Microbiology 5- Patterns of viral infection

Question 1

Define some transmission terminology

Answer 1

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)

Question 2

What % of our genome is virus

Answer 2

7%

Question 3

Describe how viruses can enter the body

Answer 3

Skin- often following an abrasion
Mucosal surfaces (Respiratory,Enteric, Genital tract)- through the epithelial layers
Conjunctiva

Blood
Bites
Needle injection

Question 4

What is meant by viremia

Answer 4

Virus in the blood

Question 5

Describe the actions of the virus once it enters the body

Answer 5

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.

Question 6

What determines whether the virus disseminates or causes local infection

Answer 6

Local infection, apical release

Dissemination, basal release

Question 7

Describe secondary viraemia

Answer 7

Virus in blood at another site

Question 8

What is meant by systemic spread

Answer 8

Systemic, haematogenous spread or neural spread

Question 9

Describe viral rashes

Answer 9

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.

Question 10

Describe the Varicella zoster virus, including how it causes chicken pox and shringles

Answer 10

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.

Question 11

What is meant by Ro

Answer 11

How many people and infected person can infect

Question 12

Describe tropism

Answer 12

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

Question 13

What determines tropism

Answer 13

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.

Question 14

Describe how the tropism of HIV is determined by receptor use

Answer 14

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.

Question 15

What occurs in HIV

Answer 15

Tropism switch during replication- different co-receptors required- found on different cell types
CCr5- Macrophages
CCXr4- T-cells

Question 16

Describe the receptors of the measles virus

Answer 16

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

Question 17

Describe the tropism of the measles virus

Answer 17

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.

Question 18

Describe the morphology of the influenza virus

Answer 18

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).

Question 19

Describe the action of HA

Answer 19

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.

Question 20

Why does the HA need to be cleaved

Answer 20

To allow the virus to unpack in the cell and replicate.

Question 21

What is the tropism of the influenza virus determined by, the availability of host proteases

Answer 21

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

Question 22

Describe how influenza tropism can be extended by mutations in the HA

Answer 22

HA can be cleaved by more ubiquitous proteases such as furin- H5 and H7, more dangerous and pathogenic.

Question 23

What is meant by pathogenicity

Answer 23

Pathogenicity is the ability of the virus to cause disease

H5 bird flu is more pathogenic than human flu.

Question 24

What is meant by virulence

Answer 24

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.

Question 25

Describe the patterns of viral infection

Answer 25

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

Question 26

Describe the viruses characteristic of each type of viral infection

Answer 26

Acute infection:
Rotavirus
Rhinovirus
Influenza virus

Persistent:
Lymphocytic choriomeningitis virus

Latent:
HSV

Persistent, slow
HIV
Measles virus
Human T-lymphotropic virus

Question 27

Describe acute infection and clearance

Answer 27

Colds and influenza. Many unapparent or asymptomatic infections.
Adaptive immune response provides immunity
Viruses continue to circulate in populations by antigenic variation

Question 28

Describe smallpox

Answer 28

Smallpox. Variola virus. Mortality 20-80%. Infection of skin. Viral growth factors induce proliferation of skin resulting in pox.

Question 29

Describe dengue fever

Answer 29

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.

Question 30

Describe acute infections due to accidental pathogenesis

Answer 30

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

Question 31

Describe persistent viral infections

Answer 31

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

Question 32

Why do we see virus persisting in skin and nervous system

Answer 32

Immune system doesn’t have many actions there

Question 33

Explain the strategies for persistence

Answer 33

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

Question 34

Describe latency

Answer 34

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

Question 35

Describe HSV latency and reactivation

Answer 35

1. Primary site of infection : productive infection of epithelial cells
2. Secondary site of infection and site of latent infection : sensory neuron- retrograde transport
3. 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.

Question 36

Describe oncogensis

Answer 36

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

Question 37

Describe how Hepatitis B and C viruses cause hepatocellular carcinoma

Answer 37

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.

Question 38

Describe Epstein barr virus

Answer 38

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.

Question 39

What does the outcome of virus infection depend on

Answer 39

Virus sequence
Virus load
Host immune response/status
Host co-morbidity
Co infections
Other medications
Host genetics
Host age, gender

Question 40

Describe the importance of viral sequence

Answer 40

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).

Question 41

Describe the impact of viral load

Answer 41

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.

Question 42

Describe co infections

Answer 42

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.

Question 43

Describe genetic resistance and susceptibility

Answer 43

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

Question 44

Describe the Predisposing co-morbidities and conditions for severe influenza

Answer 44

Asthmatics and respiratory viruses
Obesity
Immunosuppression
Immunodeficiency
Elderly
Diabetes mellitus
Pregnancy

Question 45

State some of the modes of transmission that viruses use

Answer 45

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

Question 46

What does the capacity of the virus to cause disease depend on

Answer 46

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

Question 47

Describe the characteristics of acute infection

Answer 47

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.

Question 48

Describe the characteristics of persistent infections

Answer 48

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

Question 49

Describe the different components involved in the replication of HIV

Answer 49

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.

Question 50

Describe HIV

Answer 50

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.

Question 51

Describe the replication cycle of HIV

Answer 51

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