Infection and disease Lecture 4

Viruses –part I

What are Viruses ?

Viruses

• Obligate intracellular parasites

• Nucleic acid genome: DNA or RNA

• Protein coat: Protection, entry

• Envelope (some viruses): host / viral; lipids/glycoproteins; entry

• Size: 20-350nm3

Size of viruses

How are viruses different from bacteria ?

Viruses

• DNA / RNA in a protein coat

• Do not have protein synthesis apparatus

• Require host cells to replicate

• Smaller in size

Are viruses living things ?

• Do not breathe

• Do not move

• Able to replicate

• ? Living things

Viruses cannot be seen using a light microscope

Classification of viruses

• No taxa above Family (no order, class, phylum, kingdom etc)

• Genus / species name ends in –virus

- binomial nomenclature is not yet adopted for viruses

Example

• Genus – Varicella zoster virus• Common name – chickenpox virus• Disease – chickenpox

Baltimore classification

Virus structure

Viral structure – basics

• protein which coats the genome = capsid

• capsid usually symmetrical

• capsid + genome = nucleocapsid

• may have an envelope

Viral Proteins

Viral proteins• Structural – protect viral genome and

help in attachment. Eg. Capsid

• Non-structural – essential for initiation of replicative cycle. Eg. reverse trasncriptase, Proteases

• Virus envelope – contains glycoproteins and lipids

• Peplomers = glycoprotein spikes

Virus envelope

Virus envelope

• Contain lipids and glycoproteins

• Lipids – cellular membranes derived (through budding)

• Glycoprotein- virus encoded

• Role in attachment to host cell

• Loss of envelope = loss of infectivity

Envelope

Viral nucleic acids

Virus nucleic acids

• DNA genomes- 3 Kb to 375 Kb

• RNA genomes – 7Kb to 30 Kb

• Viral nucleic acids – linear , circular, segmented (RNA only).

Nucleocapsid

• Nucleic acid + protein coat

• Structural unit of the protein coat (capsid) is the capsomer.

Symmetry of nucleocapsid

• Icosahedral

• Helical

Soccer ball

Many viruses have a similar structure !

Icosahedral symmetry

• 20 faces / facets (triangles)• 12 vertices

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Sides consist of hexons

Sides consist of pentons

Helical symmetry

• Viral protein subunits are bound to the viral nucleic acids in a periodic way

Steps in viral replication

Steps in virus replication

• Attachment

Penetration

Uncoating /disassembly

Synthesis of virus nucleic acids and proteins

Assembly

Release of virions

Virus replication – some interesting facts

• Average generation time – 6 to 40 hours

• Number of virions / infected cell– 100 to 100,000

• Much more than doubling - dramatic exponential growth !

100 – 100,000 viruses/cell, 6 – 40 hours

Poliovirus

Poliovirus pathogenesis

• Virus begins to multiply in the tissues around the oropharynx /tonsils.

• Enteroviruses are stable in acid in the stomach

• They pass to the intestines, where they replicate

• The virus begins to spill into the Blood.

Outcomes of poliovirus infection

There are 3 possible outcomes of infection:• Subclinical infection (90 - 95%) - inapparent subclinical

infection account for the vast majority of poliovirus infections.

• Abortive infection (4 - 8%) - a minor influenza-like illness occurs, recovery occurs within a few days

• Major illness (1 - 2%) - involves neuron damage in the CNS (central nervous system)

Poliovirus major illness

• Spinal form: Paralytic disease may begin with excruciating pain or spasms which may precede paralysis of the extremities.

• Bulbar form: An especially serious form is bulbar polio as it involves respiratory center in the medulla (Brain).

Poliomyelitis:

Iron lung machines

Iron lung wards

Influenza virus

Influenza virus

• 8 RNA segments

• Haemagglutinin – ability to bind to respiratory epithelial cell

• NA- increases disease severity

• Antibodies against HA /NA – protect /reduce severity of disease

38

NORMAL TRACHEAL MUCOSA

3 DAYS POST-INFECTION 7 DAYS POST-INFECTION

Lycke and Norrby Textbook of Medical Virology 1983Ramphal et al., INFECTION AND IMMUNITY 1979 25:992-997 (mouse)

Normal tracheal mucosa

3 days post infection 7 days post infection

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Where do “new” HA and NA come from?

• ~15 types HA• ~9 types NA• all circulate in birds• Humans HA1-3; HA5. • Humans NA1 and NA2.

• pigs• can be infected by

avian and human influenza viruses

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Pigs can act as host for generation of human-avian reassortments

Influenza replicates in the digestive tract of pigs and is shed in faeces

Reassortment in influenza virus

H1N1

H2N2

H1N2

H1

H2

N2

N1

H1N2

Generation of pandemic influenza strains

Genetic reassortment – new HA and NA configuration- entire human population is susceptible

Infection and diseaselecture 5

RotavirusRabiesEbolaVZVHIV

Viruses and cancerEmerging infections

Rota virus

Rotaviruses - a major public health issue

• Gastroenteritis (diarrhea)

• > 500 million infections /year

• >1.5 million deaths – mostly Asia / Africa

• Targets enterocytes lining the villi

Enterocytes

Rotavirus –the disease

• Enterocytes lining the tips of intestinal villi are

affected

• Villous atrophy, death of Enterocytes

• Enterocyte dysfucntion – net secretion of intestinal

fluid – causes diarrhoea

• Role of NSP4 (non-structural protein) as an

enterotoxin – stimulates secretory pathway NSP4 is an enterotoxin

Rotavirus – transmission

• Mainly person to person via fecal-oral route

• Food and water-borne spread; Fomites

• Large amounts of viral particles are shed in diarrheal stools (1012 particles)

• Infective dose is small – as little 100 particles (virus shedding 2 weeks).

Rabies virus

Transmission

• Usual route –dog bite

• Rare – aerosol inhalation in caves (bats)

Rabies – how does it cause disease ?

51Murray et al., Medical Microbiology

Note: no viremia

Rabies – the disease

• Disease occurs after 2-8 weeks (virus travels 6 inches in CNS /day)

- mental status varies: severe agitation / depression

- hydrophobia (most patients)

- spasms of larynx and pharynx – may spit excessive saliva

- death often due to respiratory paralysis

- dogs can bite without provocation

What should you do if a dog bites you?

• Wound – soap / water / no sutures/

• Vaccine

• HRIG – human Rabies Immunoglobulin – at site

• HRIG - injection

Ebola virus

Reservoir of Ebola virus

Ebola virus pathogenesis

• Human-to-human transmission – blood, body fluids , aerosol.

• Ebola attacks connective tissue

• it digests collagen, the protein that holds the organs together.

• The Ebola proteins chew up the body's structural proteins

• In this way, collagen in the body turns to mush, tissues die and liquefy

• 

Ebola –The disease

• Tremors /seizures

• Blood smearing all over the place

• Transmission to new host.

• The Ebola virus is transmitted by direct contact with the blood, secretions and possibly aerosol.

Ebola virus - control• Upto 90% case fatality

• Isolation of individuals

• Awareness

• Travel restrictions

• Protection of heathcare workers

• No vaccine

Varicella zoster virus

(chicken pox)

Pathogenesis - varicella

Respiratory route

• Replicates in the regional lymphnodes

• Replicates in liver

• viraemia – skin , salivary glands are seeded

• From skin to neurons in the spinal cord (Latent)

Zoster (Shingles)

Reactivation of latent virus –several years after primary infection

Zoster (Shingles)

Zoster (Shingles)

• Reactivation of latent VZV

• Similar vesicular lesions

• Often involves skin supplied by the infected part of the spinal nerves

• Occurs in >10% of individuals with a history of varicella infections; often in IC

hosts

• Usually @ > 50 years

• Trigger ?

HIV (Human immunodeficiency virus)

• Transmission – blood / sexual / vertical

• HIV infects CD4+ T lymphocytes and macrophages

• Minor illness following infection

• HIV continues to replicate – but the immune system to keep the virus to low levels for several years. HIV infected T-lymphocyte

Progression from HIV infection to AIDS

• After about 5-15 years the body is not able to replace the lost CD4+ cells

• Virus loads increase and CD4+ cells decrease (AIDS – Acquired immunodeficiency syndrome)

• The individual succumbs to opportunistic infection

HIV: Opportunistic infection

• Account for disease and death in AIDS patientsEg.• Fungi: candida species• Bacteria: mycobacterium avium-intracellulare• Viruses: cytomegalovirus

Death in about 1-2 years

Tumour viruses

History

History

• 1966 – Nobel for Rous

• 1980s – HBV, HPV

• About > 25% of all cancers are virus-related

Cancer

• Production of new cells death of old cells

• Cancer – unchecked growth of cells

• Transformation of a normal cell to cancer cell may take several years

• Clonal expansion of cancer cells

Tumour viruses

• Both DNA / RNA viruses

• Persistent infection

• No single mechanisms is common to virus-induced oncogenesis

• Virus proteins may interfere with the functioning of host proteins

• Virus may /may not be actively replicating

• “Hit and run” – no virus in virus induced cancer tissue

• “Innocent bystander” – virus in cancer tissue; but has nothing to do with the cancer

Human papilloma viruses (HPVs)

• Infect epithelial cells of skin

• Common warts

• HPV genital infections - STD

• 99% of cervical cancer cases

• Anal cancer

Hepatitis B virus / hepatitis C virus

• Chronic infection of the liver

• Major cause of liver cancer

Emerging and re-emerging infectious diseasesEmerging infectious disease: Newly identified & previously unknown mirobe that causes major problems

Re-emerging infectious disease: Infectious agents that have been known for some time, had fallen to very low levels that they were no longer considered a major problem & but increasing numbers are now being reported

Factors leading to emergence / re-emergence of infections

• Drug resistance (eg. TB- re-emergence)

• Evolution of the microbe (eg. HIV from SIV)

• Displacement of animals

• Humans populating areas close to animals

• International travel

Examples of emerging infectious diseases• HCV – described in 1990; 2% of the

world’s population is infected

• Subacute respiratory syndrome (SARS) -2003

• Middle eastern respiratory syndrome –corona virus – 21 countries in 3 years