012 w3310 13 - virology blog · • poisonous’air’ ... m...

Infec&on BasicsLecture 12

Biology W3310/4310Virology

Spring 2013

Before I came here I was confused about this

subject. Having listened to your lecture, I am

s<ll confused—but at a higher level.

–ENRICO FERMI

1

The nature of host/parasite interac&ons

The viral genome must establish itself

in a host popula<on to endure

2

Basic facts

• Every host alive today has intrinsic defenses coupled with immune defenses that evolved to deal with infecKons and tumors

• Every successful virus today must modulate host defenses to replicate and disseminate

• These host-‐virus interfaces define the front line of survival for both host and virus

3

We live and prosper in a literal cloud of viruses

• Most infecKons have no consequence-‐ Many parKcles never find a living cell to infect (land on your skin)

-‐ Many are destroyed or inacKvated as they enter the host

-‐ Many infecKons never go further than one or two cells at the site of infecKon

• If we do get infected, many infecKons are inapparent

-‐ No symptoms, but immune defenses are acKvated (e.g. anKbodies made -‐ this is how we know there are inapparent infecKons)

-‐ Virus may be replicaKng and transmiVed during these inapparent acute infecKons

4

Example: West Nile virus infec&on

• WNV spread across the US in less than 4 years (’99)-‐ By October 2004 about 1 million people were infected (anKbody posiKve)

-‐ Febrile illness developed in about 20% of infected people

-‐ Neuroinvasive illness developed in about 1% of infected people

• Many people were infected with no obvious disease-‐ Transmission of disease via blood transfusion or organ transplants

-‐ Inability to stop an epidemic because it can’t be recognized early

5

Microbes as infec&ous agents

• Poisonous air (miasma) was believed to account for epidemics of contagious disease

• AssociaKon of microorganisms with disease arose from work of German physician Robert Koch (1843-‐1910)

• Koch developed and applied a set of criteria for idenKfying the agent responsible for a specific disease -‐ a pathogen

6

Yellow fever virus -‐ first human virus, 1901

Carlos Finlay

Jesse Lazear

Walter Reed

7

Fundamental ques&ons of viral pathogenesis

• How does a virion enter the host?

• What is the iniKal host response?

• Where does primary replicaKon occur?

• How does the infecKon spread in the host?

• What organs and Kssues are infected?

• Is the infecKon cleared from the host or is a persistent infecKon established?

• How is the virus transmiVed to other hosts?

8

Three requirements for ensuring a successful infec&on

• Sufficient virus parKcles must be available

• The cells at the primary site of infecKon must be accessible, suscepKble, and permissive

• Local host anKviral defense systems must be absent or overcome

9

Sufficient virions at the site of infec&on

• How many virions does it take to infect a host?

-‐ Varies for every virus/host interacKon

• Many variables conspire to complicate the issue-‐ Host geneKcs (outbred populaKons)

-‐ Host anKviral defenses

-‐ Viral virulence

-‐ Host social behavior

-‐ Age of host

-‐ Weather/environment

10

Virion defenses to hos&le environment

• Many virus parKcles are sensiKve to heat, drying, sunlight (UV)-‐ Overcome by producing huge numbers of virions

• Many virions are stable to low pH or proteases-‐ Survive in gut; fecal-‐oral transmission (water borne)

• Many virions never experience the environment-‐ Life cycles involve insect vectors

• Many infecKons spread by physical contact-‐ Transfer by body fluids; virions not outside for long

11

Viral pathogenesis

• Pathogenesis: the process of producing a disease

• Two components of viral disease:

-‐ Effects of viral replicaKon on the host

-‐ Effects of host response on virus and host

• Virus infecKons span the range from benign to lethal

-‐ Acute and persistent infecKons can be quick or amazingly slow -‐ days to years of infecKon

12

The human body presents only a limited spectrum

of entry sites for viral infecKon.

Gaining access: site of entry is cri&cal

13

Skin: a strong barrier to infec&on

Many virions that land on the skin are inac<vated by desicca<on, acids (pH 5.5), or other inhibitors formed by our cells or by commensal microorganisms (eg an<microbial pep<des)

14

Mucosal surfaces are ripe for viral infec&on

• Lined by living cells in a ‘wet’ environment

• Depend on other primary defenses for protecKon

15

Respiratory tract

• Defenses are strong in healthy people

-‐ Mucus: normal individual produces 20-‐200 ml per day in nasal cavity, lungs

-‐ Swept by ciliary acKon to esophagus where it is swallowed (30 Kmes per hr)

-‐ Muco-‐ciliary escalator moves liquid from lungs to esophagus at 1 cm/minute

-‐ Filtering of parKcles in sinuses

-‐ Immune cells, anKbodies in lower regions

17

Alimentary tract

18

The small intes&ne

•A selecKvely permeable barrier

•Polarized epithelial cells

•Direct contact with outside world

•Direct contact with the immune system and the nervous system

19

Urogenital tract

20

Eye

21

Viral spread

• Aler replicaKon at the site of entry, viruses may remain localized: virus spreads within the epithelium, contained by Kssue structure and immune system

• Some viruses spread beyond the primary site: disseminated; if many organs are infected, systemic

• Physical and immune barriers must be breached

23

Viral spread

24

Viral spread

• Apical release facilitates virus dispersal (poliovirus); virus usually does not invade underlying Kssues

• Basolateral release provides access to underlying Kssues, may facilitate systemic spread

• Sendai virus: apical release from respiratory tract, local infecKon; mutant released from both apical and basal surfaces causes disseminated infecKon

apical

apical

basolateral

25

Hematogenous spread

26

Viremia

27

Pathogenesis of mousepox

hVp://www.virology.ws/2010/11/22/frank-‐fenner-‐md-‐1914-‐2010/28

Neural spread

• Virus spread from primary site of infecKon by entering local nerve endings

• For some (rabies, alpha herpesviruses) neural spread is definiKve characterisKc of pathogenesis

• For others (poliovirus, reovirus) invasion of the CNS is an infrequent diversion from normal replicaKon and hematogenous spread

31

Spread of virus in nerves

32

Movement of virus in nerves

33

Infec&ons of the CNS

• A neurotropic virus can infect neural cells; infecKon may occur by neural or hematogenous spread from a peripheral site

• A neuroinvasive virus can enter the CNS aler infecKon of a peripheral site

• A neurovirulent virus can cause disease of nervous Kssue

• HSV: low neuroinvasiveness, high neurovirulence

• Mumps: high neuroinvasivness, low neurovirulence

• Rabies: high neuroinvasiveness, high neurovirulence

35

Tissue invasion

Liver, spleen, bone marrow, adrenal glands

Renal glomerulus, pancreas, ileum, colon

CNS, connecKve Kssue, skeletal & cardiac muscle

36

Blood-‐brain junc&on

38

Tissue invasion: CNS

39

Tissue tropism

• The spectrum of Kssues infected by a virus

-‐ enteric, neurotropic, hepatotropic

• Tropism of some viruses is limited; other viruses are pantropic

• What are the determinants of viral tropism?

40

Some determinants of &ssue tropism

• Suscep<bility: DistribuKon of cell receptors for viruses

• Permissivity: A requirement for intracellular gene products to complete infecKon, e.g. cellular proteins that regulate viral transcripKon

• Accessibility: physical prevenKon of virus parKcles from contacKng permissive/suscepKble cells

• Defense: physical and innate defenses at the site of infecKon may be strong, weak, or absent. Even if cells are suscepKble, permissive, and accessible, viral infecKon may never be established because defense is rapid and overwhelming

41

Determinants of &ssue tropism

• Some highly virulent avian influenza virus strains contain inserKon of mulKple basic amino acids at HA cleavage site

• Permits cleavage by ubiquiKously expressed intracellular proteases (furins -‐ Golgi)

• InfecKous viruses are released from cells and can infect many organs

• Avian influenza viruses (H5N1) isolated from 16 people in Hong Kong (1997) contained similar amino acid subsKtuKons at the HA cleavage site

44

Virus shedding

• Release of virions from an infected individual; usually required for spread (except for transmission in the germline or in the blood supply)

• May occur from the primary site of replicaKon or at many sites aler disseminated replicaKon

• A virus populaKon survives only if serial infecKons can be maintained in the host populaKon

• ConcentraKon/number of parKcles is crucial for transmission

45

Virus shedding

• Respiratory secreKons -‐ aerosols produced by coughing, sneezing, speaking

• Nasal secreKons contaminaKng hands, Kssues

hVp://www.virology.ws/2013/01/23/slow-‐moKon-‐sneezing/46

Virus shedding

• Feces -‐ major means of spread in underdeveloped countries, but sKll occurs in wealthy naKons (sewage contaminaKon of water)

• Blood -‐ vector bites, health care workers

• Urine (hantaviruses), semen (HIV, herpesviruses, HBV)

• Milk (MMTV)

• Skin lesions (HSV -‐ herpes gladiatorum; poxviruses, papillomavirus warts)

48

Transmission of infec&on

• The spread of infecKon from one suscepKble host to another; required to maintain chain of infecKon

• Two general paVerns

-‐ the perpetuaKon of infecKon in one species

-‐ alternate infecKon of insect and vertebrate hosts

49

Transmission

• The site of virion excreKon and physical stability determine route of transmission

• Enveloped viruses are fragile, sensiKve to low pH -‐ olen transmiVed by aerosols or secreKons, injecKon, organ transplantaKon

• Non-‐enveloped virions withstand drying, detergents, low pH, high temperatures -‐ olen transmiVed respiratory, fecal-‐oral routes, or fomites

50

Transmission

• Iatrogenic -‐ acKvity of health care worker leads to infecKon of paKent

• Nosocomial -‐ when an individual is infected while in hospital or health care facility

• Ver<cal transmission -‐ transfer of infecKon between parent and offspring

• Horizontal transmission -‐ all other forms

• Germ line transmission -‐ agent is transmiVed as part of the genome (e.g. proviral DNA)

51

Geography and season

• Geography may restrict presence of virus -‐ requirement for specific vector or animal reservoir

• Before global travel, distribuKon of viruses was far more restricted than today

• Chikungunya virus -‐ how vector can affect localizaKon of viral infecKon

52

Chikungunya virus

• Togavirus, alphavirus genus

• Spread by Aedes aegyp<

• Rash, joint pains

53

Chikungunya virus

• Asia, Africa, never Europe or US

• 2004 -‐ outbreaks spread from Kenya to India

• 2007 -‐ outbreak in Italy, first in Europe

Réunion

54

• Recent outbreaks associated with A. albopictus

• One amino acid change in viral E1 glycoprotein

Chikungunya virus

55

Aedes albopictus, 2000

hVp://www.virology.ws/2009/03/18/chikungunya-‐an-‐exoKc-‐virus-‐on-‐the-‐move/

2007

56

Seasonality of virus infec&ons

57

Seasonal factors that affect influenza virus transmission

58

Do the tropics have a flu season?

hVp://scienceblogs.com/effectmeasure/2009/03/01/do-‐the-‐tropics-‐have-‐a-‐flu-‐seas/

hVp://wwwnc.cdc.gov/eid/arKcle/15/3/08-‐0238_arKcle.htm

59

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