Week 2 Flashcards
How pathogens have shaped human evolution
Shaping our immune system, learning to fight infections
Invasion of the genome-endogenous retroviruses, profoundly influenced the human genome
Categorising pathogens
Pathogens that cause infectious disease are classified depending effectively on how deadly they are
4 bio-safety containment levels BSL:
-BSL-1: unlikely to cause disease
-BSL-2: can cause disease but unlikely to spread in the community
-BSL-3: can cause disease and spread but treatments available
-BSL-4: the deadliest. Will cause serious disease, will spread and generally no treatments
Current issues
The rise of anti microbial resistance:
-making simple infections difficult to treat
-AMR bacteria killed more people in 2019 than HIV/AIDS and malaria combined
Epidemics and pandemics:
-in the last 10 years- major viral outbreaks
-COVID-19, Mpox, Ebola, Zika, influenza
More outbreaks will happen
Smallest to largest microbes
Prions
Viruses Host required
prokaryotes: bacteria
Eukaryotes: fungi, parasites (trypanosomes)
Prions
A mutant protein= prion protein
-causes other normal proteins to fold abnormally (spongiform encephalopathy)
-aggregates of abnormal proteins in the brain= degeneration
Prion protein (PrPc)= normal protein
-expressed in neuronal tissues and tonsils
PrPsc= abnormal protein
-sc=scrapie
Diseases caused by prions:
-creutzfeldt-Jakob disease CJD
-Kuru
-mad cow disease or vCJD
CJD- pathology and transmission
100% fatal, no treatment
Causes:
-sporadic (mutation)
-familial
-transmission (vCJD)
Transmission:
-oral (mad cow disease)
-operative (neuronal tissue)
-blood
Prions are hardy
-high resistance to disinfectants and heat
-hard to remove and/or inactivate
Transmissible forms
Kuru:
-a form of transmissible spongiform encephalopathy TSE
-Identified in a tribe in Papua New Guinea in 1960s
-caused by the ritual of eating the dead (orally transmitted)
-index case hypothetically a tribe member who developed sporadic CJD (mutation)
Mad cow disease (vCJD):
-cows/sheep also get TSEs
-larger outbreak in the UK in 1980s
-caused by feeding cows meat and bonemeal (oral)
-bovine prion can cause disease in humans
-178 people died as a result
-possibly more to come due to long incubation period
Long lasting effect on the Uk:
-health implications
-global ban on British beef exports
Viruses
Are everywhere and infect everything
Not a cell, a shell of protein (capsid) containing nucleic acids, enveloped or non-enveloped, absolutely require a host to replicate
Can be either DNA or RNA, but there are many different types and classifications
11,273 virus species currently known about, estimated to be 1.7 million virus species yet to be identified
Baltimore classification
Developed by David Baltimore
-also credited with the discovery reverse transcriptase
Based on how viruses synthesise their messenger RNA
Shared group characteristics viruses
Same basic viral lifecycle principle
Alternative splicing: increases coding capacity of viral genomes
Genome segmentation (not all): eg viral genes are encoded on separate bits of DNA/RNA, better for evolution
Host range: viruses are found across all 3 branches of life (prokaryotes, eukaryotes and archaea), some are restricted to one host (eg humans), others can jump the species barrier= zoonotic
Viral lifecycle
Large variation due to their genome and other factors- but all viruses follow the same basic principles
1. Attachment to host cell
2. Entry into host cell
3. Release of viral genome from capsid
4. Replication of viral genome
5. Assembly of new virions
6. Egress of new virions from cell
Repeat ad infinitum
Viral effects on host cells
Range from innocuous to lethal
Some viruses integrate into the host genome- HIV
Cell death: due to production of lots of virions
Cell fusion -syncytia
Increased cell proliferation- papillomaviruses
Latent infection= no clinical manifestation until the virus reactivates. Herpesviruses, herpe(creeping in latin)
Group I- dsDNA viruses
Includes herpesviruses, papillomaviruses, polyomaviruses and poxviruses
Varicella Zoster Virus (VZV)
-causes chicken pox upon initial infection
Latency in the neurons surrounding the spine
-dorsal root ganglia
Stresses can cause reactivation, shingles
Some countries vaccinate against VZV
- the Uk doesn’t but you can pay for the vaccine
Group II- ssDNA viruses
Very few infect humans and the ones that do cause no apparent disease
Parvoviruses are likely the most well known- canine parvo can kill young puppies
Torque teno virus is found >90% adults world wide, formally called transfusion-transmitted virus
Accidentally found in the serum of a hepatitis patient
Very little is known about these viruses but there have been more identified across different mammals
Group III- dsRNA viruses
Rotaviruses commonly infect humans
They cause gastrointestinal issues:
-diarrhoea
-vomiting
Can be very serious in babies and young children
Rotavirus vaccine is offered to babies in the UK, 2x doses (1st at 8 weeks and 2nd at 12 weeks)
Group IV- ssRNA (+ve) RNA virus
Lots of +ve sense ssRNA viruses infect humans:
-noroviruses, enteroviruses, flaviviruses, coronaviruses, Astroviruses
Positive sense= genome is mRNA
-Zika virus is a flavivirus that infects humans- transmitted by mosquitos and bodily fluids
Treatment is pain relief, rest and hydration
Epidemic in the Americas in 2010s
Proposed to cause:
-microcephaly in neonates
-neurological disorders (guillain-Barre syndrome)
Group V - ssRNA (-ve) RNA virus
Lots of nasty viruses contained in this group- many have high % fatality rate
-lyssavirus (rabies), influenza, Ebola, marburg, arenaviruses, hantaviruses
Ebola is a member of the filovirus family
Cause= haemorrhage fevers, high mortality rate (up to 90%)
-Zaire strain responsible for most outbreaks- including west Africa in 2013-2016
-broad ranging symptoms: characterised by blood in vomit/stools
-treatment is supportive, promising vaccine candidates
Infection control is key to ending outbreaks
Group VI- ssRNA-RT viruses
Viruses that have a DNA intermediate from RNA- reverse transcription
Human immunodeficiency virus 1= HIV-1
-DNA stage (provirus) integrates into the host genome
HIV-1 is a lifelong infection- progresses to AIDS
AIDS is the failure of the immune system- other opportunistic pathogens can cause disease
Originally jumped from chimps into humans- restricted now due to human adaptation
Between 1981&2009= 30 million deaths attributable to HIV/AIDS
Group VII- dsDNA-RT viruses
DNA viruses but have an RNA intermediate step
-use reverse transcription in virions to make their genomes
Hepatitis B virus is a major problem
95% + adults and older children can clear the acute infection- this drops to 5% in young children where it becomes chronic
~300 million people live with chronic HBV infection
Causes hepatocellular carcinoma
-chronic carriers have a 40% chance of death from HCC due to infection
Important viral pathogens
Influenza A: respiratory infection, zoonotic, lots of types that can recombine (antigenic shift)
Ebola : haemorrhagic fever. Very serious and high % mortality, high consequence of infection. Very few places allowed to work with it
Varicella Zoster: initial= chicken pox, subsequent= shingles. Herpesvirus. Has 2 lifecycles (latent and lytic) can be reactivated
Human papillomavirus 16: typically no clinical disease and cleared but causes cancer. Another DNA virus, major cause of cervical cancer but there is an effective vaccine
Sin nombre virus: heart and respiratory failure, associated with the 4 corners outbreak in USA 1990a. Carried by mice
HIV-1: lifelong infection. No cure. Integrates into human genome
Rotavirus A: gastrointestinal issues. Double stranded RNA virus. Segmented
Bacteria
10^30 bacterial cells on earth
You carry 10x more bacterial cells in your body over your own cells with 100-1000x of different species
A tiny fraction of these have been studied- many are unculturable in the lab
Bacteria found in all environments on earth
Bacteria and humans
Very few microbes are always pathogenic— obligate pathogens
Many microbes can be pathogenic— opportunistic pathogens
Most microbes are never pathogenic— commensals
Not all species are pathogens
Many bacteria can be pathogenic (most never though)
Some are always pathogenic (obligate)- salmonella typhi has no reservoir outside of humans
Some are opportunistic in their pathogenicity
Pseudomonas - will infect most body sites if given a chance
Anaerobes: eg bacteroides fragilis, can infect wounds if they are deep
Bacteria come in different shapes and sizes
Cocci
Bacilli
Budding and appendaged bacteria
Others;
- enlarged rod fusobacterium
-vibrio, comma’s form B dellovibrio
-club rod, helical form
- corkscrew form
-filamentous
-spirochete
Bacterial structure
Prokaryotes:
-lack membrane bound organelles e.g. nucleus
They usually have a cell wall- peptidoglycan
Protruding appendages: flagella, frimbriae
classification of bacteria
Theres many different phyla of bacteria and each has many classes and by definition a lot of individual species
Classification is based on nucleic acid sequences
But there’s also a large division of bacteria into 2 groups - gram negative or gram positive
Bacterial cell wall structures
Gram negative stain PINK:
- they have doubled membranes
-examples include: E.coli, Klebsiella
Gram positive stain PURPLE:
- they have single membranes
-examples include: staphylococci e.g MRSA, streptococci
How do bacteria cause disease
Varies loads
Some bacteria invade cells (intracellular)- salmonella
The pathology of disease depends upon:
-bacterial activity
-toxin production, direct tissue damage
-host response
-immune system
Bacterial toxins
Exotoxins- proteins secreted by bacteria
Synthesised for a number of reasons
-destroy host cells
-release cellular contents
- allow invasion
Clostridium botulinum:
-food poisoning
-lethal neurotoxin that causes paralysis
Also the stuff used in Botox
Symptoms:
-facial nerve paralysis
-dry mouth and throat
-nausea and vomiting
-abdominal distension
-problem of urinating
-double vision
-slurred speech
-tachycardia
-muscle weakness
Lipopolysaccharide LPS
An endotoxin - found on gram negative bacteria
Major immune stimulator- causes sepsis
Only lipid A is toxic- major immune response
There are many types possible- specificity caused by terminal repeat regions, salmonella >1000 types of LPS
Flagella
Molecular motors used to swim
Important in pathogenesis
Often v. Immunogenic and cause inflammation
Chemotaxis- can move bacteria towards or away from chemical attractants/repellants
Fimbrae (pili)
Shorter and finer than flagella
Several different functions:
-attachment to host cells (UTIs)
-host cell invasion
-roles in conjugation
Conjugation= transfer of plasmid DNA, this can drive AMR
Important bacterial pathogens
Escherichia coli: bacteraemia, UTI, GI. Gm- often part flora
Staphylococcus species: wound infection, bacteraemia. Gm+ often part of flora, MRSA
Mycobacterium tuberculosis: tuberculosis Lung, 1/3 world carry
Pseudomonas species: varied disease, Gm- environmental
Streptococcus pneumoniae: RTI, Gm+ aerosol
Campylobacter species: GI, Gm- 1 cause food poisoning
Clostridium difficile: hospital acquired infections, sporulates overgrowth after antibiotic use
Neisseria gonorrhoeae, N.meningitidis: gonorrhoea, meningitis, species specific tropism
Antibiotic resistance AMR
AMR is a major global threat to everyone
Routine surgery will become deadly due to infection
1.2 million deaths were attributable to AMR in 2019
New drugs hard to get approved - numbers declining over time
Bacteria can become resistant fast: faster than the discovery rate, misuse is another reason for resistance
The UN predicts up to 10 million deaths annually- as a direct result of AMR
Fungi
Can be single cell or multicellular
They are eukaryotic, similar to human cells
Because of this it makes them harder to treat
They have a cell wall that contains chitin
Very few have been studied thought to be up to 1.5 million species
Includes lots of useful things:
-yeast
-moulds
-mushrooms
Fungal pathogens
Numerous fungi can act as parasites or pathogens
Large spread of human diseases caused by fungi:
-simple infections EG. Athletes foot
-serious, life threatening infections (eg aspergillus infection in the lungs)
Thrush is the most common oral fungal infection:
-caused by candida albicans ( a type of yeast)
Fungal structures
Can be single cells but many grow as hyphae
-cylindrical tubes which interconnect= mycelium
Mycelium can be very large
-armillaria ostoyae grows very large, malheur national forest in oregon 2,200acres
Fruiting bodies and spores for reproduction- Can be carried on the wind
Parasites
There are several other majors diseases that are caused by parasites
Parasites can also include larger, complex organisms- worms (e.g. tapeworms)
Protozoa can be intracellular or extracellular pathogens: malaria, trypanosomes
Malaria is a major killer- 619000 deaths in 2021
Trypanosomiasis= African sleeping sickness, can be fatal without treatment
Current and emerging infection problems
Pathogens constantly evolve due to competition with each other and in response to human intervention. E.g antibiotics
-mutation rates and generation times high and short thus allowing for greater diversity and faster evolution
Bacteria: anti microbial resistance= ticking time bomb for global health
Fungi: anti-fungal resistance, new strains through evolution
Viruses: anti- viral resistance, new epidemics/pandemics
Infection control measures do work
Different shapes of bacteria
Coccus: pneumonia, skin infections eg streptococcus
Rods: E.coli, gut commensal, diarrhoea, bloodstream infections
Comma shaped: vibrio cholerae, excessive diarrhoea
Spirochete (spiral shaped): treponema pallidum, syphilus
Bacteria are small
Allows rapid metabolism as diffusion of nutrients is not limiting
Rapid turn over of sugars, amino acids, nucleotides
Microbiological media
Liquid culture: quantify growth rate, study physiology
Solid media: using agar, preliminary identification, quantify number of live bacteria, isolate a pure culture
Selective media: isolate specific bacteria, inhibits growth of others
Differential media: ability to distinguish between different bacteria
Macconkey agar
Selective and differential
Inhibits growth of many bacteria by the presence of bile salts and crystal violet
PH indicator: neutral red, below pH 6.8= pink neutral= colourless
E.coli ferments lactose- drop in pH- pH indicator turns from colourless to pink
Salmonella grows on the agar but cannot ferment lactose
Microbiological media growth requirements
Medium needs to contain:
- carbon: mostly in form of glucose or other sugars, amino acids
-nitrogen: anorganic (eg ammonia, nitrate) or organic (amino acids)
-sulphur: essential for the amino acids cysteine and methionine
-phosphorus: required for ATP, DNA, RNA taken up as inorganic phosphate PO43-
Minerals Fe2+, Mg2+, Ca2+: required for enzyme function
Defined and complex medium
Defined medium: consists of pure chemicals very reproducible
Complex medium: digests of microbial, plant and/or animal products
Microbial growth
PH: most pathogens exhibit optimal growth around physiological pH 7.4
Exceptions: helicobacter pylori causes stomach ulcers, grows in stomach pH 3. Creates micro-environment with higher pH through production with ammonia and bicarbonate, releases urease enzyme that breaks down urea
Microbial growth aerobic and anaerobic
Aerobic: many pathogens can breathe (‘microbial respiration’) most effective way to create ATP
Anaerobic: do not respire oxygen, aerotolerant anaerobes: can tolerate and grow in air. Obligate anaerobes:oxygen inhibits growth or kills the cells. Many obligate anaerobes can form spores, Extremely robust structures can tolerate high heat, oxygen, UV can grow out ‘germinate’ when conditions are favourable again.
The bacterial growth curve
-Lag phase: adaptation to new environment, start up metabolism (generate ATP make new ribosomes)
-Exponential phase: rapid cell growth and metabolism, cells run out of one or more nutrients and/or waste products limiting growth accumulate
-Stationary phase: slow/no growth, preparation for survival (sporulation) resistance to stress, production of antibiotics to kill neighbouring cells
-Death phase
The gram stain
Rapid stain by crystal violet and safranin
Visualise and distinguish bacteria in 2 groups: gram-negative bacteria (pink/red) and gram-positive bacteria (purple)
Procedure:
- flood the heat fixed smear with crystal violet for 1 min, all cells purple
-add iodine solution for 1 minute, all cells remain purple
-decolorize with alcohol for 20 seconds, gram + cells are purple, gram - cells are colourless
- counterstain with safranin for 1-2 minutes, gram + cells are purple and gram negative cells are pink to red
Reflects fundamental differences in the bacterial cell wall
Gram +: thick peptidoglycan no second membrane
Gram -: thin peptidoglycan , second membrane
Use for rapid identification by microscopy important differences in susceptibility to antibiotics since the second outer membrane of gram- functions as a barrier to many antibiotics
Clinical microbiology
Many different approaches
Immunological and antigen assays
Molecular biology assays (PCR assays, whole genome sequencing)
Growth dependent microbiology
Clinical bacteriology
Direct microscopy on clinical samples;
-standard light microscope
-staining
Very cheap very fast, very useful in low resource setting
Grow sample on agar:gold standard
-determine specific biochemical traits (eg growth on different carbon sources)
Challenging : not all bacteria can be grown easily, identification not always correct, takes time
Analyse in a matrix assisted laser desorption/ionisation TOF (MALDI-TOF) mass spectrometer
Peak pattern can be compared to extensive database, microorganism identification, proteins in colony material are positively ionised accelerated and detected -> separation by m/z mass to charge ratio
Generalised outline of antibody detection assays
- Antigen is bound to well
2.blocking agent is added - Sample added; if antibody is present it binds to the antigen
- Unbound sample is washed away
- Antihuman enzyme linked antibody is added
- Unbound antihuman antibody is washed away
- Substrate is added, if present enzyme converts substrate to coloured product
Detection of antigens
Specific components of pathogenic bacteria
Proposed for the diagnosis of cerebrospinal fluid CSF for antigens of classic bacterial meningitis: latex agglutination tests
Not always easy to interpret, no clear benefit over gram stain of CSF for rapid screening
Lateral flow tests
Widely used for COVID-19 rapid testing
lateral flow tests can be used to rapidly detect antigens
Antigens bind to antibodies conjugated with a label
Antigen is also recognised by a second antibody test
Control line contains antibodies that recognises the conjugate-labelled antibodies in the test
DNA based methodologies
Rapid amplification of DNA by polymerase chain reaction PCR
Uses primers (complementary to target DNA) and dNTPs (nucleotides in DNA) and polymerase (Taq) in multiple cycles
Visualise PCR products on an agarose gel in presence of dye binding to double stranded DNA separation by size can be used to identify bacteria
Quantitative PCR, SYBR green binds to double stranded DNA
Taqman: release of fluorescent label Taq has 5’ nuclease activity: chews up DNA in its path
Advantages: rapid 4-6 hrs from clinical sample; growing bacteria on a plate takes 24 hrs. Particularly useful when culture is difficult or will take a very long time
Limitation: primers determine what you will find , Solution: sequence all DNA in a sample to rapidly identify all microbes present
Viruses are obligate intracellular parasites
They parasitise all biomolecular aspects of life
They depend on the host cell for raw materials and energy
Replication can only occur within a host cell
They exist as either an extracellular virion containing DNA or RNA virus genome or as nucleic acid inside the host cell
Viral lifecycles
- Adsorption
- Entry
3.capsid transport to nucleus - Transcription
- Translation
- Replication
- Capsid assembly
- Glycosylation
- Glycoprotein export to cell surface
- Endocytosis of glycoprotein containing plasma membrane
- Envelopment
- Virus release
Influenza virus particle
Segmented negative sense single stranded RNA virus (8 segments- code 1/2 proteins only)
Each RNA segment codes for separate proteins
Influenza viruses
Three types of human influenza viruses A,B,C
A: pandemics; infects humans, birds, pigs, horses etc
B: seasonal epidemics; infects only humans
C: mild respiratory illness: infects humans and pigs
D: infects pigs and cattle
Divided into subtypes based upon 2 viral proteins:
-Haemagglutinin (H1-H18)
-Neuraminidase (N1-N11)
Can be classified as avian, swine or other types of animal influenza
Haemagglutinin HA mediates entry into target cells binds to alpha 2,6 sialic acid
Neutralising antibodies inhibit the interaction between HA and sialic acid
Why do we repeatedly get infected by influenza
Host survival from an acute infection usually results in protective immunity
Yet acute infections caused by some viruses occur repeatedly eg rhinoviruses, influenza virus
RNA virus is unstable
Antigenic drift
Small changes in the genes of influenza virus that happen continually over time as the virus replicates
Accumulate over time
Eventually generate proteins no longer recognised by the immune system
Neutralising antibodies to Haemagglutinin block influenza binding to cells
Mutations alter epitopes in Haemagglutinin so that neutralising antibody no longer binds
Why do these mutations happen antigenic drift
RNA viruses must replicate their genomes using RNA polymerase
RNA polymerase lacks the proofreading ability of DNA polymerase
RNA viruses have a much greater mutation rate than DNA viruses
RNA viruses can rapidly alter antigenic epitopes targeted by the immune system
Antigenic drift results from replication errors
Viruses can produce a large number of progeny:
- in vitro a single cell infected with poliovirus can yield 10^5 virus particles
-in Vivo an HIV infected person may produce 10^9 virus particles/day a hepatitis B infected person up to 10^11 virus particles a day
Replication of RNA viruses is prone to errors:
- replication of RNA viruses average one mistake/ 10^4-10^5 nucleotides (HIV genome is about 10^4 nucleotides)
-influenza average 1 mistake/ 10^3-10^4 nucleotides
-influenza genome = 13500nt therefore 1.35 to 13.5 mutations/genome
Antigenic shift
An abrupt, major change in the influenza A viruses resulting in new Haemagglutinin and or new Haemagglutinin and neuraminidase proteins
Results in a new influenza A subtype
People do not have immunity to the new (eg novel) virus
Differences between antigenic shift and antigenic drift
Antigenic shift:
- RNA segments are exchanged between viral strains in a secondary host
-no cross protective immunity to virus expressing a novel Haemagglutinin
Hepatitis B virus
Enveloped dsDNA virus
Family hepadnaviridae
8 viral genotypes
Dane particle; 42nm diameter, 3.2kb DNA
Hepatitis B virus transmission
HBV is extremely infectious (50-100 x more infectious than HIV)
It remains infectious outside the body for up to 7 days
Transmission:
-perinatal transmission (mother to child at birth)
-parenteral transmission (blood, blood products)
-needle stick injury, tattooing, piercing
-sexual
-infected body fluids (saliva, menstrual, vaginal, seminal fluids)
-medical/surgical/dental instruments
Hepatitis B virus high risk groups
Health care workers
Men who have sex with men/multiple sex partners/sex workers
Blood transfusion recipients
I.V drug users
Infants of HBV carrier mothers
Recipients of solid organ transplants
Hepatitis B virus infection
Incubation period: 30-180 days, mean 75 days
Acute infection: usually mild, particularly in children. 30-50% adults present with jaundice and hepatitis
severity: asymptomatic subclinical to fulminant fatal
Chronic infection:
-infants: 80-90% infected during first year of life, 30-50% children infected before age 6
-adults: <5% of otherwise healthy adults, 20-30% who are chronically infected will develop cirrhosis and/or liver cancer
Hepatitis b virus acute and chronic infection
Acute:
-HBV DNA and HBeAg early markers of HBV infection, effective host response:
-loss of HBeAg
-appearance of HBe antibodies
-clearance of HBV DNA and HBsAg
Chronic:
-continued viral replication
-viral DNA, HBsAg and HBeAg in serum
-elevated serum alanine and aspartate aminotransferase (ALT/AST) levels
Hepatitis C virus
Enveloped ssRNA virus
Genus hepacivirus, family flaviviridae
55-65nm diameter
Electron micrograph:
Virus particles plus lipid
Hepatitis c virus transmission
Bloodborne
Transmission:
-injecting drug use/ sharing injection equipment
-reuse or inadequate sterilisation of medical/surgical/dental equipment (esp syringes/needles)
-transfusion of unscreened blood and blood products
-sexual practices that lead to exposure to blood
-perinatal transmission (mother to child at birth) less common
Hepatitis c virus infection
Incubation period: 2 weeks to 6 months
Acute infection: 80% asymptomatic, 20% fever, fatigue, decreased appetite, nausea, vomiting, abdo pain, dark urine, joint pain, jaundice
Severity: asymptomatic subclinical to fulminant fatal
Chronic infection: infants 50-60%, adults 50-90%, 20-30% who are chronically infected will develop cirrhosis and/or liver cancer
Hepatitis c virus: infection and HIV
Approx 2.3 million people 6.2% of the estimated 3.7million living with HIV have serological evidence of past or present HCV infection
Chronic liver disease major cause of morbidity and mortality in persons living with HIV
Hepatitis C virus lab testing and diagnosis
- Antibody testing- historical infection
- Viral nucleic acid testing- current infection
- Check for cirrhosis
Treatment for chronic HCV
Aged 18 and above: pan-genomic DAA regimens for persons with chronic HCV
Aged 12-17 years: sofosbuvir/ledipasvir 12 weeks genotypes 1,4,5,6,. sofosbuvir/ribavirin, 12 weeks, genotype 2 sofosbuvir/ribavirin, 24 weeks, genotype 3
Aged <12 years: defer treatment until 12 years
Herpesviruses
1.Herpes simplex virus 1 (HSV-1)
2. Herpes simplex virus 2 (HSV-2)
3. Human cytomegalovirus (HCMV)
4. Varicella-zoster virus (VZV)
5. Epstein Barr virus (EBV)
6. Human herpesvirus 6A/6B (HHV-6A/6B)
7. Human herpesvirus 7 (HHV-7)
8. Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8)
Characteristics of herpesviruses
Family: herpesviridae
Subfamilies: alpha, beta, gamma, herpesvirinae
Size: 180-200nm
Enveloped
Genome: linear ds DNA range 120kb to 230kb
Glycoproteins: host cell specificity, virus attachment/fusion
Tegument: evasion of innate immunity
HSV epidemiology/transmission
3.7 billion people under 50 (67%)have HSV-1 infection globally
491 million people 15-49 13% have HSV-2 infection globally
Herpes infections are most contagious when symptoms are present
Transmission via oral to oral contact HSV-1; genital to genital contact HSV-2; oral to genital HSV-1/2 via sores, saliva, surfaces in or around the mouth/genitals
Most oral and genital herpes infections are asymptomatic
Transmissions during asymptomatic outbreaks
The frequencies of reoccurrence varies from person to person
Herpes simplex virus 1 HSV-1 transmission
HSV-1 primary infection (stomatitis)
Lytic cycle:
Infection of mucoepithelial cells
Replication in mucoepithelial cells
Infectious virus released
Latency:
Immunologically silent infection
Reactivation
Replication in mucoepithelial cells
Infectious virus released
HSV-1 invades sensory nerve endings
Establishes latency in Trigeminal ganglion
Herpes simplex neurovirulence and latency
HSV1/2 invade sensory neurones and establish latency in ganglia
Latency:
-HSV-1: Trigeminal ganglion
-HSV-2: sacral ganglia
Neurovirulence:
-invade and replicate in the CNS
-profound disease
- severe neurologic devastation
- meningitis/encephalitis
Herpes simplex virus latency vs lytic cycle
Lytic cycle: virus DNS replication, new progeny viruses made, full range of virus proteins expressed, highly immunogenic
Latency: no virus protein expression (modified protein expression), episomal DNA replicated with host cell DNA, immunologically silent
Herpes simplex virus and the immunocomprimised
Transplant:
-severity directly related to type of immunosuppressive therapy
-pneumonitis, oesophagitis, gastritis
HIV/AIDS:
-more exaggerated
-more frequent
-more resistant to antivirals
Varicella-Zoster virus VZV
Primary infection: chickenpox
Reactivation: shingles
Complications:
-infants, adolescents, adults, pregnant women, people with HIV/AIDS or cancer, patients who have had transplants, people on chemotherapy, immunosuppression, long term steroids
Serious complications include:
-bacterial infections of the skin and soft tissues including group A streptococcal infections (necrotising fasciitis)
-pneumonia
-encephalitis, cerebellar ataxia
-haemorrhagic complications
-sepsis
Clinical manifestations of cytomegalovirus infection
Transmission: body fluids, blood products, organ donation,bone marrow
Primary infection: usually asymptomatic, up to 8% symptomatic, fever, mononucleosis, hepatitis
Congenital CMV: in utero infection of multiple systems; pneumonia, hepatitis, encephalitis
Immunocompromised:
-transplant (solid and hematopoietic stem cell): pneumonitis, oesophagitis, gastritis, enterocolitis, hepatitis, retinitis, GRAFT-VERSUS-HOST disease
-HIV/AIDS: retinitis, oesophagitis, gastritis, enterocolitis, pneumonitis, hepatitis
Primary maternal CMV infection- 40% transmission to foetus
Epstein Barr virus infection
Transmission: saliva
Primary infection: usually asymptomatic, 4-7 week incubation period, replication in oropharyngeal epithelial cells and B cells, usually during childhood, up to 95% world population infected by adulthood
Symptomatic primary infection: delayed infection can result in infectious mononucleosis (glandular fever), fever, pharyngitis, swollen lymph nodes, hepatitis
Epstein Barr virus- associated malignancies
Site of EBV latency= b cells
Expression of: viral proteins, non coding RNAs, miRNAs, viral oncogenes
B cell malignancies: Burkitt lymphoma, Hodgkin lymphoma
Epithelial cell malignancies: nasopharyngeal carcinoma, gastric carcinoma 10%
T and NK cell malignancies: extranodal NK/T cell lymphoma, NK leukaemia
Epstein Barr virus associated malignancies: immunocompromised
EBV- associated post transplant malignancies:
-post transplant lymphoproliferative disease
-hodgkin lymphoma
EBV associated post transplant diseases:
-encephalitic/ myelitis
-pneumonia
-hepatitis
EBV and HIV related lymphoma:
-Burkitt lymphoma
-diffuse large B cell lymphoma
- primary CNS lymphoma
-hodgkin lymphoma, plasmablastic lymphoma, primary effusion lymphoma
Kaposi’s sarcoma associated herpesvirus (KSHV=HHV8)
Genome assembly and several genes are homologues of EBV
Latency in B cell and endothelial cells
Kaposi sarcoma in immunosuppression AIDS- endothelial cellen lytic and latent gene expression i kaposi’s sarcoma
Primary effusion lymphoma PEL - B cell
Multicentric castleman’s disease MCD- B cell
