Streptococcus pneumoniae endopeptidase O induces trained immunity and confers protection against various pathogenic infections
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Antibiotic resistance and the surge of infectious diseases during the pandemic present significant threats to human health. Trained immunity emerges as a promising and innovative approach to address these infections. Synthetic or natural fungal, parasitic and viral components have been reported to induce trained immunity. However, it is not clear whether bacterial virulence proteins can induce protective trained immunity. Our research demonstrates Streptococcus pneumoniae virulence protein PepO, is a highly potent trained immunity inducer for combating broad-spectrum infection. Our findings showcase that rPepO training confers robust protection to mice against various pathogenic infections by enhancing macrophage functionality. rPepO effectively re-programs macrophages, re-configures their epigenetic modifications and bolsters their immunological responses, which is independent of T or B lymphocytes. In vivo and in vitro experiments confirm that trained macrophage-secreted complement C3 activates peritoneal B lymphocyte and enhances its bactericidal capacity. In addition, we provide the first evidence that granulocyte colony-stimulating factor (G-CSF) derived from trained macrophages plays a pivotal role in shaping central-trained immunity. In summation, our research demonstrates the capability of rPepO to induce both peripheral and central trained immunity in mice, underscoring its potential application in broad-spectrum anti-infection therapy. Our research provides a new molecule and some new target options for infectious disease prevention.Keywords:
Cellular immunity
The pathogenicity of Staphylococcus aureus is determined by its ability to express multiple virulence factors. Thus far the virulence potential of S. aureus isolates has been described by the virulence gene repertoire, which, in part, varies considerably among the different isolates. Extracellular proteins constitute a reservoir of virulence factors and have been shown to play an important role in the pathogenicity of bacteria. Analyses of the expression of these virulence factors and elucidation of regulatory networks involved in S. aureus virulence by using gel based proteomics can yield information important for our understanding of the virulence potential of this pathogen and its interaction with the host. In addition, these approaches are critical for a comprehensive understanding of secretion and modification of virulence factors.
Virulence factor
Pathogenicity island
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Multiple infections are known to affect virulence evolution. Some studies even show that coinfections may decrease the overall virulence (the disease-induced mortality of a coinfected host). Yet, epidemiological studies tend to overlook the overall virulence, and within-host models tend to ignore epidemiological processes. Here, I develop an epidemiological model where overall virulence is an explicit function of the virulence of the coinfecting strains. I show that in most cases, a unique strain is evolutionarily stable (in accordance with the model I use here). However, when the overall virulence is lower than the virulence of each of the coinfecting strains (i.e., when coinfections decrease virulence), the evolutionary equilibrium may be invaded by highly virulent strains, leading to the coexistence of two strains on an evolutionary timescale. This model has theoretical and experimental implications: it underlines the importance of overall virulence and of epidemiological feedbacks on virulence evolution.
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Aeromonad virulence remains poorly understood, and is difficult to predict from strain characteristics. In addition, infections are often polymicrobial (i.e., are mixed infections), and 5-10% of such infections include two distinct aeromonads, which has an unknown impact on virulence. In this work, we studied the virulence of aeromonads recovered from human mixed infections. We tested them individually and in association with other strains with the aim of improving our understanding of aeromonosis. Twelve strains that were recovered in pairs from six mixed infections were tested in a virulence model of the worm Caenorhabditis elegans. Nine isolates were weak worm killers (median time to death, TD50, ≥7 days) when administered alone. Two pairs showed enhanced virulence, as indicated by a significantly shortened TD50 after co-infection versus infection with a single strain. Enhanced virulence was also observed for five of the 14 additional experimental pairs, and each of these pairs included one strain from a natural synergistic pair. These experiments indicated that synergistic effects were frequent and were limited to pairs that were composed of strains belonging to different species. The genome content of virulence-associated genes failed to explain virulence synergy, although some virulence-associated genes that were present in some strains were absent from their companion strain (e.g., T3SS). The synergy observed in virulence when 2 Aeromonas isolates were co-infected stresses the idea that consideration should be given to the fact that infection does not depend only on single strain virulence but is instead the result of a more complex interaction between the microbes involved, the host and the environment. These results are of interest for other diseases in which mixed infections are likely and in particular for water-borne diseases (e.g., legionellosis, vibriosis), in which pathogens may display enhanced virulence in the presence of the right partner. This study contributes to the current shift in infectiology paradigms from a premise that assumes a monomicrobial origin for infection to one more in line with the current pathobiome era.
Strain (injury)
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A given strain of Bact. aertrycke Mutton has been tested repeatedly for its virulence to mice, and on some of these occasions the virulence of 10 single colony cultures taken from this strain has likewise been tested. Between these single colony cultures such marked differences in virulence have been found as to constitute definite discontinuous variations. Side by side in the same culture there have been found virulent and avirulent organisms. Daily subculture in broth under certain atmospheric conditions resulted in the fall in virulence of the whole culture; this was accompanied by a replacement of the virulent organisms by organisms that were either completely avirulent or were only weakly virulent. The evidence suggests that the fall in virulence of the whole culture is not due to a simultaneous fall in the virulence of each of its constituent organisms, but to a replacement of the highly virulent organisms by organisms of a lower degree of virulence. During the process of replacement two or three different variants, showing discontinuous variations in virulence, may be demonstrated together in the same culture. The conclusions to be drawn from these findings, and their bearing on the interpretation of the results of experimental epidemiology, are discussed.
Subculture (biology)
Strain (injury)
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clone (Java method)
Chagas Disease
Kinetoplastida
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E. coli bacteria isolated from localized and systemic disease processes in poultry are designated as Avian Pathogenic E. coli (APEC). The disease-inducing potential of these isolates has been explained by the occurrence of specific virulence factors. Despite the extensive literature on virulence factors for E. coli, unambiguous markers of virulence have not been identified yet. The relationship between serotyping and virulence is not straightforward either and raises the question whether E. coli infections in poultry should mainly be considered as opportunistic. Investigations into the occurrence of certain (combinations of) virulence factors in APEC isolates as virulence markers should fulfil the molecular version of Koch's postulates if the former question is to be answered.
Pathogenic Escherichia coli
Virulence factor
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ABSTRACT A small percentage of natural Escherichia coli isolates (both commensal and pathogenic) have a mutator phenotype related to defects in methyl-directed mismatch repair (MR) genes. We investigated whether there was a direct link between the mutator phenotype and virulence by (i) studying the relationships between mutation rate and virulence in a mouse model of extraintestinal virulence for 88 commensal and extraintestinal pathogenic E. coli isolates and (ii) comparing the virulence in mice of MR-deficient and MR-proficient strains that were otherwise isogenic. The results provide no support for the hypothesis that the mutator phenotype has a direct role in virulence or is associated with increased virulence. Most of the natural mutator strains studied displayed an unusual virulence phenotype with (i) a lack of correspondence between the number of virulence determinants and pathogenicity in mice and (ii) an intermediate level of virulence. On a large evolutionary scale, the mutator phenotype may help parasites to achieve an intermediate rate of virulence which mathematical models predict to be selected for during long-term parasite-host interactions.
Pathogenic Escherichia coli
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Abstract Virulence (i.e. reduction of host fitness) results from the parasite–host interaction. It can be an unselected side effect or the result of short-sighted evolution. The evolutionary theory of virulence predicts virulence by the fitness advantages for the parasite. Thereby, trade-offs among virulence level and host recovery or transmission rates are critical. This process can lead to lower, higher, or intermediate virulence, depending on conditions. Vertical transmission generally selects for lower virulence, whereas co-infection tends to increase virulence levels, also depending on genetic relatedness among the parasites. The sensitivity framework more generally addresses virulence levels in different systems; in this context, manipulation by parasites can result in significant virulence effects, especially when avoiding clearance and when effects are delayed. Different vaccination mechanisms can modify the evolution of virulence. Besides, virulence can evolve within hosts; for example, adaptation to a particular host type with serial passage attenuates virulence on other hosts.
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SUMMARY The virulence of different isolates of MAC was studied in naturally susceptible BALB/c mice. In preliminary experiments, MAC bacteria forming smooth transparent colonies on solid media (SmT variants) were found to be virulent for BALB/c mice, causing progressive infection; smooth opaque (SmOp) were generally avirulent, being slowly eliminated from the infected organs; and rough (Rg) variants were either avirulent or as virulent as SmT variants. We chose to compare the virulence of different isolates of MAC of different origins, studying only the SmT morphotype. Strains of MAC isolated from naturally infected animals were those that most consistently caused progressive infections. AIDS patients-derived isolates were of intermediate virulence or devoid of virulence in mice. The environmental strains were eliminated from mice or did not proliferate. Strains of MAC isolated from individuals who were not infected by HIV varied in virulence from completely avirulent to highly virulent. There was no close correlation between virulence and restriction fragment length polymorphism (RELP) type, although all highly virulent strains were of the A/I type. There was also no correlation between virulence analysed in vivo and the ability to grow in cultured macrophages.
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