Lecture 21: Dissemination, Virulence, and Epidemiology

Text: Flint et al, Chapter 14

General points

• To establish a successful infection, viruses must – Find a way to enter the host– Find a way to get through the host defences– Move through the host– Find the right cell types to infect

• To spread infection, viruses must– Find a way for new viral progeny to exit infected cells

and host– Find a way to survive outside of host

Initiation of infection• Sufficient virus must be available

– High concentrations. • A sneeze droplet contains up to 100

million Rhinovirus particles. • Similar amount of Hepatitis B in 1ml of

infected blood.

– High survivability in harsh exterior environments• Dilution• pH changes• Dissecation

• Cells at site of infection must be1. Accessible2. Susceptible3. Permissive

• Local host defenses must be – Absent or – Initially ineffective

Viral Entry: respiratory tract

• Common route for viruses• Aerosolized droplets

– Coughing, sneezing– Large droplets deposited in nose– Smaller ones further down the Resp. tract

• Must overcome– Clearance by mucus– Inactivation by antibodies– Destruction by macrophages.

Viral Entry: respiratory tract

Fig. 14.2

Viral Entry: alimentary tract • Common route of entry and dispersal

• Virus must be resistant to– Stomach acids– Bile bases (detergents)

• Destroys most enveloped viruses. • Somehow many Coronaviruses survive

– Proteases• Many viruses, e.g. Reovirus particles, are actually

activated by intestinal proteases.

Viral Entry: into M cells

Viral Entry: into M cells • Most of gut is lined with columnar villous epithelial cells.

– Apical sides are densely packed with microvilli– “Brush border” coated with glycoproteins, glycolipids and mucus– Difficult to penetrate

• M cells: lymphoid cells scattered throughout gut– Thin, absorptive, – Normally transmit antigens to underlying lymphtocytes via

transcytosis

• Some viruses infect only M cells– e.g. Rotavirus, Coronavirus transmissible gastroenteritis– Lyse M cells, cause mucosal inflammation, diarrhea– Others transcytose through M cells into underlying basal

membranes and extracellular space. e.g. Reoviruses– From there, can go to

• Lymphatic system• Circulatory system• Rest of host

Viral Entry: through Urogenical tract

–Physical barriers: mucus, low pH (vagina only)–Viral entry via tears and abrasions due to normal sexual activity–Viruses can infect epithelium and cause local lesions, e.g. some papillomaviruses–Others infect underlying tissues, and invariably spread and persist»Neurons, e.g. herpesviruses»Lymphoid tissue, e.g. HIV

Viral Entry: through eyes

• Physical barriers: tears, mucus, proteases

• Entry via abrasions, poor sanitation

• Most infections are localized: conjunctivitis

• Herpesvirus Type I infections can spread to neurons and become persistent

Viral entry: through skin

• Presents formidable physical barriers

• Entry via breaks in skin

• Abrasions, e.g. papillomaviruses: usually local

• Insect bites, e.g. West Nile

• Animal bites, e.g. rabies

• Behavior: needles, tattoos, body piercing

Fig. 14.4

Evasion of host defenses

• Active and passive mechanisms

• Active: knock out immune mechanisms

• Passive: – Overwhelming numbers– Infect immunonaive organs, e.g. Rabies

Kinetics of viral replication and immune response

Fig. 14.5

Viral Spread

• After replication at site of entry, virus can – Remain localized

• e.g. rhinovirus in respiratory epithelium

– Spread to other tissues• e.g. polio from gut epithelium to neural tissues

• Disseminated infection – virus spread to other tissues

• Systemic infection – virus spread to many organs

• Shedding – release of virus from infected cells/tissues

Polarized viral spread

• Direction of virus particle release determines how virus will spread

• Release at apical membranes: localized or limited infection– e.g. Influenza

• Release at basal membranes: disseminated/systemic infections– e.g. VSV

Fig. 14.6Vessicular Somatitis Virus

Hematogenous Spread• Spread through the

blood.• Virus replicates at site

of entry, exits infected cells

• Enters bloodstream – primary viremia

• Infects other organs, replicates, exits into bloodstream – secondary viremia

• Replicates yet again in other organs, exits passed on.

Fig. 14.7

Neural spread

• Many viruses spread from primary site of infection by entering local nerve endings

• Typically, such viruses enter from a nerve ending or axon

• Replicate in the cell body• Directionally exit the neuron: retrograde vs.

antiretrograde• Routes of entry can be

– Neural: poliovirus, herpesviruses– Olfactory: herpesviruses, coronaviruses– Hematogenous: polio, coxackievirus, mumps, measles, CMV

Neural spread

Fig. 14.12: olfactory spread

Fig. 14.11 pathways of neural spread

Box 14.3. anterograde vs retrograde spread

Organ invasion • From viremia, subsequent replication requires invasion of

new cells and tissues• Three main types of blood vessel-tissue interfaces provide

routes for invasion1. Capillary: very tight basement membrane

2. Venule: contains pores through basement membrane

3. Sinusiod: very leaky, macrophages form part of blood-tissue junction

Fig. 14.13

Viral entry

routes into the

liver

Fig. 14.15

Virus shedding and transmissionShedding: release of infectious viruses from infected host• Respiratory secretions. e.g rhinoviruses, influenza viruses

– Aerosolization – sneezing, coughing– Contamination of fomites by nasal secretions

• Saliva. e.g. mumps, cytomegalovirus, rbies– Aerosolization – sneezing, coughing– Contamination of fomites – spitting, coughing, wiping hands– Kissing, grooming (animals)– Animal bites

• Feces, e.g. enteric and hepatic viruses– Poor sanitation, food contamination, sexual exchange

• Blood, e.g. sindbis viruses (West Nile), Denge virus, hepatitis, HIV– Transmission by biting insects, during sex, childbirth, exposure to

contaminated blood• Urine (viruea)

– Hantaviruses, arenaviruses• Semen

– HIV, some herpesviruses, hepatitis B• Milk

– Mouse Mammary tumor virus, Mumps, CMV• Skin lesions

– Poxviruses, HSV, varicella zoster, papillomaviruses, Ebola virus

Epidemiology

• Definition: The study of the occurrence of a disease in a population.

• Includes: 1. Mechanisms of viral transmission2. Risk factors for infection,3. Population size required for virus transmission4. Geography5. Season6. Means of control

Mechanisms of viral transmission

• Aerosol• Food and water• Fomites• Body secretions• Sexual activity• Birth• Transfusion/transplant• Zoonoses (animals, insects)

Factors that promote transmission

• Virus stability

• Virus in aerosols and secretions

• Asymptomatic shedding

• Ineffective immune response

Geography and Season • Vector ecology; School year; Home heating season

Risk factors

• Age• health• immunity• occupation• travel• lifestyle• children• sexual activity

Critical population size

Numbers of seronegative susceptible individuals

Means of control

• Quarantine – SARS

• Vector elimination – mosquito control and West Nile

• Immunization – MMR, DPT, etc…

• Antivirals – triple therapy and AIDS