Week 6 Flashcards
(126 cards)
1
Q
How do viruses impact genetic change in hosts?
A
Within an individual (acquired immunity)
Within a population (MHC/HLA)
During evolution (retroviruses)
2
Q
What is an overview of the life and structure of viruses?
A
Viruses are protein boxes (large number of capsids joined together) that transport genome from one cell to another
Viruses are obligate intracellular parasites
3
Q
How impactful of viruses?
A
Influenza - 50-100 million death a year
HIV - 35 million deaths a year
Comparable to WW with WW1 15 million dead and WW2 50 million dead
4
Q
What are examples of DNA viruses?
A
Pox
Herpes
Adenoviruses
5
Q
What are examples of RNA viruses?
A
Polio
Rhinovirus
Hepatitis C
6
Q
What are positive strand DNA/RNA viruses?
A
Its nucleotide sequence corresponds directly to the sequence of an RNA transcript which is translated or translatable into a sequence of amino acids
7
Q
What are negative strand DNA/RNA viruses?
A
Is reverse complementary to both the positive-sense strand and the RNA transcript, from which RNA polymerases construct the RNA transcript, but the complementary base-pairing means that the sequence of the RNA transcript will look identical to the positive-sense strand
8
Q
What is special about retroviruses?
A
Integrate into host genome
Reverse transcriptase - RNA to DNA
Integrase - DNA into chromosome
9
Q
What does a virus need for survival?
A
They must not kill the host rapidly
They must not be confined to a single host
They need a mechanism of transmission to a receptive host
10
Q
What is an overview of immunity?
A
Immunity can provide a barrier against transmission
Sterile immunity eliminates all the virus
Immunity can prevent symptoms but may not eliminate the virus. This can produce carriers
11
Q
What are the types of acquired immunity?
A
Humoral immunity - B-cell responses are soluble and do not sediment.
Cell-mediated immunity - T-cell responses sediment with a cellular fraction
12
Q
What is the mechanism of evolution of the immune system?
A
B-cells and T-cells evolve in response to millions of different antigens
13
Q
What is the structure of immunoglobulin?
A
Heavy and light chains and variable regions
14
Q
What is the work of Hozumi and Tonegawa?
A
Isolate B-cell lymphoma: an immortalised single B-cell
Inherited genes can be seen in the embryo
Probe for size of gene using a Southern Blot
Proved immunoglobulin genes can rearrange
15
Q
What are the main domains and number of genes involved of immunoglobulins?
A
constant region
Joining region - 5 genes
Diversity - 25 genes
Variable - 40 genes
16
Q
What is the overview of the repeatable region used by antibodies?
A
The repeated regions code for the variable domain.
Only one of the duplicated variable sequences is used by the antibody.
17
Q
What is an overview of VGJ recombination?
A
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation.
It results in the highly diverse repertoire of antibodies and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.
18
Q
How much diverisity does VDJ recombinatio generate?
A
Total diversity 5.0 x 10^13 genes
Each B and T cell carries out one rearrangement: 10,000 each hour
19
Q
What are ways for escape mutants in viruses too occur?
A
Reassortment
Recombination
Point mutation
20
Q
What is reassortment?
A
Reassortment also called antigenic shift allows viruses to evolve rapidly
21
Q
What is an overview of segmented genomes?
A
Segmented genomes can be mixed up when two different strains of virus infect the same cell. They are packaged into new viruses
22
Q
What are the different outcomes of reassortment when there are two segments? In the example 1 human and 1 bird strain of influenza?
A
Human virus with human cell receptor binding
Bird virus with bird cell receptor binding
Human virus with bird cell receptor binding
Bird virus with human cell receptor binding
23
Q
What happens in the real world with influenza virus reassortment?
A
Can introduce virulence genes from wild life reservoirs into viruses in domestic poultry, pigs and humans
24
Q
What is an overview of virus recombination?
A
Recombination allows viruses to evolve by stealing genes from the host
Viruses can steal genes from the host and use them in defence
Immune evasion genes
Seen in the KSHV herpes virus genome map
25
What is an overview of point mutations?
Most RNA polymerases and reverse transcriptase have low proof reading capacity and make mistakes
26
What is a consequence of point mutations in viruses?
These viruses generate a ‘quasi species’
27
What is the rate of point mutations in viruses?
1 error every 103-105 bp
3-32 kbp genome of RNA viruses means an average 0.1-1 mutations per template copied
28
What limits point mutations in viruses?
Variation is restricted by the error threshold
Too many mutations lead to a virus that does not function
29
What are the high rate of virus mutations and high rate of genetic diveristy in MHC mean?
The arms race is a battle between two methods of genetic change
30
What is an overview of antigenic drift?
The generation of escape mutants explains antigenic drift: a slow evolution of the virus
The generation of immune escape mutants allows the virus to survive eg: HIV.
31
How does HIV impact diveristy of MHC?
HIV kills helper T-cells needed to get B cells to make correct antibody. Patients cannot fight infections.
Means that overtime the number and variation of B and T cells reduces making more at risk of following infections
32
What is an overview of coronaviruses?
Coronaviruses have a relatively large genome (25-30kb) and have evolved to incorporate ‘proof reading’ into the RNA-dependent RNA polymerase. 10X less mutation than for other RNA viruses
Pandemic virus had evolved to reduce the effectiveness of mutations - resulting in number of strains that can be more virulent
33
If humans are 99.9% identical how do we prevent lethal pandemics?
Histocompatibility (transplant) antigens determine whether a tissue will be rejected.
They also determine what is ‘self’ in your personal immune system
Comes from studies of tissue transplantation
34
How large is the MHC?
Transplant antigens are found in the Major Histocompatibility Complex. This represents 0.1% of the genome. MHC varies greatly between individuals.
35
What is an overview of the MHC?
MHC-peptide complexes are used to detect viral infection (immunology revision)
This allows the immune system to ‘see’ into cells and tissues
Cytotoxic T-cells kill cells when MHC presents virus-derived peptides
36
What is a case study of host-virus co evolution?
Two brothers in South Africa have mother with HIV. Mother dies aged 25, father is still alive aged 55.
At 5 years old one brother develops: CD4+ T-cell count very low (<200/ml), blindess fro reactivated herpesvirus, skin cancer, numerous lung and fungal infection and substantial weight lost
Brother died age 15 other brother is alive and in 20s
37
Why did the other brother surivive HIV infection?
The surviving brother is an HIV elite controller
38
What is an overview of HIV elite controller?
HIV infection causes loss of CD4+ T-cells and loss of immunity to opportunistic pathogens
Without drug treatment most infected people die
A small number of people are resistant to HIV
They are called HIV controllers and do not need anti-retroviral drugs
39
How GWAS studies shown about HIV MHC mutations?
Genome wide association studies show mutations in HIV controllers cluster at a single position on chromosome 6
40
What happens in the HIV elite controller people to be more resistant?
Mutations increase binding of MHC to HIV peptides: increases immune recognition
41
How are HIV epidemics selecting for MHC alleles in human populations?
HLA B*57 populations will survive
B.51:01 are more disease susuceptible
42
What happens if it all get’s too much for HIV?
The virus will integrate into the genome and stop making proteins
In rare cases it will enter the germline and be with you throughout evolution.
43
What functional domains can be detected in Endogenous retrovirus?
LTR - promoter
GAG - Capsid gene
ENV - enovolope gene
44
What is an overview of the mechanism of the placenta?
Trophoblasts of embryo invade the endometrium of the mother this is done to gain access to maternal blood supply
trophoblasts undergo cell to cell fusion to invade endometrium called syncytia (syncytiotrophoblast)
45
How does the placenta impact infections?
Note the placental provides a good opportunity for retroviruses to infect the embryo. Vertical transmission
Retroviruses and retroviral RNA are in placental tissue
46
What was the origin of the syncyntin genes for syncytia formation?
Syncytin proteins derive from retrovirus envelope proteins and allow fusion of the trophoblasts
They come from viral envelope proteins are used to fuse the viral envelope with the host cell
47
What is the evolutionary histroy of endogenous retroviruses?
Endogenous retroviruses have provided syncytin genes independently at different times during mammalian evolution: this may explain placental diversity
48
What is an overview of the ARC1 gene?
Endogenous retrovirus and the synapse.
Arc 1 is essential for synapse maturation, learning and memory
Dysfunctional Arc associated with autism, Alzheimer’s disease.
49
How does ARC1 gene function?
m-RNA travels from nucleus to dendrites and synapses where it is translated into protein
Arc protein modulates AMPA glutamate receptor trafficking at synapses
50
What is the origin of the ARC1 gene?
The Arc protein is derived from GAG genes and assembles into a capsid
The capsid shares structural homology with HIV
51
What is similar with ARC1 and GAG genes?
The Arc protein is derived from GAG genes and assembles into a capsid and is hollow.
In common with viruses the Arc protein capsid contains Arc m-RNA
52
What is the impact of endogenous retrovirus LTR promoter?
Endogenous retrovirus LTR promoter sequences affect corticotropin relasing hormone (CRH) gene expression in the placenta (determines onset of birth)
53
What are the aetologic agent of disease?
Viruses
Bacteria
Eukaryotes
54
What is an overview of the evolution of pathogens with in a host?
Founder effect bottleneck for initial population
Overtime natural selection will select for variaiton in receptor proteins, if enough to evade immune system to leave then potential start process again in new host
55
What is an overview of the dynamic changes of gut microbiota?
The gut microbiota undergoes dynamic changes during host aging - diveristy decreases overtime
The composition of gut bacteria can change overtime depending on environmental conditions
56
What is an overview of trypanosomes?
Population goes through peaks and troughs where once the trypanosomes reach a certain population size they use quorum sensing slows down replicaiton to not kill host.
This repeats because of antigentic shift preventing the immune system from fullu clearing infection
This is an undulating parasitaemia
57
What is pathogenicity?
The ability of a microbe to cause disease
This term is often used to describe or compare species
58
What is virulence?
The degree of pathogenicity in a microorganism
This term is often used to describe or compare strains within a species
59
What is an overview of the evoltution of virulence?
Increased Pathogen load --> Increased Virulence --> Increased Transmission Rate
Or
Reduced Pathogen load --> Reduced Virulence --> Increased net transmission
60
What things can evolve for bacterial pathogens?
Antibiotic resistance (for example efflux pumps)
Metabolic adaptations to host
Virulence and bacterial cell surface
61
What is an escape mutation?
An adaptive mutation that give rise to a selective sweep, even if it has a slight fitness benefit
62
What are the species definition for eukaryotic species?
A group of closely related organisms that breed among themselves
Not 100% as some species are asexual
63
What are the species definition for prokaryotic species?
A population of cells with similar characteristics
Clone: Population derived from a single cell
Strain: Genetically different cells within a clone
64
What is the species definition for viral species?
Population of viruses with similar characteristics that occupies a particular ecological niche
65
What are an overview of viruses?
The virus diverts host resources for viral reproduction.
100s to 1000s of new viruses emerge destroying the cell.
Symptoms of colds and flu result from these dead cells.
Viral offspring infect more cells
Obligate intracellular parasites
66
What are properties and their consequences of viruses?
Filterable agents Can’t be eliminated by filter sterilization
Obligate intracellular parasites Reproduce by infection
Few or independent functions Must take over host cell
Genome may be DNA or RNA Used in Classification
May be “naked” or enveloped Used in Classification
Life cycles variable and complex Can form basis for therapy
67
What are examples of enveloped DNA viruses?
Pox
Herpes
Hepadna
68
What are examples of nakes capsid?
Papova
Adeno
Parvo (ss)
69
What are examples of positive strand RNA?
Nakes - Pircorna
Enveloped - Toga, Flavi and corona
70
What are examples of negative strand RNA?
Enveloped - Rhadbo, Orthomyxo (influenza), Paramyxo (measles) and Filamentous (ebola)
71
What are examples of positive and negative strand RNA?
Double capsid - Reo
72
What are examples of positive strand RNA via DNA?
Enveloped - Retroviruses (HIV)
73
What is an overview of a gram postive cell envelope?
1 layer of plasma membrane and thick multilayer of peptidoglycan
74
What is an overview of a gram negative cell envelope?
2 layers of plasma membrane and thin peptidoglycan layer inbetween. The outer membrane has a lipopolysaccharide attached to it
75
What are examples of different arrangements?
coccus -sphere
Strepto - chain
Staphyl - cluster
Sarcina - packet of 8
76
What is Bergey's manual of systematic bacteriology?
Classification of Bacteria - Key reference
77
What are ways to classify bacteria?
By phenotype - Morphology or biotyping
By genotype - Chromosomal DNA fragment analysis or DNA hybridisation
By analytical methods - Proteomics and whole cell lipids
78
What are potential issues with genotyping bacteria?
Bacteria have similar problems with morphology and asexuality
Additional problem of lateral gene transfer
79
What are ways to genotype bacteria?
Hybridizations studies set as gold standard - 70% cross-hybridization
ANI refined measure - 95% average nucleotide identity
16S RNA favoured as a convenient marker 97%
Difference in gene content roughly 20%
MLST for better resolution – 6-10 housekeeping genes
80
What is an overview of eukaryotic parasites?
Parasitic infections generally cause more morbidity and mortality world-wide than any other
Toxoplasma - ~30% of world population infected
Cryptosporidium - ~50 million cases, 200,000 deaths
81
How do you classify parasites?
Morphology
Presentation/Symptoms
Host Range / Culture Conditions
Genotype
82
What are traditional methods for diagnosing infectious disease?
Symptoms
Culture and Biochemistry
Morphology – Microscopy/Histology
83
What are molecular methods for diagnosing infectious disease?
Serology (ELISA)/monoclonal antibodies
DNA (PCR)
84
What is the problems for protist species?
Protists sex is often unobserved, absent or atypical and evidence for outbreeding is rare
So pathogen was named after the disease it caused
85
What are examples of other species concepts?
Unified – De Quieroz - Independently evolving metapopulation
Phenetic - Shared quantifiable phenotypic characteristics - Morphospecies
Ecological - Shared Niche – host tropism, geography
Genotypic - Genetic relatedness – DNA hybridization, ANI, whole genome, synteny, gene complement
Biologically Compatable - Chromosomes, ISL, mini-exon, ribosomal promoters
Diagnosable - an explicit set of features that together distinguish the organism from all other described species and which can include pathogenesis, morphology, metabolism, genetics
86
How can house keeping genes be used to identify parasites?
House keeping genes are essential but parasites can lose them and get requried nutrients from host, so each parasite have a unique combination of genes that are lost or not. Some genes can be species determinate and usual ways to identify parasite
87
What is an overview of the importance of Giardia host identification?
Different assemblages which infect different hosts eg Humans and Pets
Vaccine manufacoters want pets to be vaccinated but pet Giardia dont transfer to humans as we get it from humans
88
How can cryptic species be a problem?
Cryptosporidium parvum - In cattle though could transmit to humans in close contact
Cryptosporium Hominis - human to human
Crytposporidium anthroponosum - looks like parvum but is human to human
Makes lockdown and preventing firther spread harder as it would be unknown for human to human to animal to human source
89
What is the evolution of the different cyrptosporidium species?
Cryptosporidium parvum - During middle ages
Cryptosporium Hominis - Industrial revolution
Crytposporidium anthroponosum - In the last few decades
90
What is the difference between species concept and species definition?
We do not need to have an idealized species concept to formulate a pragmatic species definition.
However, Species Names once given should be robust and long-lived so the species definition should adequately reflect a consensus of species concepts
Phenotypic variation can be misleading as character traits can reflect as little as a single point mutation
Genotypic variation may be of no consequence to phenotype and particular to manifestation and treatment of a disease
Ideally a mix of genotype and phenotype
91
What are house keeping genes?
These evolve slowly and neutrally, with little homoplasy and can provide clear species identification for pathogens.
Include universal genes
92
What are contingency genes?
Genes that are heavily selected for and offer an advantage
93
What is an overview of non coding (repetitve) DNA?
Evolves neutrally and quickly (but can be homoplastic) it can be used to discriminate strains (fine typing) and even for source tracking and forensics.
94
What is an overview of contingency genes?
Evolve quickly under intense selection pressure.
Often Telomeric
95
What are the properties of virulence determinants?
Parasite surface or secreted
(Hyper)variable between isolates
Under selection pressure dN/dS
Encoded telomerically or subtelomerically
Recombination/introgression hot spots
Multicopy or gene families
Glycosylated
Lipoylated
Environmenally regulated
96
What do contingeny genes code for?
Encode Virulence Determinants
Virulence determinants influence pathogenicity
Adhesion
Colonization
Invasion
Immune evasion
97
What are the problems with using contingency genes to mark strains?
Different strains may appear related due to convergent or parallel evolution
Virulence may be an unstable phenotype and may arise multifactorially
Care - Risks of false positives with diagnostics and taxonomy based on contingency genes
98
What are the 2 main characteristics for evolutionairy pressure for pathogens?
Transmissibility - positive (allows spread)
Pathenogenicity - negative (may kill host)
99
What is an overview of vertical transmission?
Low infectious dose for infection Fixed Ro, cost to host is cost to pathogen
Evolutionary driver towards chronic illness or commensualism
100
What is an overview of horizontal transmission?
High infectious dose favors transmission, lower penalty for damaging host. Favours acute/virulent transmission – but trade-off, self restraint, altruism
101
What are the main transmission routes and examples of their infections?
Airborne – respiratory mycoses - aerosolisable
Bloodborne – haemoparasites – survive in blood
Foodborne/Waterborne – cryptosporidium, giardia, amoebiasis – environmentally resistant cysts
STD– Trichomoniasis – Resists dessication – adheres surfaces
Nosocomial (Iatrogenic) – Candidiasis (glabrata) – Biofilms
Vertical – Malaria, Toxoplasmosis – placental abruption
Environmental – amoebiosis – free living, contractile vacuole
Vectorborne – malaria, leishmaniasis – penetrative motility
102
What are biological disequilibriating factors?
Pathogen adaptation
Drug resistance, mode of transmission, host spillover
103
What are anthropocenic disequilibriating factors?
Socio-economic conditions – migrations
Wars and refugee movements
Agricultural Intensification
Intercontinental travel
Problems with public health services
Globalisation of food supplies
Global warming
104
What is the main trend for most emerging diseases?
Most Emerging Diseases are Vector Borne or Zoonotic
105
What is an overview of DNA sequencing for pandemics?
Source tracking - use DNA sequecing to track down the patient 0 to determine where from
Sequence genome to estimate whether previous strains and vaccines offered the protective resistance in new strain
Contact case forward to help reduce spread and confirm strain no longer spreading
106
What is an overview of Ebola?
Natural host is in bats
Areas with ebola infections overlap with areas that fruit bats lives in high numbers
107
How did they use source tracking for Ebola?
Index Case identified – Patient zero
Meliandou Guinea
December 2013
Emile Ouamouno – 2yo
Unknown but believed it came from playing with guano
108
What are examples of insects and disease they carry?
Fleas – Plague
Mosquitos – Malaria, Dengue, Yellow fever, Filariasis, West Nile Virus (++other encephalitus)
Ticks – Lyme disease, tick-borne viruses
Tsetse – African Trypanosomiasis
Triatomine – American Trypanosomiasis
109
What are examples of outbreak of Yersinia Pestis?
Plague of Justinian (541–542)
The "Black Death" of 1347–51
The Third Pandemic, China (1855–1950s)
110
What are the mortality rate for the black death outbreak?
West Europe - 33%
Genoa - 60%
Norwich - 30%
111
What are the mutation that allowed for Yersinia Pestis to be carried by rat?
ymt mutation which evolved ~1000 bc
112
Why isnt Yersinia Pestis no longer in the UK?
Rattus Rattus (black rat) the main host was outcompeted by rattus norvegicus
Flea and Y.pestis have lower transmission rate in black than brown rat
113
What is the history of the distrubtion of dengue virus?
Wide spread throughout South America but ddt spraying for malaria caused massive declines in dengue cases and locations however when mosquitos became DT resistant and humans learned of health consequences so us stopped debgue returned
Spread by Aegis aegypti
114
What is the traditional distrubution of dengue?
Each region had a unique varient of dengue and when you had and fought it off you became immune to that varient
115
What is the problem with being infected with 2 different strains of dengue?
When fight off one, you produce antibodies but those antibodies bind to but doesnt neutralise other varients which causes a more severe disease, dengue hemorrhagic fever
This is coming more common with regions getting more than one varient
116
What are ways to combat the vector borne diseases?
Transgenic Mosquitos: Better than SIT, since males are normal
RIDL – Release of Insects carrying a Dominant Lethal all female progeny fail to develop.
Problem/advantage – no driver for population fixation
117
What is the different between pathology of Leishmaniasis?
In India and North Africa - 90% severe reaction
Europe - 20-30% severe reaction
HIV disrupted this as immunosuppresed people have more severe oubreak
118
What is the circle of poverty?
Disease --> Less work and less schooling --> Increases poverty --> Poverty leads to worse conditions and reduced spending of disease prevention --> Increases rate of disease
119
What was the controversial way to deal wirth tsetse fly?
IAEA steralised flies
120
What is a way of using symbiotic bacteria to control disease?
Wolbachia disrupt populations through interfering with reproduction through 4 means incl cytoplasmic incompatibility
121
What is the overview of the number of cases of malaria in Uk?
Around 2,000 cases a year
Used to be dominated by milder Ali malania now the amount of Plasmodium falciparum has been increasing
Also global trend
122
How was Malaria naturally wiped out in UK?
Increased drainage of marshes
Increased livestock density
Reduced human density
Last case recorded 1951
123
What factors are causing reemergance in Africa?
Frequent armed conflicts and civil unrest in many countries, forcing large populations to settle under difficult conditions, sometimes in areas of high malaria transmission
High birth rates leading to a rapid increase in the susceptible population under 5 years of age
Agricultural development – rice paddies
adverse socioeconomic conditions leading to a much reduced health budget and gross inadequacy of funds for drugs;
changing rainfall patterns as well as water development projects such as dams and irrigation schemes
**90% of malaria is now from Africa
124
How have rice paddies increase Malaria rate?
Very few cases when area was dry but when rice production increase within 10 years increased to 27 mullion cases of Malaria
125
How much protection is good enough?
Malaria vaccine was around 40% when first discovered but thought could be better after a couple decades no real improvement so the new vaccine was rolled out to save lives not wipe out disease
126
