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A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes.

Key Points Mammals have evolved an elaborate, multifaceted immune system to respond to the ever-present threat of infection by pathogenic microorganisms. Bacterial, protozoan and fungal pathogens have responded by evolving equally elaborate systems to avoid destruction by their hosts. This process of coevolution has resulted in the development of complex genetic systems that underlie antigenic variation by numerous pathogenic microorganisms. The process of antigenic variation is focused at the host–pathogen interface, and in particular at the cell surface of the infectious organisms. Molecules displayed on the cell surface of pathogens often mediate adhesion within specific niches and are frequently virulence determinants. Some systems of antigenic variation involve the activation and silencing of genes that encode molecules exposed to the immune system of the infected host. In its simplest form, this entails changes in the expression of genes that are regulated individually, an on–off process referred to as phase variation. In other organisms, a single expression site is present for a key protein, with multiple silent gene copies or cassettes present elsewhere in the genome. The sequence of the expressed gene changes by gene conversion (or duplicative transposition) of large or small DNA sequences from the silent pseudogenes into the expression site. In more sophisticated systems, the pathogen has evolved large, multicopy gene families, with each copy encoding a different form of the surface antigen. In these organisms, each individual gene has all of the elements necessary for expression, and each undergoes silencing and activation as described above; however, there is an additional layer of regulation to ensure that only a single gene is active at any particular time. Gene silencing and activation within the family is therefore coordinated and strictly mutually exclusive. Although many of the genetic systems underlying antigenic variation — for example, slipped-strand mispairing or gene conversion — involve alterations to the genome, in several organisms changes in gene expression do not involve any alterations in the primary DNA sequence. These systems instead rely on epigenetic modifications to control gene activation and silencing, the hallmarks of which include histone modifications, the use of modified nucleotides, changes in chromatin structure and nuclear organization. In a few cases, the order in which specific antigen variants are expressed over the course of an infection is determined by the sequence of the encoding genes. This can help to extend the length of an infection or the infectious stage, thereby increasing the likelihood of transmission to a new host. Antigenic variation also enhances the capacity of a pathogen to infect a host that has resolved (or been cured of) prior infection (reinfection), or is persistently infected with the same organism (superinfection). This both expands the population of susceptible hosts and permits genetic exchange between organisms. To evade immune responses in mammalian hosts, many pathogens use complex genetic systems to vary the surface antigens that are recognized by host defences. In this Review, Kirk Deitsch and colleagues highlight how bacterial, protozoan and fungal pathogens from distinct evolutionary lineages have evolved surprisingly similar mechanisms for antigenic variation. The complex relationships between infectious organisms and their hosts often reflect the continuing struggle of the pathogen to proliferate and spread to new hosts, and the need of the infected individual to control and potentially eradicate the infecting population. This has led, in the case of mammals and the pathogens that infect them, to an 'arms race', in which the highly adapted mammalian immune system has evolved to control the proliferation of infectious organisms and the pathogens have developed correspondingly complex genetic systems to evade this immune response. We review how bacterial, protozoan and fungal pathogens from distant evolutionary lineages have evolved surprisingly similar mechanisms of antigenic variation to avoid eradication by the host immune system and can therefore maintain persistent infections and ensure their transmission to new hosts.

Key Points How intracellular pathogens exit host cells is an important and overlooked topic in the study of host–pathogen interactions. This Review highlights the diverse strategies and specialized mechanisms that are used by intracellular pathogens to escape their resident vacuole and, subsequently, the host cell. Vacuole exit is typically accomplished by the action of pathogen-secreted pore-forming proteins, or phospholipases, on vacuole membranes to cause their disruption. Strategies for pathogen exit from cells include: triggering host-cell lysis from within the cell; using actin-based motility to protrude out of the host cell; budding out of the cell; vacuole extrusion out of the cell; vacuole exocytosis; induction of inflammatory pyroptosis in the host cell; and induction of host-cell apoptosis. The exit of intracellular bacteria from host cells is a crucial stage in microbial pathogenesis that is driven by an evolutionary requirement for efficient dissemination to neighbouring cells and transmission to new hosts. In this comprehensive Review, the authors discuss the diverse repertoire of strategies that is used by intracellular pathogens to escape their host cells. The exit of intracellular pathogens from host cells is an important step in the infectious cycle, but is poorly understood. It has recently emerged that microbial exit is a process that can be directed by organisms from within the cell, and is not simply a consequence of the physical or metabolic burden that is imposed on the host cell. This Review summarizes our current knowledge on the diverse mechanisms that are used by intracellular pathogens to exit cells. An integrated understanding of the diversity that exists for microbial exit pathways represents a new horizon in the study of host–pathogen interactions.

Purine salvage is an essential function for all obligate parasitic protozoa studied to date and most are also capable of efficient uptake of preformed pyrimidines. Much progress has been made in the identification and characterisation of protozoan purine and pyrimidine transporters. While the genes encoding protozoan or metazoan pyrimidine transporters have yet to be identified, numerous purine transporters have now been cloned. All protozoan purine transporter-encoding genes characterised to date have been of the Equilibrative Nucleoside Transporter family conserved in a great variety of eukaryote organisms. However, these protozoan transporters have been shown to be sufficiently different from mammalian transporters to mediate selective uptake of therapeutic agents. Recent studies are increasingly addressing the structure and substrate recognition mechanisms of these vital transport proteins.

Five major human toxic syndromes caused by the consumption of shellfish contaminated by algal toxins are presented. The increased risks to humans of shellfish toxicity from the prevalence of harmful algal blooms (HABs) may be a consequence of large-scale ecological changes from anthropogenic activities, especially increased eutrophication, marine transport and aquaculture, and global climate change. Improvements in toxin detection methods and increased toxin surveillance programmes are positive developments in limiting human exposure to shellfish toxins.

Key Points Lipid rafts are liquid-ordered membranes, enriched in cholesterol and sphingolipids, that can selectively incorporate or exclude proteins. This allows them to regulate many protein–protein and lipid–protein interactions at the cell surface. Lipid rafts function as concentration points for B- and T-cell receptor signalling, contributing to the adaptive immune response against pathogens. By organizing signalling downstream of Toll-like receptors, lipid rafts are also involved in the innate immune response. Despite the role of rafts in the activation of the immune system, many viruses, bacteria and protozoan parasites can use these host microdomains to infect target cells. Intracellular pathogens hijack host rafts to find gateways for entry into the cell, to create sheltered environments in which to replicate, to prevent host immune responses by taking over signalling pathways or to generate areas in which new pathogens can be assembled efficiently. Several pathogens, of which HIV and Epstein–Barr virus are well-studied examples, have strategies to subvert raft-associated signalling. This enables their efficient replication in immune cells while blocking the immune response that is elicited by the target cells. Molecular dissection of the mechanisms by which microorganisms hijack host raft domains will provide new therapeutic insights for the prevention and/or treatment of certain infectious diseases. Throughout evolution, organisms have developed immune-surveillance networks to protect themselves from potential pathogens. At the cellular level, the signalling events that regulate these defensive responses take place in membrane rafts — dynamic microdomains that are enriched in cholesterol and glycosphingolipids — that facilitate many protein–protein and lipid–protein interactions at the cell surface. Pathogens have evolved many strategies to ensure their own survival and to evade the host immune system, in some cases by hijacking rafts. However, understanding the means by which pathogens exploit rafts might lead to new therapeutic strategies to prevent or alleviate certain infectious diseases, such as those caused by HIV-1 or Ebola virus.

Water-related parasitic diseases are directly dependent on water bodies for their spread or as a habitat for indispensable intermediate or final hosts. Along with socioeconomic development and improvement of sanitation, overall prevalence is declining in the China. However, the heterogeneity in economic development and the inequity of access to public services result in considerable burden due to parasitic diseases in certain areas and populations across the country. In this review, we demonstrated three aspects of ten major water-related parasitic diseases, i.e., the biology and pathogenicity, epidemiology and recent advances in research in China. General measures for diseases control and special control strategies are summarized.

Virulence is one of a number of possible outcomes of host‐microbe interaction. As such, microbial virulence is dependent on host factors, as exemplified by the pathogenicity of avirulent microbes in immunocompromised hosts and the lack of pathogenicity of virulent pathogens in immune hosts. Pathogen‐centered views of virulence assert that pathogens are distinguished from nonpathogens by their expression of virulence factors. Although this concept appears to apply to certain microbes that cause disease in normal hosts, it does not apply to most microbes that cause disease primarily in immunocompromised hosts. The study of virulence is fraught with the paradox that virulence, despite being a microbial characteristic, can only be expressed in a susceptible host. Thus, the question “What is a pathogen?” begs the question, “What is the outcome of the host‐microbe interaction?” We propose that host damage provides a common denominator that translates into the different outcomes of host‐microbe interaction.

1. Studies have considered how intrinsic host and parasite properties determine parasite virulence, but have largely ignored the role of extrinsic ecological factors in its expression. 2. We studied how parasite genotype and host plant species interact to determine virulence of the protozoan parasite Ophryocystis elektroscirrha ( McLaughlin & Myers 1970 ) in the monarch butterfly Danaus plexippus L. We infected monarch larvae with one of four parasite genotypes and reared them on two milkweed species that differed in their levels of cardenolides: toxic chemicals involved in predator defence. 3. Parasite infection, replication and virulence were affected strongly by host plant species. While uninfected monarchs lived equally long on both plant species, infected monarchs suffered a greater reduction in their life spans (55% vs. 30%) on the low-cardenolide vs. the high-cardenolide host plant. These life span differences resulted from different levels of parasite replication in monarchs reared on the two plant species. 4. The virulence rank order of parasite genotypes was unaffected by host plant species, suggesting that host plant species affected parasite genotypes similarly, rather than through complex plant species-parasite genotype interactions. 5. Our results demonstrate that host ecology importantly affects parasite virulence, with implications for host-parasite dynamics in natural populations.