Current topics in microbiology and immunology最新文献

Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H. pylori infection represents a prime example of chronic inflammation and cancer-inducing bacterial pathogens. The microbe utilizes a remarkable set of virulence factors and strategies to control cellular checkpoints of inflammation and oncogenic signal transduction. This chapter emphasizes on the pathogenicity determinants of H. pylori such as the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system (T4SS), effector protein CagA, lipopolysaccharide (LPS) metabolite ADP-glycero-β-D-manno-heptose (ADP-heptose), cytotoxin VacA, serine protease HtrA, and urease, and how they manipulate various key host cell signaling networks in the gastric epithelium. In particular, we highlight the H. pylori-induced disruption of cell-to-cell junctions, pro-inflammatory activities, as well as proliferative, pro-apoptotic and anti-apoptotic responses. Here we review these hijacked signal transduction events and their impact on gastric disease development.

Males and females differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections and cancers. Cellular targets and molecular pathways underlying sexual dimorphism in immunity have started to emerge and appeared multifactorial. It became increasingly clear that sex-linked biological factors have important impact on the development, tissue maintenance and effector function acquisition of distinct immune cell populations, thereby regulating multiple layers of innate or adaptive immunity through distinct mechanisms. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in susceptibility to autoimmune diseases and allergies, and the sex-biased responses in natural immunity and cancer.

Fitness of viruses has become a standard parameter to quantify their adaptation to a biological environment. Fitness determinations for RNA viruses (and some highly variable DNA viruses) meet with several uncertainties. Of particular interest are those that arise from mutant spectrum complexity, absence of population equilibrium, and internal interactions among components of a mutant spectrum. Here, concepts, fitness measurements, limitations, and current views on experimental viral fitness landscapes are discussed. The effect of viral fitness on resistance to antiviral agents is covered in some detail since it constitutes a widespread problem in antiviral pharmacology, and a challenge for the design of effective antiviral treatments. Recent evidence with hepatitis C virus suggests the operation of mechanisms of antiviral resistance additional to the standard selection of drug-escape mutants. The possibility that high replicative fitness may be the driver of such alternative mechanisms is considered. New broad-spectrum antiviral designs that target viral fitness may curtail the impact of drug-escape mutants in treatment failures. We consider to what extent fitness-related concepts apply to coronaviruses and how they may affect strategies for COVID-19 prevention and treatment.

Viruses are studied at each level of biological complexity: from within-cells to ecosystems. The same basic evolutionary forces and principles operate at each level: mutation and recombination, selection, genetic drift, migration, and adaptive trade-offs. Great efforts have been put into understanding each level in great detail, hoping to predict the dynamics of viral population, prevent virus emergence, and manage their spread and virulence. Unfortunately, we are still far from this. To achieve these ambitious goals, we advocate for an integrative perspective of virus evolution. Focusing in plant viruses, we illustrate the pervasiveness of the above-mentioned principles. Beginning at the within-cell level, we describe replication modes, infection bottlenecks, and cellular contagion rates. Next, we move up to the colonization of distal tissues, discussing the fundamental role of random events. Then, we jump beyond the individual host and discuss the link between transmission mode and virulence. Finally, at the community level, we discuss properties of virus-plant infection networks. To close this review we propose the multilayer network theory, in which elements at different layers are connected and submit to their own dynamics that feed across layers, resulting in new emerging properties, as a way to integrate information from the different levels.

Mitochondria are major cellular organelles that play an essential role in metabolism, stress response, immunity, and cell fate. Mitochondria are organized in a network with other cellular compartments, functioning as a signaling hub to maintain cells' health. Mitochondrial dysfunctions and genome alterations are associated with diseases including cancer. Mitochondria are a preferential target for pathogens, which have developed various mechanisms to hijack cellular functions for their benefit. Helicobacter pylori is recognized as the major risk factor for gastric cancer development. H. pylori induces oxidative stress and chronic gastric inflammation associated with mitochondrial dysfunction. Its pro-apoptotic cytotoxin VacA interacts with the mitochondrial inner membrane, leading to increased permeability and decreased ATP production. Furthermore, H. pylori induces mitochondrial DNA damage and mutation, concomitant with the development of gastric intraepithelial neoplasia as observed in infected mice. In this chapter, we present diverse aspects of the role of mitochondria as energy supplier and signaling hubs and their adaptation to stress conditions. The metabolic activity of mitochondria is directly linked to biosynthetic pathways. While H. pylori virulence factors and derived metabolites are essential for gastric colonization and niche adaptation, they may also impact mitochondrial function and metabolism, and may have consequences in gastric pathogenesis. Importantly, during its long way to reach the gastric epithelium, H. pylori faces various cellular types along the gastric mucosa. We discuss how the mitochondrial response of these different cells is affected by H. pylori and impacts the colonization and bacterium niche adaptation and point to areas that remain to be investigated.

Simian varicella virus (SVV) was first isolated in 1966 from African green monkeys (Cercopithecus aethiops) imported from Nairobi, Kenya, to the Liverpool School of Tropical Medicine in the United Kingdom (UK) (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967). SVV infection caused severe disease that resulted in a 56% case fatality rate (CFR) in the imported animals within 48 h of the appearance of a varicella-like rash (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967; Hemme et al., Am J Trop Med Hyg 94:1095-1099, 2016). The deceased animals presented with fever, widespread vesicular rash, and multiple hemorrhagic foci throughout the lungs, liver, and spleen (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967). This outbreak was quickly followed by a second outbreak in 47 patas monkeys (Erythrocebus patas) imported from Chad and Nigeria by Glaxo Laboratories (London, England, UK), which quickly spread within the facility (McCarthy et al., Lancet 2:856-857, 1968).

Lassa fever is caused by Lassa virus (LASV), an Old World Mammarenavirus that is carried by Mastomys natalensis and other rodents. It is endemic in Sierra Leone, Nigeria, and other countries in West Africa. The clinical presentation of LASV infection is heterogenous varying from an inapparent or mild illness to a fatal hemorrhagic fever. Exposure to LASV is usually through contact with rodent excreta. After an incubation period of 1-3 weeks, initial symptoms such as fever, headache, and fatigue develop that may progress to sore throat, retrosternal chest pain, conjunctival injection, vomiting, diarrhea, and abdominal pain. Severe illness, including hypotension, shock, and multiorgan failure, develops in a minority of patients. Patient demographics and case fatality rates are distinctly different in Sierra Leone and Nigeria. Laboratory diagnosis relies on the detection of LASV antigens or genomic RNA. LASV-specific immunoglobulin G and M assays can also contribute to clinical management. The mainstay of treatment for Lassa fever is supportive care. The nucleoside analog ribavirin is commonly used to treat acute Lassa fever but is considered useful only if treatment is begun early in the disease course. Drugs in development, including a monoclonal antibody cocktail, have the potential to impact the management of Lassa fever.

Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic fever that is endemic in West Africa. LASV virions are enveloped and contain two single-stranded RNA genome segments. Both segments are ambisense and encode two proteins. The nucleoprotein associates with viral RNAs forming ribonucleoprotein complexes. The glycoprotein complex mediates viral attachment and entry. The Zinc protein serves as the matrix protein. Large is a polymerase that catalyzes viral RNA transcription and replication. LASV virion entry occurs via a clathrin-independent endocytic pathway usually involving alpha-dystroglycan and lysosomal associated membrane protein 1 as surface and intracellular receptors, respectively. Advances in understanding LASV structural biology and replication have facilitated development of promising vaccine and drug candidates.

Mutation, recombination and pseudo-recombination are the major forces driving the evolution of viruses by the generation of variants upon which natural selection, genetic drift and gene flow can act to shape the genetic structure of viral populations. Recombination between related virus genomes co-infecting the same cell usually occurs via template swapping during the replication process and produces a chimeric genome. The family Geminiviridae shows the highest evolutionary success among plant virus families, and the common presence of recombination signatures in their genomes reveals a key role in their evolution. This review describes the general characteristics of members of the family Geminiviridae and associated DNA satellites, as well as the extensive occurrence of recombination at all taxonomic levels, from strain to family. The review also presents an overview of the recombination patterns observed in nature that provide some clues regarding the mechanisms involved in the generation and emergence of recombinant genomes. Moreover, the results of experimental evolution studies that support some of the conclusions obtained in descriptive or in silico works are summarized. Finally, the review uses a number of case studies to illustrate those recombination events with evolutionary and pathological implications as well as recombination events in which DNA satellites are involved.

The wealth of variability amongst genes controlling immunity against potyviruses in pepper (Capsicum spp.) has been instrumental in understanding plant-virus co-evolution and major determinants of plant resistance durability. Characterization of the eukaryotic initiation factor 4E1 (eIF4E1), involved in mRNA translation, as the basis of potyvirus resistance in pepper initiated a large body of work that showed that recessive resistance to potyviruses and other single-stranded positive-sense RNA viruses resulted from mutations in eukaryotic initiation factors in many plant crop species. Combining mutations in different eIF4Es in the same pepper genotype had complex effects on the breadth of the resistance spectrum and on resistance durability, revealing a trade-off between these two traits. In addition, combining eIF4E1 mutations with a quantitatively resistant genetic background had a strong positive effect on resistance durability. Analysing the evolutionary forces imposed by pepper genotypes onto virus populations allowed identifying three key factors improving plant resistance durability: the complexity of mutational pathways involved in virus adaptation to the plant resistance, the decrease of competitivity induced by these mutations on the virus and the intensity of genetic drift imposed by plant genotypes on the virus during its infection cycle.