Week 12 Flashcards
(113 cards)
1
Q
What is the organism that causes the plague?
What animal transmits the disease?
A
Bacterium: Yersinia pestis
Oriental rat flea: Xenopsylla cheopis
1
Q
What are the different forms of the plague?
A
Bubonic,
Pneumonic,
Septicaemic
2
Q
Is Yersinia pestis gram-positive or gram-negative? What type of anaerobes are they?
A
Gram-negative
Facultative (capable of surviving in both aerobic and anaerobic environments)
3
Q
What are the two main habitats of Yersinia pestis?
A
- The gut of a flea, at ambient temperature
- Blood or tissues of a mammalian host, at body temperature
4
Q
What are the two cycles that can cause the plague?
A
Sylvatic cycle (between fleas and rodents)
Urban cycle (between fleas and domestic rodents (this is what caused plague pandemics in the past))
5
Q
Bubonic plague in humans can change into what secondary plague?
A
Plague pneumoniae, which can transfer direct human to human
6
Q
Some wild rodents are relatively resistant to plague so form…?
A
Permanent foci of infection
7
Q
The link between wild and domestic rodents is usually _____ but the source of human infection is the ______
A
Brown rat (Rattus narvegicus)
Black rat (Rattus rattus)
8
Q
How many species of fleas have been found to be infected with Y. pestis?
A
~80 species.
9
Q
What physiological mechanisms account for differences in vector efficiency of plague (not fully known but could include)?
A
Insect immunity
Midgut digestive enzymes
Frequency of feeding and defecation
Flea life span after infection
10
Q
How do vectors become infected with the plague?
A
Following uptake of a blood meal, pathogen replicates and disseminates in the vector.
11
Q
What is the difference between pandemic and epidemic?
A
Pandemic = prevalent throughout entire country, continent or world
Epidemic = over a large area
12
Q
Gap fill: Transmission by the flea (plague)
Y. pestis remains confined to the flea _______ tract and is transmitted by _______. It does not adhere to, or ______, the ______ epithelium and so it is potentially susceptible to elimination in flea _______.
A
Digestive
Regurgitation
Invade
Midgut
Faeces
13
Q
Y. pestis persistence in the flea depends on what two factors?
A
Formulation of multicellular aggregates (too large to be passed in faeces)
Their ability to form a biofilm and which creates a blockage in the proventriculus
14
Q
What is the proventriculus?
A
A valve that connects the oesophagus and midgut.
15
Q
Yersinia pestis pathogenicity results from what?
A
The ability to overcome the host defences and multiply within the body. It is mainly an extracellular pathogen
15
Q
Gap fill: Transmission by the flea (plague)
As the ______ grows, it fills the ______ and when the flea tries to feed it impedes _______ flow into midgut.
Blocking the ________ valve enhances ________ transmission of the bacterium.
A
Biofilm
Lumen
Blood
Proventricular
Regurgitative
16
Q
After inoculation of Y. pestis, what occurs?
A
Induction of a local lesion and inflammation followed by rapid spread and multiplication.
Infection results in the accumulation of neutrophils.
17
Q
What produced by Yersinia pestis causes most harm? What does this cause?
A
Toxins, causing endothelial damage and necrosis leading to vascular destruction and local haemorrhaging.
18
Q
What do lesions result from after inoculation of Yersinia pestis?
A
From destruction of tissue and effects of endotoxins causing peripheral vascular collapse and disseminated intravascular coagulation (Blood clotting throughout the body)
19
Q
What are the three major recorded plague pandemics through history?
A
541 The Justinianic Plague
1347 Black Death (or The Great Plague)
1894 Modern Plague
20
Q
What did the three major plague pandemics lead to?
A
Profound social and economic changes after devastating human populations
21
Q
Where did the Black Death originate?
A
China 1334 and spread along great trade routes to Istanbul and the onto Europe.
Estimated to have killed 30-50% f the European population
22
Q
Where did the Modern Plague begin?
A
China in 1860s and appeared in Hong Kong by 1894.
Over the next 20 years it spread to port cities around the world and estimated to have caused approximately 10 million deaths
23
What did the Medieval Plague lead to?
The Renaissance and waning of religious control in Europe
24
Is plague confined to the history books?
No as animal plague is found in most continents. There is always a risk of human plague wherever the natural cycle exists in proximity with human populations
25
Why is the potential use of plague as a biological weapon of great concern?
1. Widespread availability around the world
2. Capacity for mass production and aerosol dissemination
3. High fatality rate of pneumonic plague
4. Potential for rapid secondary spread
5. WHO published a report estimating the deliberate release of 50kg Yersinia pestis in an aerosolised form over a city of 5M could result in up to150,000 infected and 36,000 deaths
26
What is the incubation period for the plague?
2-4 days, but may be as long as 10 days
27
What symptoms do patients often develop as a result of plague?
'Flu-like' symptoms - sudden onset of fever, chills, head and body-aches, weakness, vomiting and nausea
28
The bubonic plague is the most common form of the disease and is usually initiated by what?
An infected flea bite
Bacteria enter body and multiply at site of entry then spreads via the lymphatic system to lymph nodes
29
Where in the body does the bubonic plague affect?
Lymph nodes become painful and enlarged forming buboes with haemorrhagic inflammation 2-6 days after flea bite.
In later stages of infection, buboes may suppurate. And can develop into secondary septicaemic plague.
30
Where in the body does the septicaemic plague affect?
causing what?
The bloodstream causing meningitis, endotoxic shock and disseminated intravascular coagulation (leading to gangrene of the extremities and multi-organ failure)
31
Where in the body does the pneumonic plague affect?
Caused by infection spreading to the lungs in advanced bubonic plague, but can result from person-person transmission.
Individuals form aerosolised infective droplets, and infection causes acute pulmonary insufficiency, sepsis and toxic shock
32
In what ways can the plague be transmitted?
Flea bites (results in primary bubonic or septicaemic plague)
Contact with contaminated fluid or tissue (results in primary bubonic or septicaemic plague)
Infectious droplets (results in pneumonic plague)
Environmental transmission is also a possibility
33
How is an individual diagnosed with the plague?
Visualisation of bipolar-staining, ovoid, Gram-negative organisms. Allowing rapid presumptive diagnosis.
34
Where can specimens be obtained to diagnose presumptive plague?
Lymph nodes,
Blood,
Sputum,
Bronchial/tracheal washing
35
What is used to treat plague?
If given early, and in large doses treatment with antibiotics such as streptomycin, tetracycline and chloramphenicol are effective. Treatment should start as soon as plague is suspected and the treatment is usually 10-14 days.
36
What can still occur despite treatment of the plague?
It can still kill patients through toxaemia, despite the fact bacilli have been killed. Therefore supportive therapy is essential (rehydration, maintenance of blood pressure)
37
How can the plague be prevented?
Quarantine, Vaccines, Preventive measures such as:
- Avoid direct contact,
- Rodent control,
- Inform people when zoonotic plague is present
- Advise people to take precautions against flea bites
38
What are the major drivers of bacterial evolution (evolution of Yersinia pestis)?
Gene gain and gene loss; a pathway often described as 'add DNA, stir and reduce.' (horizontal gene transfer, intra-genomic changes, gene deletions and accumulation of pseudogenes)
39
Where has Yersinia pestis diverged from?
Yersinia pseudotuberculosis within the last 10,0000 years. This disease causes relatively mild, self-limiting disease and is transmitted by faecal-oral route
40
Genetic and molecular basis of evolution to a flea-borne route of transmission?
In fleas, Y. pseudotuberculosis induces an acute toxic response resulting in rapid elimination of the blood meal and flea death
DNA from human skeletons dating from early Bronze Age reveals ancestral Y. pestis was NOT flea transmitted but evolved into a flea-borne pathogen at beginning of the 1st millennium BC
41
What is paleomicrobiology?
Microbial genomics of ancient pathogens - useful to understand what could cause high mortality of past diseases, how they spread, how vectors and host reservoirs contribute, transmission and origins and diversity of pathogens in the past
42
What protein protects Y. pestis within the flea gut? How was this gene acquired?
Yersinia murine toxin gene encodes the protein, known as phospholipase D.
The gene was acquired through horizontal gene transfer, enabling bacterium found in the gut to use an arthropod vector
43
How have mutations within Y. pseudotuberculosis resulted in loss of function?
Can form a biofilm in some environments but not within fleas. Homologues of >200 Y. pseudotuberculosis genes are present as non-functional pseudogenes in Y. pestis. So selective loss of gene function enabled Y. pestis to form a biofilm in flea gut
44
What does MHC stand for? Where are they found?
Major Histo-Compatibility group proteins; they are membrane bound glycoproteins
45
Where are the two types of MHC expressed?
MHC-I expressed by all nucleated cells
MHC-II is expressed by specialised antigen presenting cells
46
What do CD8+CTLs and CD4+TH recognise?
CD8+CTLs recognise MHC-I & antigen presented by infected cells
CD4+TH recognise MHC-II & antigen on antigen presenting cells
47
Properties of the professional APC: dendritic cell
Phagocytes,
Migrate from site of infection to lymphoid tissues,
Display processed antigen to naive helper T cells
Important in triggering a primary immune response
48
Can Macrophages present antigens?
Yes but are less able to activate naive T-cells than dendritic cells.
They are important in activating the secondary immune response
49
How do B cells act as APC?
B cells bind antigen via B cell receptor
Receptor & antigen endocytosed
B cells present antigens via MHC II to helper T cells with same epitope recognition
Activated helper T cell secretes cytokines
Cytokines activate B cell to produce memory B cells and plasma cells.
50
What are the three major immune processes?
Inflammation,
Humoral mediated immunity,
Cell-mediated immunity
51
Humoral immunity is mediated by.....?
B-cell mediated,
Antibody-antigen mediated,
Phagocytosis and Complement-mediated killing
52
Explain the process of antigen-driven cloning of lymphocytes (clonal selection)?
Variety of B cells all with different antigen specificity.
Antigen molecules bind to the BCR specific to the antigen.
Expansion of activated antigen specific to B cells.
Clonal selection results in clone of plasma cells and memory cells.
53
Step 1 of the humoral response?
Macrophage or dendritic cell phagocytoses pathogen
Antigen processed in macrophage or DC & presented on surface via MHC II
54
Step 2 of the humoral response?
Specific helper T cell recognises processed antigen and binds (aided by CD4 binding to MHC II)
Helper T cell activated
55
Step 3 of the humoral response?
B-cell phagocytoses BCR & antigen, presents antigen on MHC-II
Helper T cell recognises antigen presented by B cell
56
Step 4 of the humoral response?
Cytokines from activated helper T cell fully activate B cell.
B cell activated to produce clones of plasma cells and memory B cells
57
Step 5 of the humoral response?
Antibody production from plasma cells.
Elimination of pathogen.
58
Binding of antibodies to antigens inactivates antigens by?
Neutralization enhancing phagocytosis (blocks viral binding sites; coating bacteria and opsonization)
Agglutination of antigen-bearing particles enhancing phagocytosis
Precipitation of soluble antigens enhancing phagocytosis
Complement fixation leading to cell lysis
59
What three ways can complement be activated?
Classical, lectin and alternative
Classical = antibody-activated pathway; all routes end with formation of Membrane attack complex
60
Classical complement activation?
Complement binds to antigen-antibody complexes on cell surface,
Complement cascade activated; several complement proteins form MAC and a hole is formed in the foreign cell. Therefore cell lyses occurs.
61
In response to complement activation, membrane attack complexes assemble from what? What is this known as?
Fluid-phase proteins to form pores in liquid bilayers where it directly lyses pathogens by a multi-hit mechanism.
This is known as the 'Split-washer conformation'
62
What is the cell type, recognition of foreign material and killing mechanism of the cell-mediated response?
Cell type: T-cell mediated
Recognition of foreign material: MHC I-antigen-T-cell receptor mediated
Killing mechanism: Cytotoxic T cell mediated killing and humoral response activation by Helper T cells
63
What triggers the humoral response and supplies cytokines to Cytotoxic Lymphocytes?
Helper T cells
64
What is the process of the Cell-mediated response?
Infected cell presents antigen on MHC I to CTL
T cell receptor (TCR) binds presented antigen
CD8 binds to MHC I (MHC I on all somatic cells)
CTL cell activated
Perforin – forms pores in target cell membrane
Granzymes – initiate apoptosis in target cell
65
Cell-mediated immunity results in.... while the humoral immunity results in....?
Attack on infected cells
Secretion of antibodies by plasma cells
66
What Genus causes malaria?
Caused by a protozoan parasite - Genus Plasmodium
67
In England 16-19th C what was Malaria known as? Why?
Ague or Marsh Fever because of the association with swamps being the breeding ground for mosquitoes
68
How many species of Plasmodium are said to cause Malaria in humans?
~175 species recognised, but only 5 or 6 species infect humans!
69
What chemical was used to reduce/control Malaria across the globe?
DET (An insecticide, but now scientists are looking at other approaches to reduce the disease)
70
How many estimated cases of Malaria were their in 2023?
263 million cases with 597,000 deaths (83 countries) - In comparison to to 2015, this shows Malaria numbers are increasing again)
71
According to WHO, what is the estimated percentage of all Malaria deaths in the African Region?
~90% The heaviest Burden across the globe
72
What are the four Plasmodium species that infect and cause Malaria in humans?
P. falciparum
P. vivax
P. malariae
P. ovale
P. knowlesi
73
Features of Plasmodium falciparum?
Causes ~50% of malaria cases.
Periodicity of fever = 48 hrs
Malignant Tertian
Dangerous - responsible for the majority of deaths
74
Features of Plasmodium vivax?
~43% of cases of malaria
Periodicity of fever is 48 hrs
Benign Tertian
Acute self-limiting febrile illness; no complications or death (this type may reoccur later in life)
75
Features of Plasmodium malaeiae?
~7% of cases of malaria
Periodicity of fever is 72 hrs
Quartan
76
Features of Plasmodium ovale?
1% of cases of malaria
Periodicity of fever is 48 hrs
Benign Tertian
77
Features of Plasmodium knowlesi?
Rare
Periodicity of fever is 24hrs
Quotidian
Capable of producing severe illness
78
What is periodic fever caused by in a malaria patient?
Synchronised erythrocyte destruction
79
What are the different types of malaria defined by?
The periodicity of fever - quotidian, tertian, quartan
80
What is the main source of Malaria transmition?
By the bite of a female Anopheles mosquito (when a blood meal is needed for egg development)
81
What are the different types of ways Malaria can be transmitted?
Introduced malaria (Transmitted locally)
Airport malaria (Transmitted by aircraft to non-endemic countries)
Transfusion malaria (Transmitted by blood transfusion)
Mainline malaria (Transmitted by shared needles)
Congenital malaria (Transmitted from mothers to child during pregnancy)
82
What is the Sporogenic cycle of Malaria?
Gametocyte ingested by mosquito after blood meal from human. Microgamete enters macrogamete (now a zygote) after its been deflagellated forming ookinetes.
Ookinetes evade the immune/digestive system by burrowing through gut wall where they form oocytes that develop sporozoites.
Sporozoites move from gut to salivary gland where they can be transmitted into the human when the mosquito has a blood meal.
83
What is the Exo-erythricytic cycle of Malaria?
Sporozoites inoculated into skin by mosquito, penetrate blood vessel and enter circulation before penetrating hepatocytes (liver cells) to initiate infection and the nucleus divides many times forming schizont, rupturing to release merozoites that infect erythrocytes
At this stage, some Plasmodium species can form hypnozoites which are less sensitive to antimalarial drugs and can lay dormant, reactivating many years after initial infection
84
What is the Erythrocytic cycle of Malaria?
Merozoites infect rbcs and become immature trophozoite where they go through ring stage producing mature trophozoites developing into schizonts; mature ones produce merozoites and rupture, releasing them into the blood and they infect other RBCs (the cycle repeats)
Sometimes immature trophozoites in RBCs develop into gametocytes these don't rupture so when the person is bitten these are transmitted into the mosquito where the sporogonic cycle occurs again.
85
Properties of merozoites?
Apical organelles (rhoptries and micronemes) which contain proteins required for parasite invasion.
They must invade RBCs to continue infection.
They also multiply asexually, resulting in the erythrocytic part of the parasite life style (the disease causing stage)
86
Properties of trophozoites?
Single-celled nucleated mass of protoplasm - highly metabolically active
the growing parasite needs to acquire nutrients from host and modified erythrocyte to meet nutritional demands
Ingest haemoglobin, broken down into haemozoin accumulates in the food vacuole
Modified RBCs membrane to enable nutrient uptake
87
Properties of Schizont?
After several hours growth within the erythrocyte schizogony occurs.
Trophozoite divides to give 8-16 merozoites, which are released when the rbc ruptures.
Irregular appearance of the RBC surface due to the presence of 'knobs', impacting the rbcs function
88
Properties of gameocytes?
Sexual forms of trophozoites;
take ~4 days to mature, but stay viable in blood for prolonged periods.
Taken up by mosquito in a blood meal
89
Properties of a zygote in malaria?
Within minutes of ingestion by a mosquito the male and female gametocytes which contain flagellum burst from rbcs.
micro and female macrogamete fuse to form a zygote
zygote is only stage in Plasmodium life cycle that is diploid
90
Properties of Ookinete?
Over course of 5-10hrs, zygote differentiates into an invasive ookinete
It is motile and actively penetrates intestinal wall of mosquito, differentiates and becomes an oocyte (this attaches to external side of midgut wall of mosquito)
91
Properties of Oocyst?
Grow rapidly and divide internally into sporozoites
Longest phase in life cycle and is temperature dependent.
Mosquito has to survive long enough for oocyst to mature
Mosquito survival - most important single factor in malaria transmission
92
What is the single most important factor in malaria transmission?
Mosquito survival
93
Oocysts to sporozoites inside the mosquito?
Oocyst produce up to 1000 sporozoites, which are released into the body cavity of mosquito when they rupture
Sporozoites migrate to salivary glands and accumulate in salivary duct, where they are injected into the human host at a blood meal.
94
How is mosquito behaviour manipulated by sporozoites?
They show increased host seeking behaviour when the sporozoites reach salivary glands
95
Pathogenesis of malaria: when are toxins released?
Toxins released when schizonts burst stimulate T-cells to produce cytokines such as TNFa, which mediate fever, bone marrow depression and erythrophagocytosis
96
Pathogenesis of malaria: What does parasite growth within erythrocytes cause?
Loss of rbcs causing a depression of erythropoiesis and erythrophagocytosis leading to anaemia.
97
Pathogenesis of malaria: Other than loss of RBC due to parasite growth and toxin release, what other conditions may occur due to infection?
Hypoglycaemia in severe malaria
Clotting defects may develop
Immunodepression may lead to enhanced susceptibility to septicaemia (infections in the blood)
98
What are clinical features and complications of malaria?
Periodic fevers (caused by synchronous emergence of merozoites from RBCs)
Anaemia (deficiency of RBC or haemoglobin)
Acute respiratory distress syndrome (body deprived of O2)
Hypoglycaemia (Abnormally low blood sugar)
Hepatomegaly and splenomegaly (enlargement of liver and spleen)
Haemoglobinaemia (haemoglobin in blood plasma)
Haemoglobinuria (haemoglobin in urine (blackwater fever))
Capillary blockages (leading to haemorrhage and anoxia (esp P. falciparum))
99
P. falciparum and the result of cerebral malaria?
Sequestration: infected RBCs stick (cytoadhere) to endothelial cells lining post-capillary venules in brain, heart, liver, kidney, muscles and placenta.
Parasite proteins transported to surface of iRBCs, and also bind to host receptors on endothelial cells
100
How is malaria diagnosed?
By blood smears - stained with Giemsa to detect and identify Plasmodium species.
Rapid diagnostic tests detect Plasmodium proteins by a finger-prick sample - results ~15-30 minutes
Nucleic acid amplification-based diagnostics - sensitive detection of low density malaria infections
101
How is malaria treated?
Quinine - originally extracted from the bark of the cinchona tree. Only effective treatment for 300 years until after WWII when it was replaced by synthetic drugs such as chloroquine.
102
What was quinine replaced with synthetic drugs such as chloroquine to treat malaria?
Safer
More effective (against all Plasmodium species)
Easier to make
Few side effects - low cost
103
How can malaria be prevented? Is this better than a cure?
Prevention is better than cure!
Mosquitoes mainly bite at night so (insecticide-treated) bed nets result in up to 31% reduction in mortality for children.
Cheap ~US$5 however poor rural African communities my struggle to afford.
High community coverage would reduce number and lifespan of mosquitos so all members of community are protected regardless of bed net use. However, ~43% of population of sub-Saharan Africa are not protected by bed nets
104
Can vaccines be used to reduce Malaria?
Vaccines (RTS,S/AS01 malaria vaccine) have been shown to significantly reduce malaria and deadly severe malaria among young children
A second safe vaccine is known as R21/Matrix-M
Malaria vaccines in Africa are expected to save tens of thousands of lives every year.
105
When will the highest impact of Malaria prevention be achieved?
The highest impact will be achieved when vaccines are introduced alongside a mix of other WHO-recommended malaria interventions such as bednets and chemoprophylaxis.
106
Antibodies enable destruction of a pathogen in the following ways
- recruit complement proteins, which enables production of a membrane attack complex, which results in lysis of the pathogen.
- enable precipitation of soluble antigens, which facilitates phagocytosis.
- opsonise pathogens, which facilitates phagocytosis
107
Which of the following are true:
a. B cells differentiate into plasma cells and secrete antibodies.
b. Infected cells display processed antigen molecules on their surface via MHC I
c. CD8 T cell receptors bind to antigen displayed on the surface of infected cells.
d. Antibodies recruit complement proteins which lyse the infected cell.
e. CD8 T cells release perforins and granzymes which destroy the infected cell.
f. CD8 on the surface of the infected cell binds to the T cell receptor on the CD8+ T cell.
g. CD8 on the surface of the CTL binds to MHC I on the surface of the infected cell.
B, C, E, G
108
Which of the following statements are true:
a. The primary immune response is slower than the secondary immune response.
b. The secondary immune response can originate from memory B-cells
c. The primary immune response originates from naive B-cells
d. The secondary response to an antigen lasts longer than the primary immune response
e. The primary immune response takes over a week to become effective.
All of them are true!
109
The bubo in bubonic plague is
An enlarged lymph node
110
Five species of Plasmodium commonly infect man. Which species is the most pathogenic to man?
Plasmodium falciparum
111
Sequestration by the malarial parasite is responsible for which of the following clinical symptoms of malaria?
Cerebral malaria
