Microbiology 5- Patterns of viral infection Flashcards
Define some transmission terminology
Iatrogenic HCW eg contaminated needles Nosocomial Acquired in hospital Vertical From parent to offspring Horizontal All other forms Germ line Part of the host genome (eg intergrated retrovirus)
What % of our genome is virus
7%
Describe how viruses can enter the body
Skin- often following an abrasion
Mucosal surfaces (Respiratory,Enteric, Genital tract)- through the epithelial layers
Conjunctiva
Blood
Bites
Needle injection
What is meant by viremia
Virus in the blood
Describe the actions of the virus once it enters the body
From the site of entry the virus may travel, often in the blood (primary viraemia), to another organ where amplification via replication takes place. There may be secondary viraemia to the main organ site for replication.
What determines whether the virus disseminates or causes local infection
Local infection, apical release
Dissemination, basal release
Describe secondary viraemia
Virus in blood at another site
What is meant by systemic spread
Systemic, haematogenous spread or neural spread
Describe viral rashes
Systemic viral infection
Virus leaves blood and enters skin
Cells destroyed by virus replication
Koplik spots in the mouth from measles infection
Lesion on mucus membranes of soft respiratory tract tissues occur before skin rashes: Measles and chicken pox spread through the air before the rash is visible.
Spreads all over the body, on reaching the skin it can be transmitted to the next host.
Describe the Varicella zoster virus, including how it causes chicken pox and shringles
Virus enters body through respiratory route
Primary viremia- replication in spleen, liver and other organs.
2 week incubation before secondary viremia- infection of skin and appearance of rash.
VZV can infect many cell types including PBMCs and skin cells.
This leads to mild self limiting illness in most childhood cases.
From the skin site, it can infect sensory neurones where it remains latent, in the sensory ganglions.
Following a stressed state or lower cell-mediated immunity. the latent varicella-zoster virus in the sensory ganglion begins to replicate and migrate to the peripheral nerves. Burning, painful skin lesions develop over the nerve endings.
What is meant by Ro
How many people and infected person can infect
Describe tropism
The predilection of viruses to infect certain tissues and not others.
Can be defined by receptor interactions (susceptibility) but also by ability to use the host cell to complete replication (permissivity) and whether the virus can reach a tissue (accessibility).
It is the place where the virus replicates
What determines tropism
Tropism may be determined by the expression of the host cell receptor. HIV enters cells through the CD4 molecule found on T cells.
Tropism may also be limited by the ability of the virus to replicate inside a particular cell type due to abundance or paucity of essential intracellular host cell components. Polioviruses with mutations in their 5’ noncoding regions cannot utilize neuronal host cell factors to translate their mRNAs.
Tropism may also depend on extracellular factors required for activation of virus infectivity. Influenza virus HA protein requires to be cleaved by a host encoded protease expressed in respiratory secretions.
Describe how the tropism of HIV is determined by receptor use
CD4 and
CCR5 or CXCR4 co receptors
Delta 32 mutation in CCR5 confers resistance to HIV in Exposed Uninfected
Viral attachment protein gp120
As well as T helper cells, macrophages, monocytes and central nervous dendritic cells express CD4.
What occurs in HIV
Tropism switch during replication- different co-receptors required- found on different cell types
CCr5- Macrophages
CCXr4- T-cells
Describe the receptors of the measles virus
Two receptors:
CD155 or SLAM
And Nectin 4
Vaccine strain Edmonson uses CD55- lad virus do not use same receptors as wild virus
SLAM- dendritic cells
Describe the tropism of the measles virus
Entry to new host: SLAM on immune cells:
immunosuppresion!
Exit from infected host:
Nectin 4 on airway epithelia
Spreads through nasopharyngeal secretions by air or by direct contact. The virus multiplies in the respiratory mucous membranes. Incubation lasts for 2 weeks prior to development of rash.
Describe the morphology of the influenza virus
2 distinct types of glycoprotein. Hemagglutinin Activity and Neuraminidase activity, anchoring the bases of each of these spikes on the inside of the viral lipid bilayer are membrane proteins (M proteins).
Describe the action of HA
Entry through endosomes
Low endosomal pH triggers fusion- HA cleavage is required for exposure of fusion peptide
Binding of host cell membrane with the virion membrane results in the dumping of the viral genome into the host cell.
Why does the HA need to be cleaved
To allow the virus to unpack in the cell and replicate.
What is the tropism of the influenza virus determined by, the availability of host proteases
Proteases secreted by certain cells as part of innate immune system (upper respiratory tract), cleave HA to allow virus to become active inside the cell
Although the influenza virus can enter most cells, it may not unpack, thus an inactive virus will leave the cell- no infection
Describe how influenza tropism can be extended by mutations in the HA
HA can be cleaved by more ubiquitous proteases such as furin- H5 and H7, more dangerous and pathogenic.
What is meant by pathogenicity
Pathogenicity is the ability of the virus to cause disease
H5 bird flu is more pathogenic than human flu.
What is meant by virulence
Virulence describes the capacity of a virus to cause disease.
Viral disease depends on how much replication the virus undergoes but is affected by other factors too such as the host response.
Describe the patterns of viral infection
Acute infection followed by viral clearance
Acute infection but ‘accidental’ tissue infected with permanent damage despite viral clearance
Persistent infection: latent, slow, transforming
Long incubations
Oncogenesis
Describe the viruses characteristic of each type of viral infection
Acute infection:
Rotavirus
Rhinovirus
Influenza virus
Persistent:
Lymphocytic choriomeningitis virus
Latent:
HSV
Persistent, slow
HIV
Measles virus
Human T-lymphotropic virus
Describe acute infection and clearance
Colds and influenza. Many unapparent or asymptomatic infections.
Adaptive immune response provides immunity
Viruses continue to circulate in populations by antigenic variation
Describe smallpox
Smallpox. Variola virus. Mortality 20-80%. Infection of skin. Viral growth factors induce proliferation of skin resulting in pox.
Describe dengue fever
Dengue haemorrhagic fever. Responsible for 500,00 hospitalizations each year with 5% fatalities.
Leakage of blood plasma from capillaries.
Detected by increase in red cell count and decrease in protein level in blood.
Tendency to severe bruising, and bleeding. Patient deteriorates even after fever drops; shock. Treat with iv fluid replacement.
Describe acute infections due to accidental pathogenesis
Symptoms not due to replication of virus
Poliovirus transmitted by fecal oral route, causing a localized infection of small intestine.
Poliomyelitis. Neurovirulent virus infects motor neurons causing paralysis.
Rubella causes mild rash except in early stage fetus where virus has a strong tropism for dividing neuronal tissue. Leads to a classic triad
Deafness
Eye abnormalities (cataracts)
Congenital heart disease
Describe persistent viral infections
Chronic infection with low level replication of viruses in tissues which regenerate. Papillomaviruses in warts.
Chronic carriers of hepatitis B and C viruses.
Latent infection where viral genomes are maintained but no virus is seen until episodes of reactivation when host immunity wanes. Herpes viruses eg Herpes Simplex, Varicella Zoster
Why do we see virus persisting in skin and nervous system
Immune system doesn’t have many actions there
Explain the strategies for persistence
Evading immune surveillance- mutations in accessory genes MHC downregulation, compensation for lost MHC class I; HCMV cytomegalovirus
CTL escape by mutation. Hepatitis C virus.
Infecting tissues with reduced immune surveillance.
CNS; measles SSPE, herpes viruses
skin; papillomavirus
Describe latency
Herpes simplex virus
No virions or viral products detected, except for Latency Associated transcripts or LATs.
Neurons do not divide, and contain hundreds of copies of HSV genome
Reactivation frequency varies between hosts
Virus not detected by host, when immune system drops-latent infection
Describe HSV latency and reactivation
- Primary site of infection : productive infection of epithelial cells
- Secondary site of infection and site of latent infection : sensory neuron- retrograde transport
- Site of recurrent infection : productive infection of epithelial cells- anterograde transport
If too much virus produced- can travel to CNS upon reactivation- Alzheimer’s if glycoproteins are covered in Amyloid-beta, clump together and precipitate.
Describe oncogensis
Viruses that cause cancer
May encode oncogenes
Interfere with the cell cycle in order to enhance their own replication
Papillomaviruses encode inhibitors of tumour suppressor p53, E6 and E7 genes. This forces the cell into S phase.
HHV8 and Merkel cell polyoma virus discovered by Chang and Moore by finding non-human genetic material in tumours.
HTLV-1 causes adult leukaemia
Describe how Hepatitis B and C viruses cause hepatocellular carcinoma
350 million chronic carriers of HBV.
600,000 annual deaths
Hepadnavirus utilizing a reverse transcription step in its replication cycle.
HBV spread by blood and semen- much more infectious than HIV
Vaccination with sAg expressed from yeast.
Hepatitis C infected a lot of people in the ‘70s and ‘80s before blood was screened
We are now seeing a rise in liver cancer resulting from these chronic infections.
4% those infected by HCV will progress to hepatocellular carcinoma.
Antiviral therapies for HCV are available.
Describe Epstein barr virus
A gamma herpes virus, the most common virus infection of mankind.
95% of us are infected with this virus.
In most people it causes a lytic infection in childhood or infectious mononucleosis in young adulthood. And then remains latent in B cells.
Passed on in saliva.
It also causes Burkitts lymphoma
Hodgkins lymphoma
Nasopharyngeal carcinoma.
The incidence of these varies geographically
suggesting other predisposing factors to these outcomes.
What does the outcome of virus infection depend on
Virus sequence Virus load Host immune response/status Host co-morbidity Co infections Other medications Host genetics Host age, gender
Describe the importance of viral sequence
Two strains of poliovirus might vary in their virulence. A single mutation in the genome can mean that one strain acts as a live attenuated vaccine (Sabin) whilst another invades the motor neurone and causes flaccid paralysis (poliomyelitis).
Describe the impact of viral load
The first child in the family to contract chicken pox often has a milder illness than the second child. This may be because the second child is in closer contact and become infected by a higher dose.
Might be affected by the route of transmission.
Describe co infections
Secondary bacterial infection following influenza (Morens and Taubenberger).
HHV8 causes Kaposi’s Sarcoma in HIV
infected individuals.
Hepatitis delta virus, a small defective RNA virus that only infects people with Hepatitis B virus infection.. suppresses HBV replication but causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation.
Describe genetic resistance and susceptibility
CCR5 delta 32 mutation protects against HIV-1 infection
KIRs can determine the outcome of hepatitis C virus infection
IFITM3 associated with severe outcome in 2009 pH1N1 pandemic- SNP in this gene is associated with more severe influenza
Describe the Predisposing co-morbidities and conditions for severe influenza
Asthmatics and respiratory viruses Obesity Immunosuppression Immunodeficiency Elderly Diabetes mellitus Pregnancy
State some of the modes of transmission that viruses use
Transmission of a virus from one host to another usually requires it to be shed into the environment.
Rarely viruses are transmitted through the germline, acquired through cannibalism (prion diseases like Kuru) or through nosocomial blood contamination (HIV or hepatitis B or C).
Respiratory transmitted viruses are carried in aerosols (influenza, rhinovirus).
Viruses may be shed into the oral cavity and transmitted in saliva (human cytomegalovirus, EBV, mumps).
Enteric viruses are transmitted through the fecal oral route (poliovirus, norovirus, hepatitis A virus)
Viraemic viruses are transmitted through blood (dengue virus when bitten by an arthropod, Ebola virus)
Virus can be present in urine of animals (hantaviruses in rodents) but urine is rarely a source of human to human transmission.
Viruses in skin can be transmitted by direct skin contact, poxvirus, papillomaviru
What does the capacity of the virus to cause disease depend on
the effects of its replication
the strength of the host’s defence system
the ability of the virus to spread in and amongst its hosts
Describe the characteristics of acute infection
Rapid production of infectious virus, rapid resolution and elimination of virus by host immune system.
The outcome is determined by intrinsic and innate immunity.
Acquired immunity stimulated after several days mediates final clearance from the host. Memory provides defense against subsequent exposure.
Acute infections frequently cause epidemics. Transmission occurs before symptoms. Inapparent infections (asymptomatic) are common.
Describe the characteristics of persistent infections
Persistent infections also have to overcome innate defense at the start of infection. They are not cleared by the adaptive immune response. They may be chronic or lifelong (latent, slow).
75-85% people infected by Hepatitis C virus will not clear the virus with their CTL response. This may be because the virus rapidly mutates to escape the response by changing its T cell epitopes. Of these chronically infected people, 1-5 % will develop hepatocellular carcinoma. Since more than 170 million people are infected, this accounts for up to 3 million hep carcinoma cases. Chronically infected hepatocytes are destroyed by the immune system leading to fibrous scars (cirrhosis).
The classic example of a latent virus infection is herpes simplex virus. The virus first replicates in mucosal or epidermal cells. Perpiheral ganglia become infected and produce a large burst of virus that disappears after 1-2 weeks. The virus establishes a latent infection in terminally differentiated non-dividing neurons of the peripheral nervous system. Since neurons do not replicate their DNA nor divide, the HSV genome survives inside these host cells. The only evidence of the virus is the expression of RNAs known at latency associated transcripts LATs. By this time the infected host is ‘immune’, they have antibodies to their latent virus. Some people reactivate their virus every 2-3 weeks, others experience few or no reactivation events. Stress signals can trigger reactivation. Reacitvation can also be by drugs like glucocorticoids that stimulate transcription but suppress immune responses. Transient production of virions allows spread of the virus across innervated mucosal surfaces to a new host. Then the infected host’s immune response curtails virus production
Describe the different components involved in the replication of HIV
gp120 – an HIV glycoprotein having a molecular weight of 120 that protrudes from the outer surface of the virion. This glycoprotein binds to a CD4 receptor on a T cell to facilitate entry of viral nucleic acid and proteins into the cell. CD4 – a large glycoprotein that is found on the surface of helper T cells, regulatory T cells, monocytes, and dendritic cells. Its natural function is as a co–receptor that assists the T cell receptor (TCR) to activate its T cell following an interaction with an antigen presenting cell. CD4 is a primary receptor used by HIV–1 to gain entry into host T cells. Co–receptor (CCR5 or CXCR4) – protein molecules on the surface of lymphocytes or monocytes that bind to the gp120 protein of HIV and facilitate, usually with CD4, entry of viral nucleic acid and proteins into the cell. Fusion of virus and cell membranes – a merging of cell and virus membranes that permits HIV proteins and nucleic acids to enter the host cell. Preintegration complex (PIC) – It is composed of viral RNA and proteins (nucleocapsid, p6, Vpr, integrase, and matrix) as well as some host proteins. It functions to reverse transcribe genomic RNA into double stranded DNA prior to integration into the host genomic DNA. Reverse transcriptase – an enzyme found in HIV that creates double stranded DNA using viral RNA as a template and host tRNA as primers. Integrase – An enzyme found in retroviruses including HIV that permits the viral DNA to be integrated into the DNA of the infected cell. Protease – an enzyme that hydrolyzes or cuts proteins and is important in the final steps of HIV maturation.
Describe HIV
HIV (human immunodeficiency virus) is a lentivirus and a member of the retrovirus family. HIV infects and destroys helper T cells of the immune system causing a marked reduction in their numbers. Loss of CD4 cells leads to generalized failure of the immune system and susceptibility to life threatening opportunistic infections.
Describe the replication cycle of HIV
Fusion of the HIV cell to the host cell surface.
HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
Viral DNA is formed by reverse transcription.
Viral DNA is transported across the nucleus and integrates into the host DNA.
New viral RNA is used as genomic RNA and to make viral proteins.
New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
The virus matures by protease releasing individual HIV proteins
