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Infec&on BasicsLecture 12
Virology W3310/4310Spring 2012
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
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The nature of host/parasite interac&ons
• Part 3 of the tripar0te strategy evolved by all viruses:
-‐ All viral genomes are able to establish themselves in a host popula0on so that virus survival is ensured
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Basic facts
• Every host alive today has intrinsic defenses coupled with immune defenses that evolved to deal with infec0ons 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
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We live and prosper in a literal cloud of viruses
• Most infec0ons have no consequence-‐ Many parBcles never find a living cell to infect (land on your skin)
-‐ Many are destroyed or inacBvated as they enter the host
-‐ Many infecBons never go further than one or two cells at the site of infecBon
• If we do get infected, many infec0ons are inapparent-‐ No symptoms, but immune defenses are acBvated (e.g. anBbodies made -‐ this is how we
know there are inapparent infecBons)
-‐ Virus may be replicaBng and transmiQed during these inapparent acute infecBons
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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 (anBbody posiBve)
-‐ 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
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Microbes as infec&ous agents
• Poisonous air (miasma) was believed to account for epidemics of contagious disease
• Associa0on of microorganisms with disease arose from work of German physician Robert Koch (1843-‐1910)
• Koch developed and applied a set of criteria for iden0fying the agent responsible for a specific disease -‐ a pathogen
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Yellow fever virus -‐ first human virus, 1901
Carlos Finlay
Jesse Lazear
Walter Reed
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Fundamental ques&ons of viral pathogenesis
• How does a virion enter the host?
• What is the ini0al host response?
• Where does primary replica0on occur?
• How does the infec0on spread in the host?
• What organs and 0ssues are infected?
• Is the infec0on cleared from the host or is a persistent infec0on established?
• How is the virus transmiTed to other hosts?
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Three requirements for ensuring a successful infec&on
• Sufficient virus par0cles must be available
• The cells at the primary site of infec0on must be accessible, suscep0ble, and permissive
• The local host an0viral defense systems must be absent or at least ini0ally defec0ve
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Sufficient virions at the site of infec&on
• How many virions does it take to infect a host?
-‐ Varies for every virus/host interac0on
• Many variables conspire to complicate the issue-‐ Host geneBcs (outbred populaBons)
-‐ Host anBviral defenses
-‐ Viral virulence
-‐ Host social behavior
-‐ Age of host
-‐ Weather/environment
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Virion defenses to hos&le environment
• Many virus par0cles are sensi0ve 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 infec0ons spread by physical contact-‐ Transfer by body fluids; virions not outside for long
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Viral pathogenesis
• Pathogenesis: the process of producing a disease
• Two components of viral disease:
-‐ Effects of viral replica0on on the host
-‐ Effects of host response on virus and host
• Virus infec0ons span the range from benign to lethal
-‐ Acute and persistent infec0ons can be quick or amazingly slow -‐ days to years of infec0on
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The human body presents only a limited spectrum
of entry sites for viral infecBon.
Gaining access: site of entry is cri&cal
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Skin: a strong barrier to infec&on
• Many virions that land on the skin are inacBvated by desiccaBon, acids (pH 5.5), or other inhibitors formed by commensal microorganisms
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Mucosal surfaces are ripe for viral infec&on
• Lined by living cells in a ‘wet’ environment
• Depend on other primary defenses for protec0on
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Respiratory tract
• Defenses are strong in healthy people
-‐ Mucus: normal individual produces 20-‐200 ml per day in nasal cavity, lungs
-‐ Swept by ciliary ac0on to esophagus where it is swallowed (30 0mes per hr)
-‐ Muco-‐ciliary escalator moves liquid from lungs to esophagus at 1 cm/minute
-‐ Filtering of par0cles in sinuses
-‐ Immune cells, an0bodies in lower regions
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Alimentary tract
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The small intes&ne
•A selecBvely permeable barrier
•Polarized epithelial cells
•Direct contact with outside world
•Direct contact with the immune system and the nervous system
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Urogenital tract
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Eye
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Viral spread• Aber replicaBon at the site
of entry, viruses may remain localized: virus spreads within the epithelium, contained by Bssue 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
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Viral spread
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Viral spread
• Apical release facilitates virus dispersal (poliovirus); virus usually does not invade underlying Bssues
• Basolateral release provides access to underlying Bssues, may facilitate systemic spread
• Sendai virus: apical release from respiratory tract, local infecBon; mutant released from both apical and basal surfaces causes disseminated infecBon
apical
apical
basolateral
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Hematogenous spread
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Viremia
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Pathogenesis of mousepox
hQp://www.virology.ws/2010/11/22/frank-‐fenner-‐md-‐1914-‐2010/28
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Neural spread
• Virus spread from primary site of infecBon by entering local nerve endings
• For some (rabies, alpha herpesviruses) neural spread is definiBve characterisBc of pathogenesis
• For others (poliovirus, reovirus) invasion of the CNS is an infrequent diversion from normal replicaBon and hematogenous spread
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Spread of virus in nerves
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Movement of virus in nerves
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Infec&ons of the CNS
• A neurotropic virus can infect neural cells; infecBon may occur by neural or hematogenous spread from a peripheral site
• A neuroinvasive virus can enter the CNS aber infecBon of a peripheral site
• A neurovirulent virus can cause disease of nervous Bssue
• HSV: low neuroinvasiveness, high neurovirulence
• Mumps: high neuroinvasivness, low neurovirulence
• Rabies: high neuroinvasiveness, high neurovirulence
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Tissue invasion
Liver, spleen, bone marrow, adrenal glands
Renal glomerulus, pancreas, ileum, colon
CNS, connecBve Bssue, skeletal & cardiac muscle
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Blood-‐brain junc&on
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Tissue invasion: CNS
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Tissue tropism
• The spectrum of 0ssues infected by a virus
-‐ enteric, neurotropic, hepatotropic
• Tropism of some viruses is limited; other viruses are pantropic
• What are the determinants of viral tropism?
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Some determinants of &ssue tropism
• Suscep<bility: DistribuBon of cell receptors for viruses
• Permissivity: A requirement for intracellular gene products to complete infecBon, e.g. cellular proteins that regulate viral transcripBon
• Accessibility: physical prevenBon of virus parBcles from contacBng permissive/suscepBble cells
• Defense: physical and innate defenses at the site of infecBon may be strong, weak, or absent. Even if cells are suscepBble, permissive, and accessible, viral infecBon may never be established because defense is rapid and overwhelming
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Determinants of &ssue tropism
• Some highly virulent avian influenza virus strains contain inserBon of mulBple basic amino acids at HA cleavage site
• Permits cleavage by ubiquiBously expressed intracellular proteases (furins -‐ Golgi)
• InfecBous 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 subsBtuBons at the HA cleavage site
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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 replica0on or at many sites acer disseminated replica0on
• A virus popula0on survives only if serial infec0ons can be maintained in the host popula0on
• Concentra0on/number of par0cles is crucial for transmission
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Virus shedding
• Respiratory secre0ons -‐ aerosols produced by coughing, sneezing, speaking
• Nasal secre0ons contamina0ng hands, 0ssues
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Virus shedding
• Feces -‐ major means of spread in underdeveloped countries, but s0ll occurs in wealthy na0ons (sewage contamina0on of water)
• Blood -‐ vector bites, health care workers
• Urine (hantaviruses), semen (HIV, herpesviruses, HBV)
• Milk (MMTV)
• Skin lesions (HSV -‐ herpes gladiatorum; poxviruses, papillomavirus warts)
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Transmission of infec&on
• The spread of infec0on from one suscep0ble host to another; required to maintain chain of infec0on
• Two general paTerns
-‐ the perpetua0on of infec0on in one species
-‐ alternate infec0on of insect and vertebrate hosts
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Transmission
• The site of virion excre0on and physical stability determine route of transmission
• Enveloped viruses are fragile, sensi0ve to low pH -‐ ocen transmiTed by aerosols or secre0ons, injec0on, organ transplanta0on
• Non-‐enveloped virions withstand drying, detergents, low pH, high temperatures -‐ ocen transmiTed respiratory, fecal-‐oral routes, or fomites
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Transmission
• Iatrogenic -‐ ac0vity of health care worker leads to infec0on of pa0ent
• Nosocomial -‐ when an individual is infected while in hospital or health care facility
• Ver<cal transmission -‐ transfer of infec0on between parent and offspring
• Horizontal transmission -‐ all other forms
• Germ line transmission -‐ agent is transmiTed as part of the genome (e.g. proviral DNA)
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Geography and season
• Geography may restrict presence of virus -‐ requirement for specific vector or animal reservoir
• Before global travel, distribu0on of viruses was far more restricted than today
• Chikungunya virus -‐ how vector can affect localiza0on of viral infec0on
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Chikungunya virus
• Togavirus, alphavirus genus
• Spread by Aedes aegyp<
• Rash, joint pains
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Chikungunya virus
• Asia, Africa, never Europe or US
• 2004 -‐ outbreaks spread from Kenya to India
• 2007 -‐ outbreak in Italy, first in Europe
Réunion
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• Recent outbreaks associated with A. albopictus
• One amino acid change in viral E1 glycoprotein
Chikungunya virus
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Aedes albopictus, 2000
hQp://www.virology.ws/2009/03/18/chikungunya-‐an-‐exoBc-‐virus-‐on-‐the-‐move/
2007
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Seasonality of virus infec&ons
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Seasonal factors that affect influenza virus transmission
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But...
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