L2 – How Bacterial Toxins Contribute to Disease and Dissemination Flashcards
What are bacterial toxins and why are they important in disease progression?
Bacterial toxins are secreted substances that damage the host; they aid in nutrient acquisition, immune evasion, transmission, and competition.
What are the two broad classifications of bacterial toxins?
Endotoxins and exotoxins.
How does an endotoxin differ from an exotoxin?
Endotoxins are components of the Gram-negative cell wall (e.g. LPS) and typically cause non-specific inflammatory responses, whereas exotoxins are actively secreted proteins with specific targets.
What structural components make up lipopolysaccharide (LPS) in endotoxins?
LPS consists of an O-antigen, core polysaccharide, and lipid A.
What is the primary determinant of endotoxicity in LPS?
The acyl chain length and substitution pattern of the lipid A component.
How are endotoxins released from bacteria?
They are released during cell division, bacterial death (often antibiotic-induced), or via immune-mediated lysis.
What host responses are triggered by endotoxins?
Endotoxins activate toll-like receptors, inflammasomes, and complement systems, often leading to fever, septic shock, and organ failure.
Why might endotoxin release be considered a double-edged sword for bacteria?
Although endotoxins trigger severe inflammatory responses, they can also assist in evading host defences and promoting transmission before host death.
What is the structural organisation of cholera toxin?
It has a classical AB5 structure, with one active A subunit and a pentameric B subunit that binds to host cell receptors.
Which receptors does cholera toxin target on host cells?
The primary receptors are GM1 gangliosides, with possible interaction with histo-blood group antigens.
Describe the intracellular pathway of cholera toxin after internalisation.
It is trafficked from the endosome to the Golgi and then to the ER, where the A1 subunit is activated to ADP-ribosylate a G protein, ultimately increasing cAMP levels.
How does the increase in cAMP caused by cholera toxin contribute to disease?
Elevated cAMP activates protein kinase A, which opens chloride channels (e.g. CFTR), leading to electrolyte and water efflux and the severe diarrhoea of cholera.
What is the general structure of botulinum neurotoxin?
It is a binary AB toxin with a zinc-dependent metalloprotease domain (A) linked to a binding/translocation domain (B).
How does botulinum toxin affect neuronal function?
It is internalised into neurons where the light chain cleaves SNARE proteins, preventing the release of acetylcholine at neuromuscular junctions.
What clinical effect does botulinum toxin have due to its mechanism?
It causes flaccid paralysis, which can lead to life-threatening respiratory failure.
How might botulinum toxin benefit the bacterium in an ecological context?
By incapacitating hosts and promoting spore germination in decaying tissues, it may aid in nutrient release and transmission.
What is the role of leukotoxins, such as those from Staphylococcus aureus?
They target and kill immune cells, release nutrients from host tissues, and contribute to pus formation for transmission.
What is a key structural feature of Shiga toxin?
It is an AB5 toxin with an enzymatically active A subunit and a pentamer of B subunits that bind to the glycolipid Gb3 on host cells.
How does Shiga toxin disrupt host cell function?
It inactivates ribosomes by removing a specific adenine from 28S rRNA, thereby inhibiting protein synthesis and leading to cell death.
What additional ecological role might Shiga toxin have aside from causing human disease?
It may play a role in intestinal colonisation and provide protection against protozoan predation in the natural environment.
How do toxins contribute to the long-term survival of bacteria?
Toxins aid in immune evasion and facilitate transmission to new hosts by causing symptoms that promote spread (e.g. diarrhoea, pus formation).
Why might some toxins have alternative roles beyond causing host damage?
They can also be involved in niche competition, colonisation, or even in microbial interactions outside the human host.
What is the evolutionary dilemma associated with toxin-induced host death?
Killing the host can be an evolutionary dead-end, so toxins may also function to modulate the immune response rather than solely cause damage.
How does understanding toxin structure assist in designing therapeutic interventions?
Detailed structural knowledge enables the rational design of inhibitors and vaccines that can block toxin activity.
What are the different functions bacterial toxins can perform beyond host damage?
Bacterial toxins can aid in niche competition, facilitate colonisation, and act as signalling molecules in microbial communities.
How do bacterial toxins contribute to immune evasion?
They can kill or disable immune cells, interfere with signalling pathways, and modulate inflammatory responses.
What role do toxins play in bacterial competition?
Some bacterial toxins target competing bacteria by disrupting their membranes or metabolic processes.
How does the structural organisation of LPS contribute to its function as an endotoxin?
The three main components—lipid A, core polysaccharide, and O-antigen—each play a role in immune recognition and pathogenesis.
Why does lipid A play a crucial role in endotoxin activity?
Lipid A is the toxic component that interacts with host receptors, triggering strong immune responses.
How can endotoxins lead to septic shock?
Endotoxins bind to TLR4 on immune cells, triggering excessive cytokine release, leading to systemic inflammation and organ failure.
What is the function of the O-antigen in LPS?
The O-antigen helps bacteria evade host defences by varying its structure to prevent immune recognition.
How does the immune system recognise endotoxins?
Endotoxins are recognised by Toll-like receptor 4 (TLR4) on immune cells, leading to activation of inflammatory pathways.
What intracellular signalling pathway is activated by LPS?
The NF-κB signalling pathway is activated, resulting in the production of pro-inflammatory cytokines.
How does cholera toxin differ from Shiga toxin in its mechanism of action?
Cholera toxin increases cAMP levels, causing severe diarrhoea, while Shiga toxin inhibits protein synthesis, leading to cell death.
Why is cholera toxin particularly effective at promoting bacterial transmission?
By causing profuse diarrhoea, cholera toxin ensures efficient shedding and transmission to new hosts.
How does botulinum toxin enter neurons?
It binds to neuronal receptors and enters via endocytosis, eventually reaching the cytosol.
What molecular target does botulinum toxin cleave to cause paralysis?
It cleaves SNARE proteins, preventing synaptic vesicles from fusing with the neuronal membrane.
How does botulinum toxin block neurotransmitter release?
Without SNARE proteins, acetylcholine cannot be released at neuromuscular junctions, leading to paralysis.
What makes botulinum toxin one of the most potent toxins known?
It has extreme potency due to its enzymatic activity, requiring only a few molecules to cause paralysis.
How does Shiga toxin gain entry into host cells?
It binds to Gb3 receptors on host cells, triggering receptor-mediated endocytosis.
What is the role of the Gb3 receptor in Shiga toxin-mediated disease?
The Gb3 receptor determines tissue tropism, particularly affecting kidney and intestinal cells.
How does Shiga toxin damage host cells at the molecular level?
It enzymatically cleaves ribosomal RNA, preventing protein synthesis and inducing cell death.
How can bacterial toxins contribute to disease persistence?
Some toxins suppress immune responses, allowing bacteria to persist in host tissues for extended periods.
What are some potential applications of bacterial toxins in medicine?
Bacterial toxins have been adapted for therapeutic uses, including Botox for medical treatments and vaccine adjuvants.
How can bacterial toxin structures be exploited for vaccine development?
By identifying neutralising epitopes, vaccines can be designed to block toxin activity before it affects the host.
Why might a toxin-producing bacterium evolve to regulate its toxin production?
Overproduction of toxins can be harmful to the bacterium itself, so regulatory mechanisms control expression based on environmental conditions.
How do environmental factors influence bacterial toxin expression?
Toxin production can be influenced by host signals, temperature, pH, and nutrient availability.
What are some common strategies used to neutralise bacterial toxins therapeutically?
Antitoxins, neutralising antibodies, and receptor mimetics can prevent toxin-mediated damage.
Why are AB toxins particularly effective at targeting host cells?
AB toxins have a dual structure: the A subunit exerts enzymatic activity, while the B subunit ensures cell entry.
What determines the tissue specificity of bacterial toxins?
The presence of specific host cell receptors determines which tissues are affected by a given bacterial toxin.
How does GWAS contribute to understanding bacterial pathophysiology?
GWAS helps identify genetic factors that contribute to bacterial virulence, antibiotic resistance, and infection outcomes, improving our understanding of bacterial pathophysiology.
What types of genetic variations are typically analyzed in bacterial GWAS?
Single nucleotide polymorphisms (SNPs), insertions, and deletions are commonly analyzed to find associations between genotype and phenotype.
Why is whole genome sequencing crucial for bacterial GWAS studies?
Whole genome sequencing allows comprehensive analysis of genetic variations, ensuring that all potential mutations contributing to a phenotype are considered.
What is the significance of a Manhattan plot in GWAS research?
A Manhattan plot visualizes genetic associations by plotting genomic locations (x-axis) against statistical significance (-log10 P-value) (y-axis), highlighting strong associations.
How does GWAS help in identifying antimicrobial resistance genes?
By identifying genetic mutations associated with resistance traits, GWAS helps uncover the genetic basis of antimicrobial resistance and potential drug targets.
Why is population structure important to consider in bacterial GWAS?
Population structure must be accounted for to distinguish true genetic associations from spurious correlations due to clonal expansion.
What are the main challenges of performing GWAS on bacteria compared to humans?
Unlike human populations, bacterial reproduction is clonal and asexual, leading to high linkage disequilibrium and challenges in pinpointing causal mutations.
How does linkage disequilibrium affect the interpretation of bacterial GWAS results?
Linkage disequilibrium causes nearby genetic variants to be inherited together, making it difficult to separate causative mutations from linked but non-functional variations.
What role do phylogenetic approaches play in bacterial GWAS?
Phylogenetic methods help correct for evolutionary relationships between bacterial strains, reducing confounding effects in GWAS analyses.
How can GWAS be used to predict clinical outcomes of bacterial infections?
GWAS can reveal genetic markers linked to infection severity and patient outcomes, aiding in risk assessment and personalized treatment strategies.
What is homoplasy, and why does it complicate bacterial GWAS studies?
Homoplasy occurs when the same mutation arises independently in different bacterial strains, making it difficult to determine whether a genetic variant is truly associated with a trait.
How do mixed models help address challenges in bacterial GWAS?
Mixed models account for population structure by incorporating genetic relationships between bacterial strains, improving the accuracy of GWAS findings.
How has GWAS been applied to studying Staphylococcus aureus?
In Staphylococcus aureus, GWAS has identified mutations linked to antibiotic resistance and virulence factors, helping to understand its pathogenic potential.
What genetic factor was linked to vancomycin resistance in Staphylococcus aureus GWAS studies?
A GWAS study found a mutation in the orpB gene associated with vancomycin resistance, providing insight into antibiotic resistance mechanisms.
What strategies are used to validate GWAS-identified genetic variants in bacteria?
Functional validation strategies include the use of transposon mutant libraries and knockout experiments to confirm the role of identified genetic variants.
Why is Mycobacterium tuberculosis a useful model for bacterial GWAS?
Mycobacterium tuberculosis has a well-documented population structure and extensive genomic data, making it a suitable model for GWAS in bacterial infections.
How can GWAS provide insights into bacterial virulence mechanisms?
GWAS can identify genetic determinants of bacterial virulence by associating specific mutations with pathogenic traits like toxin production and immune evasion.
What is the relationship between bacterial genetic variation and infection severity in patients?
Genetic variations in bacterial strains can influence disease severity by affecting toxin expression, immune system interactions, and antibiotic susceptibility.
How can integrating genotypic and phenotypic data improve disease outcome predictions?
Combining genomic and phenotypic data allows for more accurate predictive models of disease progression, improving clinical decision-making.
In what ways can GWAS findings contribute to the development of new antimicrobial therapies?
By identifying key resistance and virulence genes, GWAS can guide the development of novel antimicrobial agents and targeted therapeutic strategies.
