Salmonella enterica
Salmonella and Cancer
Salmonella as the paradigm for bacterial therapy of cancer: A progress report
from Robert M. Hoffman writing in Salmonella: From Genome to Function
For over 300 years it has been observed that cancer patients who became infected with bacteria sometimes experienced spontaneous remission of their cancer. Recently, there have been attempts to develop cancer treatments by using tumor-targeting bacteria. Anaerobic microorganisms, such as Clostridium, that preferentially grow in necrotic tumor areas have mostly been used. However, the resulting tumor killing was, at best, limited. Salmonella was originally developed as an antitumor agent by attenuating the bacteria with multiple mutations, including auxotrophs. These multiple auxotrophs appeared to direct the bacteria to the metastatic areas of tumors where more nutrients are available. We have developed a more effective bacterial cancer therapy strategy by targeting viable tumor tissue with Salmonella enterica serovar Typhimurium containing only two auxotrophic mutations. These auxotrophs grow in viable as well as necrotic areas of tumors. However, the auxotrophy severely restricts growth of these bacteria in normal tissue, making this a safe treatment. The S. Typhimurium A1-R mutant, which is auxotrophic for leucine and arginine and had been selected for high antitumor virulence, was effective as monotherapy against human prostate and breast tumors that had been orthotopically implanted in nude mice. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. Exploitation of the tumor-killing capability of Salmonella has great potential for a new paradigm of cancer therapy.
Further reading: Salmonella: From Genome to Function
from Robert M. Hoffman writing in Salmonella: From Genome to Function
For over 300 years it has been observed that cancer patients who became infected with bacteria sometimes experienced spontaneous remission of their cancer. Recently, there have been attempts to develop cancer treatments by using tumor-targeting bacteria. Anaerobic microorganisms, such as Clostridium, that preferentially grow in necrotic tumor areas have mostly been used. However, the resulting tumor killing was, at best, limited. Salmonella was originally developed as an antitumor agent by attenuating the bacteria with multiple mutations, including auxotrophs. These multiple auxotrophs appeared to direct the bacteria to the metastatic areas of tumors where more nutrients are available. We have developed a more effective bacterial cancer therapy strategy by targeting viable tumor tissue with Salmonella enterica serovar Typhimurium containing only two auxotrophic mutations. These auxotrophs grow in viable as well as necrotic areas of tumors. However, the auxotrophy severely restricts growth of these bacteria in normal tissue, making this a safe treatment. The S. Typhimurium A1-R mutant, which is auxotrophic for leucine and arginine and had been selected for high antitumor virulence, was effective as monotherapy against human prostate and breast tumors that had been orthotopically implanted in nude mice. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. Exploitation of the tumor-killing capability of Salmonella has great potential for a new paradigm of cancer therapy.
Further reading: Salmonella: From Genome to Function
Anti-Salmonella immunity
Anti-Salmonella immunity: Highlighting new research in vaccines, mucosal immunology and systemic disease
from Jennifer L. Bishop, Ellen T. Arena, Kenneth W. Harder and B. Brett Finlay writing in Salmonella: From Genome to Function
Enteric fever and non-typhoidal salmonelloses (NTS) are caused by a wide variety of Salmonella enterica serovars and are a serious health threat throughout the world. Immunity to systemic typhoid and NTS requires intricate crosstalk between both innate and adaptive immune cells spanning multiple organ systems. The development of a number of new mouse and in vitro culture models suitable for studying gastroenteritis has highlighted the complexity of mucosal responses and shown how a diverse subset of cells interact within the intestinal architecture to elicit anti-Salmonella immunity. These include specific dendritic cell subsets, natural killer cells and TH17 skewed T helper cells and the repertoire of cytokines they produce, including IL-17, IL-23, IL-22 and IL-15. Furthermore, the importance of commensal microflora has been stressed in various Salmonella models, and new research has shown the various effects of prebiotics, probiotics and antibiotics on Salmonella pathogenesis. Systemic immune responses are also more explicitly understood, as the location and phenotype of cells harboring intracellular bacteria become more defined. A forthcoming book reviews these recent advances and how they are being translated into new therapies and vaccine studies in the human population.
Read more: Salmonella: From Genome to Function
from Jennifer L. Bishop, Ellen T. Arena, Kenneth W. Harder and B. Brett Finlay writing in Salmonella: From Genome to Function
Enteric fever and non-typhoidal salmonelloses (NTS) are caused by a wide variety of Salmonella enterica serovars and are a serious health threat throughout the world. Immunity to systemic typhoid and NTS requires intricate crosstalk between both innate and adaptive immune cells spanning multiple organ systems. The development of a number of new mouse and in vitro culture models suitable for studying gastroenteritis has highlighted the complexity of mucosal responses and shown how a diverse subset of cells interact within the intestinal architecture to elicit anti-Salmonella immunity. These include specific dendritic cell subsets, natural killer cells and TH17 skewed T helper cells and the repertoire of cytokines they produce, including IL-17, IL-23, IL-22 and IL-15. Furthermore, the importance of commensal microflora has been stressed in various Salmonella models, and new research has shown the various effects of prebiotics, probiotics and antibiotics on Salmonella pathogenesis. Systemic immune responses are also more explicitly understood, as the location and phenotype of cells harboring intracellular bacteria become more defined. A forthcoming book reviews these recent advances and how they are being translated into new therapies and vaccine studies in the human population.
Read more: Salmonella: From Genome to Function
The Intracellular lifestyle of Salmonella
The intracellular lifestyle of Salmonella enterica and novel approaches to understand the adaptation to life within the Salmonella-containing vacuole
from Roopa Rajashekar and Michael Hensel writing in Salmonella: From Genome to Function
Salmonella enterica is a facultative intracellular pathogen that resides in a unique membrane-bound compartment, referred to as Salmonella-containing vacuole or SCV. Within the SCV, Salmonella is able to survive the antimicrobial activities of phagocytic cells and can rapidly multiply in a variety of host cells. Intracellular life of Salmonella is dependent on a large number of virulence traits, but the function of the type III secretion system (T3SS) encoded by Salmonella Pathogenicity Island 2 (SPI2) is of central importance. Although more than 20 effector proteins have been identified as translocated by the SPI2-T3SS, the molecular function and contribution to intracellular live is only known for a few of these proteins. Intracellular Salmonella modify basic functions of the host cell such as the structure of the microtubule cytoskeleton and induce a massive reorganization of vesicular transport and the endosomal system. Unique phenomena are the SPI2-dependent induction of extensive tubular membrane aggregations of endosomal or Golgi-derived vesicles. The SCV itself has features of a novel organelle and the fate of this compartment is controlled by the pathogen. Previous observations indicated that the SCV is arrested in the state of late endosomal compartment, but recent studies using advanced ultrastructural analyses and live cell studies indicate a complex and highly dynamic interaction of the intracellular Salmonella and their host cells.
Further reading: Salmonella: From Genome to Function
from Roopa Rajashekar and Michael Hensel writing in Salmonella: From Genome to Function
Salmonella enterica is a facultative intracellular pathogen that resides in a unique membrane-bound compartment, referred to as Salmonella-containing vacuole or SCV. Within the SCV, Salmonella is able to survive the antimicrobial activities of phagocytic cells and can rapidly multiply in a variety of host cells. Intracellular life of Salmonella is dependent on a large number of virulence traits, but the function of the type III secretion system (T3SS) encoded by Salmonella Pathogenicity Island 2 (SPI2) is of central importance. Although more than 20 effector proteins have been identified as translocated by the SPI2-T3SS, the molecular function and contribution to intracellular live is only known for a few of these proteins. Intracellular Salmonella modify basic functions of the host cell such as the structure of the microtubule cytoskeleton and induce a massive reorganization of vesicular transport and the endosomal system. Unique phenomena are the SPI2-dependent induction of extensive tubular membrane aggregations of endosomal or Golgi-derived vesicles. The SCV itself has features of a novel organelle and the fate of this compartment is controlled by the pathogen. Previous observations indicated that the SCV is arrested in the state of late endosomal compartment, but recent studies using advanced ultrastructural analyses and live cell studies indicate a complex and highly dynamic interaction of the intracellular Salmonella and their host cells.
Further reading: Salmonella: From Genome to Function
Flagella of Salmonella
New insights into the role and formation of flagella in Salmonella
from Rasika M. Harshey writing in Salmonella: From Genome to Function
The flagellum of Salmonella enterica serovar Typhimurium is the best studied of all flagellar systems. The major function of the flagellum is to enable swimming and chemotaxis in liquid media, and swarming on surfaces. New structural information, along with biochemical, physicochemical and genetic analyses has greatly accelerated our understanding of the self-assembly of this highly sophisticated nano-machine. The study of swarming motility is a relatively new field, but has begun to reveal new roles for the flagellum, new functions for motility genes and new regulatory circuits that control the decision between motility and sessility. Morphological and functional similarities between flagella and needle complexes, discovery of partial flagellar structures that likely function in export rather than motility, and a rapidly accumulating genome database are gradually illuminating the evolutionary origins of the flagellum.
Further reading: Salmonella: From Genome to Function | Pili and Flagella
from Rasika M. Harshey writing in Salmonella: From Genome to Function
The flagellum of Salmonella enterica serovar Typhimurium is the best studied of all flagellar systems. The major function of the flagellum is to enable swimming and chemotaxis in liquid media, and swarming on surfaces. New structural information, along with biochemical, physicochemical and genetic analyses has greatly accelerated our understanding of the self-assembly of this highly sophisticated nano-machine. The study of swarming motility is a relatively new field, but has begun to reveal new roles for the flagellum, new functions for motility genes and new regulatory circuits that control the decision between motility and sessility. Morphological and functional similarities between flagella and needle complexes, discovery of partial flagellar structures that likely function in export rather than motility, and a rapidly accumulating genome database are gradually illuminating the evolutionary origins of the flagellum.
Further reading: Salmonella: From Genome to Function | Pili and Flagella
Salmonella evolution
Evolutionary trends associated with niche specialization as modeled by whole genome analysis of egg-contaminating Salmonella enterica serovar Enteritidis
from Jean Guard, Devendra Shah, Cesar A. Morales and Doug Call writing in Salmonella: From Genome to Function
The mosaic nature of the Salmonella enterica genome facilitates its access to multiple environments. Many large scale genomic events have been described that contribute to the combinatorial complexity of the pathogenic Salmonellae. However, the impact of small scale genetic change occurring at the level of single nucleotide polymorphism (SNP) on the emergence of niche specialization is just now becoming appreciated. A recent review describes concepts behind the evolution that culminated in the remarkable ability of Salmonella enterica serovar Enteritidis to contaminate and survive in the internal content of eggs produced by otherwise healthy hens. Evidence suggests that combinations of SNPs facilitate niche specialization by Salmonella enterica. However, few typing methods incorporate unbiased strategies for their detection. Selection of appropriate biological assays for ranking SNPs and combinations of SNPs for their impact on the ability of Salmonella enterica to propagate outbreaks, pandemics and disease will be a significant challenge to improve the safety of the food supply.
Further reading: Salmonella: From Genome to Function
from Jean Guard, Devendra Shah, Cesar A. Morales and Doug Call writing in Salmonella: From Genome to Function
The mosaic nature of the Salmonella enterica genome facilitates its access to multiple environments. Many large scale genomic events have been described that contribute to the combinatorial complexity of the pathogenic Salmonellae. However, the impact of small scale genetic change occurring at the level of single nucleotide polymorphism (SNP) on the emergence of niche specialization is just now becoming appreciated. A recent review describes concepts behind the evolution that culminated in the remarkable ability of Salmonella enterica serovar Enteritidis to contaminate and survive in the internal content of eggs produced by otherwise healthy hens. Evidence suggests that combinations of SNPs facilitate niche specialization by Salmonella enterica. However, few typing methods incorporate unbiased strategies for their detection. Selection of appropriate biological assays for ranking SNPs and combinations of SNPs for their impact on the ability of Salmonella enterica to propagate outbreaks, pandemics and disease will be a significant challenge to improve the safety of the food supply.
Further reading: Salmonella: From Genome to Function