The Natural History of Infectious Disease I: Bacterial Diseases I Flashcards
1
Q
Describe Koch’s postulates
A
– microbe is found in all cases of disease and is absent in its absence
– microbe can be isolated and grown in pure culture
– cultured microbe can cause disease in a healthy host
– microbe can be re-isolated and cultured from this host
2
Q
Describe the revisiting of Koch’s postulates
A
in the light of knowledge on molecular pathology and the microbiome.
3
Q
Describe the multidisciplinary approach of infectious diseases
A
- Microbiology (germs)
- Epidemiology (spread)
- Resistance (immunology)
- Virulence (host-microbe-environment interactions)
4
Q
What are the molecular Koch’s postulates interested in?
A
virulence genes and diseases
5
Q
What are the ecological Koch’s postulates interested in?
A
dysbiotic microbiota
6
Q
Describe the human microbiota
A
normally the body is colonised harmlessly and stably
7
Q
When can dysbiotic disease occur?
A
- microbes change host biology: cancer, immunological diseases
- normal microbiota invade: ‘accidental’ pathogens;
- other microorganisms invade
8
Q
Describe the invasion of other microorganisms into the microbiota
A
– obligate ‘professional’ pathogens
– opportunistic pathogens
9
Q
The same microbes can
A
play different roles, depending on circumstances, i.e. ecology, host immune responses etc.
10
Q
Describe dysbiotic diseases
A
- IBD
- liver disease
- chronic kidney disease
- brain disorders
- diabetes
- respiratory disease
- cancer
- heart disease
11
Q
Describe IBD
A
- Crohn’s disease
- ulcerative colitis
12
Q
Describe liver disease
A
- Cirrhosis
- Hepatitis
13
Q
Describe brain disorders
A
- Parkinson’s disease
- Alzheimer’s disease
- depression
14
Q
Describe diabetes
A
- Type 1
- Type 2
- gestational
15
Q
Describe respiratory disease
A
- asthma
- bronchitis
16
Q
Describe cancer
A
- lung cancer
- colorectal cancer
- pancreatic cancer
- oral cancer
17
Q
Describe heart disease
A
- hypertension
- atherosclerosis
18
Q
Describe immunopathology
A
Host damage (pathology) can be due to host immune responses
19
Q
List some host immune responses
A
- Rheumatic fever.
- Group A streptococcal (S. pyogenes) infections of the throat.
- Bacterial molecular mimicry results in host damage by autoantibodies.
- Haemolytic anaemia.
- Mycoplasma pneumoniae, atypical pneumonia.
- Autoantibodies against host cells.
- Glomeronephritis.
- Streptococcus pyogenes.
- Circulating immune complexes settle in the glomeruli
- Septic shock.
- Inflammatory response.
- Commonly Gram positive (Staphylococcus, Streptococcus) or Gram negative (Neisseria meningitidis).
- Toxic shock syndrome (‘super antigen’ endotoxins).
- Staphylococcus, Streptococcus.
20
Q
Describe the basis of sepsis
A
excessive inflammation
21
Q
Describe leukocytes and parenchymal cells in sepsis
A
- release of pro-inflammatory mediators
- cell injury with release of DAMPs
22
Q
Describe endothelia in sepsis
A
- release of pro-inflammatory mediators with adhesive and procoagulant properties
23
Q
What is the function of the endothelium
A
barrier
24
Q
Describe the platelets in sepsis
A
- release of pro-inflammatory mediators
- activation of neutrophils and the endothelium
- microvascular thrombi
25
Describe the general effects of sepsis
- coagulation activation (microvascular thrombosis)
- complement activation
26
Describe immune suppression enactants
- CD4+ cells
- CD8+ cells
- neutrophils
- antigen-presenting cells
- lymph node
- + others
27
Describe the CD4+ cells in immune suppression
- enhanced apoptosis
- exhaustion
- TH2 cell polarisation
28
Describe the CD8+ cells in immune suppression
- enhanced apoptosis
- exhaustion
- decreased cytotoxic function
29
Describe the neutrophils in immune suppression
- down regulated apoptosis
- enhanced immature cells with decreased antimicrobial functions
30
Describe the antigen-presenting cells in immune suppression
- reprogramming of macrophages to an M2 phenotypes
- reduced HLA-DR expression
31
Describe the lymph node in immune suppression
apoptosis of B cells and follicular DCs
32
Describe other functions in immune suppression
expansion of T-regs and MDSC populations
33
Describe protective immunity
- localised innate immune response
- local repair mechanisms
34
Describe the localised innate immune response
- release of pro-inflammatory mediators
- leukocyte recruitment
- complement activation
- coagulation activation
35
Describe the local repair mechanisms
- inhibition and resolution of inflammation
- tissue repair
- return to homeostasis
36
Describe the microbiome and cancer
- microbes can promote cancers by a number of specific mechanisms
- macrobiont, can become perturbed
37
Describe the microbial promotion of cancers
- promotion of inflammation by Helicobacter pylori.
- immune responses
- dysbiosis
- genotoxicity
- metabolism
38
Describe quantitative changes in the microbiome in cancer
- bacterial overgrowth
- occurs in some locations only
- qualitative and meta genomic changes
39
Describe the qualitative and metagenomic changes occurring in the microbiome during cancer
- suppression of health-promoting symbionts
- enhancement of invasive and inflammation-inducing bacteria
- enhancement of genotoxic bacteria
- enhancement of cancer-promoting metabolites
40
Give an example of a cancer-promoting metabolite
DCA
41
Describe macrobiotic inflammation associated with cancer
- MAMP or PRR signalling
- TH17 cytokines
- NF-kappaB
- IL6, TNF, EREG
- survival and proliferation
42
Describe the barrier failure associated with cancer
- antibacterial peptides
- IgA
- low pH
- mucous layer
- tight junctions
- GALT
43
Describe the Natural History of the Meningococcus
- ordinarily a commensal, causing disease rarely.
- invasion plays no role in transmission
- accidental pathogen
- acquisition/colonisation; invasion; disease; shedding; clearance
44
Define accidental
not essential to the existence of a thing; not necessarily present; incidental; secondary; subsidiary
45
Describe Meningococcal transmission, carriage, invasion and virulence factors
- transmission competent meningococci express pili and capsules
- some meningococci are acapsulate, or cnl
- adhesion to the epithelium requires pili, then other outer membrane proteins
- down-regulation of capsule expression is required
- growth in the bloodstream usually requires expression of a capsule, which is necessary for immune evasion
- acquisition of nutrients also important
46
capsule null
cnl
47
Describe the acquisition of nutrients in infectious diseases
iron obtained from host tissues.
48
Describe the transmission of N. meningitidis
oropharynx
49
Describe the role of capsules in colonisation and disease
- anti-phagocytic
- host-mimicry
- antigenic diversity
- adhesion and biofilm formation
50
Describe anti-phagocytic capsules
serogroup A capsules of Neisseria meningitidis
51
Describe host-mimetic capsules
serogoup B capsules of Neisseria meningitidis
52
Describe antigenic diversity in capsules
Streptococcus pneumoniae; >100 capsular types
53
Describe adhesion and biofilm formation in capsules
Klebsiella pneumoniae
54
Most bactertial capsules are ... but Borrelia burgdorferi...
- carbohydrates
- which causes Lyme Disease, has a protein capsule: Osp.
55
Osp
outer surface protein
56
Neisseria
grows on agar
57
Describe the highly variable surface structures of Neisseria meningitidis
- interact with host cells
- phase variation (on/off);
- multiple copies (antigenic variation).
- evolved to promote commensalism;
- can promote pathogenesis
58
Describe how surface structures promoting pathogenesis
including tropism to particular tissues and the evasion of immune responses
59
Give examples of pathogens with surface structures
– Bordetella pertussis fimbriae
– Escherchia coli P fimbriae
– Streptococcus mutans glycan
60
Describe secreted toxins
- especially proteinous
- attack and damage the host or act to modulate and control signalling systems
- downregulate the host immune response
61
Describe pathogens with secreting toxins
- AB exotoxins
– Diphtheria toxin, Corynebacterium
diphtheriae
– Tetanus toxin, Clostridium tetani
– Anthrax toxin, Bacillus anthraces
– Cholera toxin, Vibrio cholerae
– YOPS
– Cytotoxins, e.g. Salmonella sp and Clostridium perfringens
62
YOPS
Yersinia outer proteins
63
Describe diphtheria pathology
- bull neck: enlarged lymph nodes
- thick pseudomembrane in posterior pharynx
- cutaneous legion
64
Describe diphtheria
- Corynebacterium diphtheriae
- carrying toxin-encoding phage (tox+)
65
Describe diphtheria vaccine
- immunisation with toxoid
- protects against disease and transmission of tox+ bacteria.
- vaccine-induced herd immunity can eradicate disease
- does not eradicate Corynebacterium diphtheriae
66
toxoid
inactive toxin
67
Describe M. tuberculosis
- a ‘professional pathogen’
- obligate parasite of man and animals
- pulmonary tuberculosis necessary for spread via aerosol droplets
- chronic infections are established: asymptomatic
68
Describe the pathogenesis of tuberculosis
- primary or secondary infection
- innate immune phase
- delayed onset of CD4+ and CD8+ cell responses
- immunological equilibrium: latency
- reactivation
- transmission
- inflammatory lung tissue damage
69
Describe immunological equilibrium
- equilibrium between effector Ts and T-regs
- latency
70
Describe the contributing mechanisms to tuberculosis pathogenesis
- defective CD4+ T cells as in HIV+ individuals
- TNF blockage, glucocorticoids
- T cell exhaustion
- imbalance between T-effectors and T-regs
- altered antigen expression
- altered cell trafficking
71
Decsribe inactive TB
spontaneous immunological control or bacterial switch to dormancy
72
Describe the two transmission types of TB
- high level
- low level
73
Describe high level transmission of TB
- cavitary; high bacterial burden in lungs
- non-cavitary; low bacterial burden in lungs
74
Describe what happens on primary or secondary infection of TB
- intracellular growth
- modification of PAMPs to limit inflammation
75
Give the general pathogenesis of TB
Stage 1: Infection
Stage 2: Symbiotic phase
Stage 3: Host mounts a delayed-type hypersensitivity reaction.
Stage 4: Calcified lesions formed, infected tissue surrounded by macrophages latent infection.
Stage 5: Reactivation.
76
Describe infection with tuberculosis
- small numbers of M. tuberculosis infect via the lung, invading macrophages & growing
- host-to-host
77
Describe the symbiotic phase of tuberculosis
Bacteria invade immature macrophages forming clusters of infection
78
Describe the innate immune phase in response in response to TB infection
- neutrophil
- innate lymphocyte
79
Describe the adaptive immune phase in response to TB infection
containment of infection in 90% of individuals
80
Describe a caseated granuloma
encased in immune T and B cells
81
Describe TB reactivation
+ dissemination occurs in 10% of infected individuals
82
Describe the host immune response to TB
- rapid TH1 cell response develops
- interferon decreases the amount of fibrosis
83
Describe blood-borne TB
spread 3 weeks after unimmunized individuals are first infected by aerosol
84
Describe the characteristic symptoms of TB
- weight loss
- cavitation and fibrosis
- progression to cavitary TB
85
Describe the progression to cavitary TB
cavities open into the bronchi; allows the spread of TB by aerosols during coughing
86
Describe some things that can reactivate TB
- immunosuppression
- HIV infection
- smoking
87
blood-borne
haematogenous
88
Describe Treponema pallidum
- causative agent of sexually transmitted syphilis
- bacterium
- grows poorly in vitro, slow generation times
- derives most of its metabolites from the host
– large number of transport systems
- no porins
89
Why does Treponema palladium grow poorly in vitro
– lack of metabolic capabilities
– limited stress response
– highly sensitive to raised body temperature
90
Describe the genome of Treponema pallidum
- small
- 1.14Mbp
91
Describe Tp0453
may perturb the outer membrane allowing nonselective diffusion of nutrients into the periplasm.
92
Almost always, the metabolic capacity of a pathogen is
much more limited than the ancestral organism from which it evolved
93
Describe the ecology of Vibrio cholerae
- opportunistic pathogen
- associated with reservoir
- antagonistic organisms that shape its virulence potential
94
List some reservoirs of V. cholerae
- crustaceans
- copepods
- chironomid egg masses
- phytoplankton
- fish
- turtles
- aquatic birds
- shellfish
- protozoa
95
Describe the antagonist interactions of V. cholerae
- protists
- bacteriophages
- predatory bacteria
96
Describe the pre-adaptation of V. cholerae to human infection
convergence of the aquatic environment and the human host
97
List some factors involved in Vibrio cholerae colonisation, survival, and toxicity in the human host and the aquatic environment:
- CT
- MSHA
- TCP
- GbpA
- VPI-2
- VSP-1
- HAP
- PrtV
- MARTXvc
- T6SS
- VSP-2
- VBNC
98
CT
cholera toxin
99
MSHA
mannose-sensitive hemagglutinin
100
TCP
toxin-coregulated pilus
101
GbpA
N-acetylglucosamine-binding protein A
102
VPI-2
Vibrio pathogenicity island 2
103
VSP-1
Vibrio seventh pandemic island I
104
HAP
hemagglutinin protease
105
PrtV
Vibrio metalloprotease
106
MARTXvc
multifunctional autoprocessing repeats-in-toxin
107
T6SS
type VI secretion system
108
VSP-2
Vibrio seventh pandemic island II
109
Describe the factors involved in V. cholerae colonisation
- TCP
- GbpA
- VPI-2
- VSP-1
110
Describe the factors involved in V. cholerae antibacterial activity
- T6SS
- VSP-2
111
Describe the factors involved in V. cholerae quorum sensing
- HapR
- PrtV
- HAP
112
List some V. cholerae toxins
- CT
- cholix toxin
- MARTXvc
113
Describe the factor involved in V. cholerae bile resistance
OmpU
114
Describe the factor involved in V. cholera biofilm formation
MSHA
115
List some factors involved in aquatic V. cholera toxicity
- T6SS
- cholix toxin
- MARTXvc
116
List some factors involved in the interaction between V. cholerae and Protozoa
- T6SS
- ToxR
- OmpU
117
Describe the factor involved in V. cholerae chemotaxis
VSP-1
118
Describe the factor involved in V. cholerae in microcolony formation
TCP
119
Describe the factor involved in early attachment of V. cholerae
GbpA
120
Describe the factor in V. cholerae phage predation
OmpU
121
Describe Yersinia pestis
- many key Y. pestis virulence factors are located on plasmids: accessory genome of Y. pestis ancestors, acquired in separate evolutionary events
- virulent obligate pathogen of today is an ancestral clone, which successively acquired virulence genes on episomes.
122
Describe the evolution of Yersinia
- non-pathogenic Yersinia acquiries virulence plasmid and becomes pathogenic
- acquires hms and HPI insect toxins from bacteria in soil or animal gut
- Y. pseudotuberculosis
- acquires pFra from Salmonella or other enterobacteria
- acquires mutliple copies of pPst from bacteria in rat or flea gut
123
hms
chromosomal gene in Yersinia for biofilm formation
124
pFra
- plasmid
- encodes phospholipase D
- allows for survival (but inefficient transmission) in the flea
125
pPst
- encodes plasminogen activator for dissemination of primary pneumonia in mammalian host
- makes flea transmission more frequent
126
Describe the effect of ymt on host range in Y. pestis
- on pMT1/pFra
- Ymt- can cycle between brown rats, black rats, fleas and humans
- Ymt+ introduces other mammals such as mice
127
Describe the pathology of the bubonic plague in humans
- infected flea bite
- pre-inflammatory phase
- cytokine release
- IL-1RA
- efferocytosis by macrophages
- free-floating and cell-borne Y. pestis via the lymph to subcapsular node
- inflammatory phase
- hijacks apoptosis, pyroptosis and necroptosis causing lysis and spreading
- chemotaxis of effector cells and chemokines
- septicaemia leads to multi-organ infection and failure
- clinical signs and death
128
Describe the pathogenesis of pneumonic plague in humans
- Y. pestis established in permissive lung environment
- alveolar phagocytosis, induced programmed death
- biphasic role of attracted neutrophils
- lung failure, septicaemia, cytokine storm and death
129
Describe the innovation of the pneumonic plague
pneumonia secondary to bubonic plague releases aerosols infected with Y. pestis
130
Describe the biphasic role of the neutrophils
- control Y. pestis
- cause necrosis
131
Describe bacterial movement and pathogenicity
- primary role for flagella is motility
- movement between hosts (Vibrio cholerae)
- movement within hosts (e.g. Helicobacter pylori)
- formation of biofilms (e.g. Salmonella sp.)
- attachment to host cells (e.g. Campylobacter jejuni)
132
Infectious disease is the product of biological interactions at the
molecular, organismal, population, and ecological levels.
133
Bacteria diseases can arise from the healthy microbiota:
– as a consequence of bacterial presence (cancer, immunopathology);
– when the bacteria gain virulence factors (e.g. diphtheria);
– by ‘accident’ – failed or dysfunctional host-pathogen interaction (e.g. meningococcal disease).
– host immune suppression (e.g. post-transplant infections).
134
Explain some of the diversity of bacterial diseases in terms of duration, location, and effect on the host
– obligate opportunistic, and accidental pathogens
– respiratory, feacal/oral, sexual, zoonotic transmission
135
Interactions modulated by specific bacterial components include
– attachment or movement in the host
– immune evasion, modulation
– host damage, both direct and indirect
