic necrosis (IPN) is a disease of great concern in aquaculture, mainly among salmonid farmers, since losses in salmonid fish—mostly very young rainbow trout (Salmo gairdnery) fry and Atlantic salmon (Salmo salar) post-smolt—frequently reach 80–90% of stocks. The virus causing the typical signs of the IPN disease in salmonids, named infectious pancreatic necrosis virus (IPNV), has also been isolated from other fish species either suffering related diseases (then named IPNV-like virus) or asymptomatic; the general term aquabirnavirus is used to encompass all these viruses. Aquabirnaviruses are non-enveloped, icosahedral bisegmented dsRNA viruses, whose genome codifies five viral proteins, three of which are structural, and one of them is an RNA-dependent RNA polymerase. Due to the great importance of the disease, there have been great efforts to find a way to predict the level of virulence of IPNV isolates. The viral genome and proteins have been the main focus of research. However, to date such a reliable magic marker has not been discovered. This review describes the processes followed for decades in the attempts to discover the viral determinants of virulence, and to help the reader understand how viral components can be involved in virulence modulation in vitro and in vivo. There is also a brief description of the disease, of host defenses, and of the molecular structure and function of the virus and its viral components. Full article

The ideal laboratory test to detect Neisseria gonorrhoeae (Ng) should be sensitive, specific, easy to use, rapid, and affordable and should provide information about susceptibility to antimicrobial drugs. Currently, such a test is not available and presumably will not be in the near future. Thus, diagnosis of gonococcal infections presently includes application of different techniques to address these requirements. Microscopy may produce rapid results but lacks sensitivity in many cases (except symptomatic urogenital infections in males). Highest sensitivity to detect Ng was shown for nucleic acid amplification technologies (NAATs), which, however, are less specific than culture. In addition, comprehensive analysis of antibiotic resistance is accomplished only by in vitro antimicrobial susceptibility testing of cultured isolates. As a light at the end of the tunnel, new developments of molecular techniques and microfluidic systems represent promising opportunities to design point-of-care tests for rapid detection of Ng with high sensitivity and specificity, and there is reason to hope that such tests may also provide antimicrobial resistance data in the future. Full article

Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenance of life and that characterize the execution of activities of daily life generally present periodic variations, which are mostly synchronized with the light–dark cycle determined by Earth’s rotation on its axis. These rhythms with 24-h periodicity, defined as circadian, influence events linked to the interaction between hosts and hosted microorganisms and can dramatically determine the outcome of this interplay. As for the various pathological conditions resulting from host–microorganism interactions, a particularly interesting scenario concerns infections by viruses. When a viral agent enters the body, it alters the biological processes of the infected cells in order to favour its replication and to spread to various tissues. Though our knowledge concerning the mutual influence between the biological clock and viruses is still limited, recent studies start to unravel interesting aspects of the clock–virus molecular interplay. Three different aspects of this interplay are addressed in this mini-review and include the circadian regulation of both innate and adaptive immune systems, the impact of the biological clock on viral infection itself, and finally the putative perturbations that the virus may confer to the clock leading to its deregulation. Full article

West Nile virus (WNV) continues to be a major cause of human arboviral neuroinvasive disease. Susceptible non-human vertebrates are particularly diverse, ranging from commonly affected birds and horses to less commonly affected species such as alligators. This review summarizes the pathology caused by West Nile virus during natural infections of humans and non-human animals. While the most well-known findings in human infection involve the central nervous system, WNV can also cause significant lesions in the heart, kidneys and eyes. Time has also revealed chronic neurologic sequelae related to prior human WNV infection. Similarly, neurologic disease is a prominent manifestation of WNV infection in most non-human non-host animals. However, in some avian species, which serve as the vertebrate host for WNV maintenance in nature, severe systemic disease can occur, with neurologic, cardiac, intestinal and renal injury leading to death. The pathology seen in experimental animal models of West Nile virus infection and knowledge gains on viral pathogenesis derived from these animal models are also briefly discussed. A gap in the current literature exists regarding the relationship between the neurotropic nature of WNV in vertebrates, virus propagation and transmission in nature. This and other knowledge gaps, and future directions for research into WNV pathology, are addressed. Full article

Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient packaging. However, in cells, capsid interacts with many proteins and nucleic acids and we are only beginning to understand the broad range of functions of flaviviral capsids. It is known that capsid dimers interact with the membrane of lipid droplets, aiding in both viral packaging and storage of capsid prior to packaging. However, capsid dimers can bind a range of nucleic acid templates in vitro, and likely interact with a range of targets during the flavivirus lifecycle. Capsid may interact with host RNAs, resulting in altered RNA splicing and RNA transcription. Capsid may also bind short interfering-RNAs and has been proposed to sequester these species to protect flaviviruses from the invertebrate siRNA pathways. Capsid can also be found in the nucleolus, where it wreaks havoc on ribosome biogenesis. Here we review flavivirus capsid structure, nucleic acid interactions and how these give rise to multiple functions. We also discuss how these features might be exploited either in the design of effective antivirals or novel vaccine strategies. Full article

Ascomycete Sclerotinia sclerotiorum (Lib.) de Bary is one of the most damaging soilborne fungal pathogens affecting hundreds of plant hosts, including many economically important crops. Its genomic sequence has been available for less than a decade, and it was recently updated with higher completion and better gene annotation. Here, we review key molecular findings on the unique biology and pathogenesis process of S. sclerotiorum, focusing on genes that have been studied in depth using mutant analysis. Analyses of these genes have revealed critical players in the basic biological processes of this unique pathogen, including mycelial growth, appressorium establishment, sclerotial formation, apothecial and ascospore development, and virulence. Additionally, the synthesis has uncovered gaps in the current knowledge regarding this fungus. We hope that this review will serve to build a better current understanding of the biology of this under-studied notorious soilborne pathogenic fungus. Full article

Chloroplasts play a central role in plant immunity through the synthesis of secondary metabolites and defense compounds, as well as phytohormones, such as jasmonic acid and salicylic acid. Additionally, chloroplast metabolism results in the production of reactive oxygen species and nitric oxide as defense molecules. The impact of viral and bacterial infections on plastids and chloroplasts has been well documented. In particular, bacterial pathogens are known to introduce effectors specifically into chloroplasts, and many viral proteins interact with chloroplast proteins to influence viral replication and movement, and plant defense. By contrast, clear examples are just now emerging for chloroplast-targeted effectors from fungal and oomycete pathogens. In this review, we first present a brief overview of chloroplast contributions to plant defense and then discuss examples of connections between fungal interactions with plants and chloroplast function. We then briefly consider well-characterized bacterial effectors that target chloroplasts as a prelude to discussing the evidence for fungal effectors that impact chloroplast activities. Full article

Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein–Barr virus (EBV) infection, and biopsies display variable levels of expression of the viral oncoprotein, latent membrane protein 1 (LMP1). Emerging evidence suggests an important role for cancer-associated fibroblasts (CAFs) in the NPC tumour microenvironment, yet the interaction between the virus, its latent gene products and the recruitment and activation of CAFs in the NPC tumour stroma remains unclear. This short review will discuss the current evidence for the importance of CAFs in NPC pathogenesis and outline a putative role for the EBV-encoded oncoprotein, LMP1, in governing tumour–stromal interactions. Full article

Neisseria species are extremely well-adapted to their mammalian hosts and they display unique phenotypes that account for their ability to thrive within niche-specific conditions. The closely related species N. gonorrhoeae and N. meningitidis are the only two species of the genus recognized as strict human pathogens, causing the sexually transmitted disease gonorrhea and meningitis and sepsis, respectively. Gonococci colonize the mucosal epithelium of the male urethra and female endo/ectocervix, whereas meningococci colonize the mucosal epithelium of the human nasopharynx. The pathophysiological host responses to gonococcal and meningococcal infection are distinct. However, medical evidence dating back to the early 1900s demonstrates that these two species can cross-colonize anatomical niches, with patients often presenting with clinically-indistinguishable infections. The remaining Neisseria species are not commonly associated with disease and are considered as commensals within the normal microbiota of the human and animal nasopharynx. Nonetheless, clinical case reports suggest that they can behave as opportunistic pathogens. In this review, we describe the diversity of the genus Neisseria in the clinical context and raise the attention of microbiologists and clinicians for more cautious approaches in the diagnosis and treatment of the many pathologies these species may cause. Full article

The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is a key molecule on the bacterial cell wall that is recognized by the host to deploy an immune defence in order to neutralize invading pathogens. However, LPS also promotes bacterial survival in a host environment by protecting the bacteria from these threats. This review explores the relationship between the different LPS glycoforms of the opportunistic pathogen Pseudomonas aeruginosa and the ability of this organism to cause persistent infections, especially in the genetic disease cystic fibrosis. We also discuss the role of LPS in facilitating biofilm formation, antibiotic resistance, and how LPS may be targeted by new antimicrobial therapies. Full article

Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates to longstanding consequences of infection, and optimal case management, also remain shrouded in controversy. At the heart of this multidisciplinary issue are the causative spirochetal pathogens belonging to the Borrelia Lyme complex. Their unusual physiology and versatile lifestyle have challenged microbiologists, and may also hold the key to unlocking mysteries of the disease. The goal of this review is therefore to integrate established and emerging concepts of Borrelia biology and pathogenesis, and position them in the broader context of biomedical research and clinical practice. We begin by considering the conventions around diagnosing and characterizing Lyme disease that have served as a conceptual framework for the discipline. We then explore virulence from the perspective of both host (genetic and environmental predispositions) and pathogen (serotypes, dissemination, and immune modulation), as well as considering antimicrobial strategies (lab methodology, resistance, persistence, and clinical application), and borrelial adaptations of hypothesized medical significance (phenotypic plasticity or pleomorphy). Full article

West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis. Full article

Tissue resident memory (T_RM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. T_RM cells often recognize conserved peptide epitopes shared among different strains of a pathogen and so offer a protective role upon secondary encounter with the same or related pathogens. Several recent studies have begun to shed light on the intrinsic and extrinsic factors regulating T_RM. In addition, work is being done to understand how canonical “markers” of T_RM actually affect the function of these cells. Many of these markers regulate the generation or persistence of these T_RM cells, an important point of study due to the differences in persistence of T_RM between tissues, which may impact future vaccine development to cater towards these important differences. In this review, we will discuss recent advances in T_RM biology that may lead to strategies designed to promote this important protective immune subset. Full article

West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions. Full article

A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. Full article

When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection. Full article

Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER multiprotein complexes as vital factors for flavivirus replication. The detailed mechanisms of the role of ER complexes in flavivirus replication are still largely elusive. This review highlights the fact that the ER multiprotein complexes are crucial for the formation of flavivirus replication and assembly complexes, and the ER complexes could be considered as a target for developing successful broad-spectrum anti-flavivirus drugs. Full article

Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD. Full article

Japanese encephalitis virus (JEV) is an emerging flavivirus of the Asia-Pacific region. More than two billion people live in endemic or epidemic areas and are at risk of infection. Recently, the first autochthonous human case was recorded in Africa, and infected birds have been found in Europe. JEV may spread even further to other continents. The first section of this review covers established and new information about the epidemiology of JEV. The subsequent sections focus on the impact of JEV on humans, including the natural course and immunity. Furthermore, new concepts are discussed about JEV’s entry into the brain. Finally, interactions of JEV and host cells are covered, as well as how JEV may spread in the body through latently infected immune cells and cell-to-cell transmission of virions or via other infectious material, including JEV genomic RNA. Full article

The airway epithelium is the primary target of respiratory syncytial virus infection. It is an important component of the antiviral immune response. It contributes to the recruitment and activation of innate immune cells from the periphery through the secretion of cytokines and chemokines. This paper provides a broad review of the cytokines and chemokines secreted from human airway epithelial cell models during respiratory syncytial virus (RSV) infection based on a comprehensive literature review. Epithelium-derived chemokines constitute most inflammatory mediators secreted from the epithelium during RSV infection. This suggests chemo-attraction of peripheral immune cells, such as monocytes, neutrophils, eosinophils, and natural killer cells as a key function of the epithelium. The reports of epithelium-derived cytokines are limited. Recent research has started to identify novel cytokines, the functions of which remain largely unknown in the wider context of the RSV immune response. It is argued that the correct choice of in vitro models used for investigations of epithelial immune functions during RSV infection could facilitate greater progress in this field. Full article

Persistent infection is a characteristic feature of babesiosis, a worldwide, emerging tick-borne disease caused by members of the genus Babesia. Persistence of Babesia infection in reservoir hosts increases the probability of survival and transmission of these pathogens. Laboratory tools to detect Babesia in red blood cells include microscopic detection using peripheral blood smears, nucleic acid detection (polymerase chain reaction and transcription mediated amplification), antigen detection, and antibody detection. Babesia microti, the major cause of human babesiosis, can asymptomatically infect immunocompetent individuals for up to two years. Chronically infected blood donors may transmit the pathogen to another person through blood transfusion. Transfusion-transmitted babesiosis causes severe complications and death in about a fifth of cases. Immunocompromised patients, including those with asplenia, HIV/AIDS, malignancy, or on immunosuppressive drugs, often experience severe disease that may relapse up to two years later despite anti-Babesia therapy. Persistent Babesia infection is promoted by Babesia immune evasive strategies and impaired host immune mechanisms. The health burden of persistent and recrudescent babesiosis can be minimized by development of novel therapeutic measures, such as new anti-parasitic drugs or drug combinations, improved anti-parasitic drug duration strategies, or immunoglobulin preparations; and novel preventive approaches, including early detection methods, tick-avoidance, and blood donor screening. Full article

Bacteriophages (phages) are biological entities that have attracted a great deal of attention in recent years. They have been reported as the most abundant biological entities on the planet and their ability to impact the composition of bacterial communities is of great interest. In this review, we aim to explore where phages exist in natural and artificial environments and how they impact communities. The natural environment in this review will focus on the human body, soils, and the marine environment. In these naturally occurring environments there is an abundance of phages suggesting a role in the maintenance of bacterial community homeostasis. The artificial environment focuses on wastewater treatment plants, industrial processes, followed by pharmaceutical formulations. As in natural environments, the existence of bacteria in manmade wastewater treatment plants and industrial processes inevitably attracts phages. The presence of phages in these environments can inhibit the bacteria required for efficient water treatment or food production. Alternatively, they can have a positive impact by eliminating recalcitrant organisms. Finally, we conclude by describing how phages can be manipulated or formulated into pharmaceutical products in the laboratory for use in natural or artificial environments. Full article

A growing world population and an increasing demand for greater food production requires that crop losses caused by pests and diseases are dramatically reduced. Concurrently, sustainability targets mean that alternatives to chemical pesticides are becoming increasingly desirable. Bacteria in the plant root microbiome can protect their plant host against pests and pathogenic infection. In particular, Streptomyces species are well-known to produce a range of secondary metabolites that can inhibit the growth of phytopathogens. Streptomyces are abundant in soils and are also enriched in the root microbiomes of many different plant species, including those grown as economically and nutritionally valuable cereal crops. In this review we discuss the potential of Streptomyces to protect against some of the most damaging cereal crop diseases, particularly those caused by fungal pathogens. We also explore factors that may improve the efficacy of these strains as biocontrol agents in situ, as well as the possibility of exploiting plant mechanisms, such as root exudation, that enable the recruitment of microbial species from the soil to the root microbiome. We argue that a greater understanding of these mechanisms may enable the development of protective plant root microbiomes with a greater abundance of beneficial bacteria, such as Streptomyces species. Full article

Cattle infected with Babesia bovis face a bifurcated fate: Either die of the severe acute infection, or survive and carry for many years a highly persistent but generally asymptomatic infection. In this review, the author describes known and potential contributions of three variable or highly variant multigene-encoded families of proteins to persistence in the bovine host, and the mechanisms by which variability arises among these families. Ramifications arising from this variability are discussed. Full article

Respiratory syncytial virus (RSV) is a human respiratory pathogen which remains a leading viral cause of hospitalizations and mortality among infants in their first year of life. Here, we review the biology of RSV, the primary laboratory isolates or strains which have been used to best characterize the virus since its discovery in 1956, and discuss the implications for genetic and functional variations between the established laboratory strains and the recently identified clinical isolates. Full article

Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current knowledge on fungal-bacterial interactions during their commensal and pathogenic lifestyle. We focus on distinct mucosal niches: the oral cavity, lung, gut, and vagina. In addition, we describe interactions during bloodstream and wound infections and the possible consequences for the human host. Full article

Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal surface is an essential prerequisite for fungal colonisation and epitomises the complex interface between microbe and host. C. albicans exhibits numerous adaptations to a healthy host that permit commensal colonisation of mucosal surfaces without provoking an overt immune response that may lead to clearance. Conversely, fungal adaptation to impaired immune fitness at mucosal surfaces enables pathogenic infiltration into underlying tissues, often with devastating consequences. This review will summarise our current understanding of the complex interactions that occur between C. albicans and the mucosal surfaces of the human body. Full article

The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are contrasted by the important host beneficial effects of this cytokine. IL-17 is essential for regulating microbial colonization in barrier tissues. Rare congenital defects in the IL-17 pathway exemplify the relevance of IL-17 in protective immunity against the opportunistic fungal pathogen C. albicans. However, more recently, evidence is accumulating that IL-17 can also provide protection against fungi other than C. albicans. Importantly, protective IL-17 responses directed against commensal fungi can, under certain conditions, promote inflammation with detrimental consequences for the host, thereby assigning fungi a new role as disease-promoting factors apart from their role as potential infectious agents. Full article

Apicomplexan parasites are protozoan organisms that are characterised by complex life cycles and they include medically important species, such as the malaria parasite Plasmodium and the causative agents of toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp.). Apicomplexan parasites can infect one or more hosts, in which they differentiate into several morphologically and metabolically distinct life cycle stages. These developmental transitions rely on changes in gene expression. In the last few years, the important roles of different members of the ApiAP2 transcription factor family in regulating life cycle transitions and other aspects of parasite biology have become apparent. Here, we review recent progress in our understanding of the different members of the ApiAP2 transcription factor family in apicomplexan parasites. Full article

Life expectancy in the West is the highest it has ever been, due to the introduction of better hygiene practices and sophisticated medical interventions for cancer, autoimmunity and infectious disease. With these modern advances, a rise in the prevalence of opportunistic infections has also been observed. These include several fungal infections, which present a particular clinical challenge due to the lack of fungal vaccines, limited diagnostics and increasing antifungal drug resistance. This mini-review outlines how modern-day clinical practices have shaped the recent increase in fungal diseases observed in the last few decades. We discuss new research that has implicated the use of immune-modulating drugs in the enhanced susceptibility of vulnerable patients to life-threatening fungal infections. Full article

Over the last decades, fungal infections have emerged as a growing threat to human health. Although the human body is at potential risk, various body sites host several commensal fungal species, including Candida albicans. In healthy individuals, C. albicans colonizes different mucosal surfaces without causing harm, while under diverse circumstances the fungus can proliferate and cause disease. In this context, the understanding of host–C. albicans interactions in health and during infection may lead to novel therapeutic approaches. Importantly, host cells express pattern recognition receptors (PRRs), which sense conserved fungal structures and orchestrate innate immune responses. Herein, important findings on the topic of the recognition of C. albicans at host barrier sites are discussed. This review briefly summarizes the importance and functions of myeloid PRRs, reviews the fungal recognition and biology of stromal cells, and highlights important C. albicans virulence attributes during site-specific proliferation and invasion. Full article

The Fusarium species has diverse ecological functions ranging from saprophytes, endophytes, and animal and plant pathogens. Occasionally, they are isolated from dead and alive insects. However, research on fusaria-insect associations is very limited as fusaria are generalized as opportunistic insect-pathogens. Additionally, their phytopathogenicity raises concerns in their use as commercial biopesticides. Insect biocontrol potential of Fusarium is favored by their excellent soil survivability as saprophytes, and sometimes, insect-pathogenic strains do not exhibit phytopathogenicity. In addition, a small group of fusaria, those belonging to the Fusarium solani species complex, act as insect mutualists assisting in host growth and fecundity. In this review, we summarize mutualism and pathogenicity among fusaria and insects. Furthermore, we assert on Fusarium entomopathogenicity by analyzing previous studies clearly demonstrating their natural insect-pathogenicity in fields, and their presence in soils. We also review the presence and/or production of a well-known insecticidal metabolite beauvericin by different Fusarium species. Lastly, some proof-of-concept studies are also summarized, which demonstrate the histological as well as immunological changes that a larva undergoes during Fusarium oxysporum pathogenesis. These reports highlight the insecticidal properties of some Fusarium spp., and emphasize the need of robust techniques, which can distinguish phytopathogenic, mutualistic and entomopathogenic fusaria. Full article

Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. Approximately 1.7 billion people are latently infected with TB and on reactivation many of these infections are drug resistant. As the current treatment is ineffective and diagnosis remains poor, millions of people have the potential to reactivate into active TB disease. The immune system seeks to control the TB infection by containing the bacteria in a granuloma, where it is exposed to stressful anaerobic and nutrient deprived conditions. It is thought to be these environmental conditions that trigger the NRP state. A number of in vitro models have been developed that mimic conditions within the granuloma to a lesser or greater extent. These different models have all been utilised for the research of different characteristics of NRP Mycobacterium tuberculosis, however their disparity in approach and physiological relevance often results in inconsistencies and a lack of consensus between studies. This review provides a summation of the different NRP models and a critical analysis of their respective advantages and disadvantages relating to their physiological relevance. Full article

In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world’s foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa virus (LASV) isolated from West African patient samples was far greater than that of the Ebola isolates from the West African epidemic of 2013–2016. Thus, vaccines produced against Lassa virus disease face the added challenge that they must be broadly-protective against a wide variety of LASV. In this review, we discuss what is known about the immune response to Lassa infection. We also discuss the approaches used to make broadly-protective influenza vaccines and how they could be applied to developing broad vaccine coverage against LASV disease. Recent advances in AIDS research are also potentially applicable to the design of broadly-protective medical countermeasures against LASV disease. Full article

This review considers current knowledge surrounding species boundaries of the Armillaria root-rot pathogens and their distribution. In addition, a phylogenetic tree using translation elongation factor subunit 1-alpha (tef-1α) from isolates across the globe are used to present a global phylogenetic framework for the genus. Defining species boundaries based on DNA sequence-inferred phylogenies has been a central focus of contemporary mycology. The results of such studies have in many cases resolved the biogeographic history of species, mechanisms involved in dispersal, the taxonomy of species and how certain phenotypic characteristics have evolved throughout lineage diversification. Such advances have also occurred in the case of Armillaria spp. that include important causal agents of tree root rots. This commenced with the first phylogeny for Armillaria that was based on IGS-1 (intergenic spacer region one) DNA sequence data, published in 1992. Since then phylogenies were produced using alternative loci, either as single gene phylogenies or based on concatenated data. Collectively these phylogenies revealed species clusters in Armillaria linked to their geographic distributions and importantly species complexes that warrant further research. Full article

Silks are the long threads at the tips of maize ears onto which pollen land and sperm nuclei travel long distances to fertilize egg cells, giving rise to embryos and seeds; however fungal pathogens also use this route to invade developing grain, causing damaging ear rots with dangerous mycotoxins. This review highlights the importance of silks as the direct highways by which globally important fungal pathogens enter maize kernels. First, the most important silk-entering fungal pathogens in maize are reviewed, including Fusarium graminearum, Fusarium verticillioides, and Aspergillus flavus, and their mycotoxins. Next, we compare the different modes used by each fungal pathogen to invade the silks, including susceptible time intervals and the effects of pollination. Innate silk defences and current strategies to protect silks from ear rot pathogens are reviewed, and future protective strategies and silk-based research are proposed. There is a particular gap in knowledge of how to improve silk health and defences around the time of pollination, and a need for protective silk sprays or other technologies. It is hoped that this review will stimulate innovations in breeding, inputs, and techniques to help growers protect silks, which are expected to become more vulnerable to pathogens due to climate change. Full article

Takayasu arteritis (TAK) is a chronic vasculitis that mainly affects the aorta, its major branches, and the pulmonary arteries. Since the description of the first case by Mikito Takayasu in 1908, several aspects of this rare disease, including the epidemiology, diagnosis, and the appropriate clinical assessment, have been substantially defined. Nevertheless, while it is well-known that TAK is associated with a profound inflammatory process, possibly rooted to an autoimmune disorder, its precise etiology has remained largely unknown. Efforts to identify the antigen(s) that trigger autoimmunity in this disease have been unsuccessful, however, it is likely that viruses or bacteria, by a molecular mimicry mechanism, initiate or propagate the auto-immune process in this disease. In this article, we summarize recent advances in the understanding of TAK, with emphasis on new insights related to the pathogenesis of this entity that may contribute to the design of novel therapeutic approaches. Full article

The Toxoplasma gondii cellular cycle has been widely studied in many lifecycle stages; however, the egress event still is poorly understood even though different types of molecules were shown to be involved. Assuming that there is no purpose or intentionality in biological phenomena, there is no such question as “Why does the parasite leaves the host cell”, but “Under what conditions and how?”. In this review we aimed to summarize current knowledge concerning T. gondii egress physiology (signalling pathways), structures, and route. Full article

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic flavivirus, is an enveloped positive-strand RNA virus that can cause a spectrum of clinical manifestations, ranging from mild febrile illness to severe neuroinvasive disease. Today, several killed and live vaccines are available in different parts of the globe for use in humans to prevent JEV-induced diseases, yet no antivirals are available to treat JEV-associated diseases. Despite the progress made in vaccine research and development, JEV is still a major public health problem in southern, eastern, and southeastern Asia, as well as northern Oceania, with the potential to become an emerging global pathogen. In viral replication, the entry of JEV into the cell is the first step in a cascade of complex interactions between the virus and target cells that is required for the initiation, dissemination, and maintenance of infection. Because this step determines cell/tissue tropism and pathogenesis, it is a promising target for antiviral therapy. JEV entry is mediated by the viral glycoprotein E, which binds virions to the cell surface (attachment), delivers them to endosomes (endocytosis), and catalyzes the fusion between the viral and endosomal membranes (membrane fusion), followed by the release of the viral genome into the cytoplasm (uncoating). In this multistep process, a collection of host factors are involved. In this review, we summarize the current knowledge on the viral and cellular components involved in JEV entry into host cells, with an emphasis on the initial virus-host cell interactions on the cell surface. Full article

Zika virus (ZIKV) is a single-stranded RNA virus belonging to the arthropod-borne flaviviruses (arboviruses) which are mainly transmitted by blood-sucking mosquitoes of the genus Aedes. ZIKV infection has been known to be rather asymptomatic or presented as febrile self-limited disease; however, during the last decade the manifestation of ZIKV infection has been associated with a variety of neuroimmunological disorders including Guillain–Barré syndrome, microcephaly and other central nervous system abnormalities. More recently, there is accumulating evidence about sexual transmission of ZIKV, a trait that has never been observed in any other mosquito-borne flavivirus before. This article reviews the latest information regarding the latter and emerging role of ZIKV, focusing on the consequences of ZIKV infection on the male reproductive system and the epidemiology of human-to-human sexual transmission. Full article

The aim of this study was to evaluate the occurrence of parasitic infections in solid organ transplant (SOT) recipients. We conducted a systematic review of literature records on post-transplant parasitic infections, published from 1996 to 2016 and available on PubMed database, focusing only on parasitic infections acquired after SOT. The methods and findings of the present review have been presented based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. From data published in the literature, the real burden of parasitic infections among SOT recipients cannot really be estimated. Nevertheless, publications on the matter are on the increase, probably due to more than one reason: (i) the increasing number of patients transplanted and then treated with immunosuppressive agents; (ii) the “population shift” resulting from immigration and travels to endemic areas, and (iii) the increased attention directed to diagnosis/notification/publication of cases. Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of awareness, identification, and pre-emptive therapy are needed in transplant recipients. Full article