DD 02-24-14 10-11am Viral Pathogenesis - vanDyk Flashcards
Viral disease - factors
= the cumulative effect of virus replication and the host response
Depends on…
-effects of virus replication on host cells
-host response to infection
-ability of virus to spread w/in and among hosts
Factors that influence disease induction & outcome upon virus infection include (8):
- Route of infection
- Initial site of replication
- Virus spread from initial site
- Mechanisms of virus-induced symptoms/signs of infection.
- Tropism.
- Transmission & shedding
- Host factors in susceptibility to viral disease
- Immune-mediated pathology
Routes of infection (Primary, others)
Primary initial routes of virus infection or modes of transmission are:
1. Respiratory
2. Alimentary
3. Genitourinary
All mucosal surfaces have sophisticated immune defense which most viruses must overcome, yet still the most common entry point for most viral pathogens.
Can also initiate in:
- Mucous membranes of eyes (via skin abrasions)
- Parenterally
Most viruses can initiate infection at more than one site (though most prefer certain sites).
Initial site of viral replication
Usually in epithelial cells near body surface or barriers.
Some are limited to this site, while other spread further and cause systemic infection.
Requirements for successful initial infection
- Sufficient virus
- Cells at entry site susceptible & permissive to infection
- Local host defenses absent / initially insufficient to block infection
“Sufficient virus”
Free virus particles must survive environmental exposure or limit exposure between hosts.
Virus must be abundant enough to initiate infection (concentration, virus particles can be defective)
Initial infection can be quite inefficient.
Virus spread from initial site
- Initial site of entry often dictates pattern of spread.
- To spread beyond initial site, must breach local barriers
- Cells at mucosal barriers are often polarized, leading to direction & predictable virus release
- Some cells spread hematogenously, often infecting endothelial cells or by direct inoculation into the bloodstream (e.g. insect borne viruses)
- Viruses can traffic among tissue or through blood/lymph w/in infected cells
Spread: Breaching local barriers
Necessary to spread beyond initial site,
Ex: Must first breach epithelium, then basement membranes, then tissue fluids, lymphatics, phagocytes, etc., which play a role both in clearing & trafficking of pathogens
Spread: Polarized mucosal cells
Lead to directional release of viruses from these cells, and thus predictable consequences…
EX: Viruses release on apical side are back to where they started & likely to remain local; they are well positioned for efficient transmission to new host.
EX: Viruses released on basolateral side are likely to gain access & spread to or beyond underlying tissue.
Manifestations of viral spread in skin
Virus spread is sometimes apparent in skin as rashes / lesions.
Mechanisms of virus-induced symptoms / signs of infection
Consists of…
- Direct virus effects on infected host cells (e.g. lysis of host cells)
- Effects of host immune response
Tropism (definition, examples, effect)
= a given virus is likely to infect certain tissues & not others (i.e. tissue specificity)
EX: Entertropic viruses replicate in gut
EX: Neurotropic viruses replicate in nervous system tissue
Effect: Can drive virus population variants among/within individuals, particularly in viruses with highly error prone replication systems
Tropism is determined by…
- Access to tissue in which it can replicate
- Receptors required for virus binding & entry
- Expression of host genes required for virus infection & production of new progency virus
- Relative failure of host defenses
Transmission & Shedding
= release of infectious particles from an infected host
Transmission may be within a single susceptible host, or may alternate infection of one host w/another (e.g. insect to human cycle).
Mostly horizontal transmission, but vertical (parent/child) and germ-line transmission allow the propagation in some.
Some show seasonal / geographic patterns
Local infections: site of shedding
occurs at site of initial infection
Disseminated / Systemic infection; site of shedding
Shedding could take place from multiple or distant sites
Means of transmission affected by…
- sites of viral replication & release
- relative stability of virus
Transmission of enveloped vs. non-enveloped viruses…
EX: Enveloped viruses are fragile & sensitive to many environmental stresses like pH, so often transmitted by close contact.
EX: Non-enveloped viruses are hardier & can sustain drying, low pH, detergents, high temps…so, often transmitted via virus-associated objects / fomites and use repiratory or fecal/oral routes.
Seasonal / geographic patterns of viral transmission
May indicate…
- need for particular animal or vector host
- existence of susceptible or naive population
Host factors in susceptibility to viral disease
Include:
- expression of appropriate receptors for virus entry
- accessibility & permissivity of infected cells
- age of host
- genetic background
- immune status
Permissivity
ability of cells to support viral replication
Immune-mediated pathology
Some viral disease is actually mediated by host immune response to the infection.
Include:
- antibody-mediated (immune complex disease)
- cell-mediated responses (rash, fever, malaise)
- virus-induced inflammation
- autoimmunity (possibly due to cross-reactivity with virus)
- transient immune modulation (such as immune suppression)
- antibody-dependent enhancement of infection
Acute viral infection
- high viral replication rate
- production of large number of progeny
- replication is transient in individual host, as limited by either death of host (and/or host cells inside the host) or by the host immune response
- whether local or systemic depends on initial events of infection and virus tropism
Persistent viral infection
- lasts longer periods of time than an acute infection
- may be result of acute primary infection that is not cleared
- the ability of the virus to be transmitted to other organisms or offspring of host is maintained
- usually mild or inapparent disease in healthy host
- manifestation of disease is usually coincident with immune suppression or other complications
- includes latent infections…
Latent infections
- type of persistent infection
- involves substantial periods in which host produces no detectable virus
Acute local infection
- usually infection of epithelial cells at body surface (gut, resp. tract, eyes, etc.)
- often short incubation times (1-2 days)
- often many serotypes (rapidly mutating)
- result in short-lived immunity with reinfections common
- primarily induces secretory IgA)
- EX: colds, diarrheal disease
Acute systemic infection
- usually primary infection is in the epithelium (as in acute local infections)
- viremia & systemic infection result in secondary infection and tertiary at various sights
- secondary replication sites in spleen, lung, liver
- longer incubation periods (10-21 days)
- results lifelong immunity (via both secretory IgA and serum IgG)
EX: measles, smallpox
Persistent vs. Latent infection
Persistent - usually viral infection that continues to produce new virus over long period of time
Latent - viral infection in which virus genome is relatively silent, there is little transcription in most infected cells, and there is little to no disease in healthy host for a long time (often even life)
Dead-end vs. Latent infections
Dead-end infection = caused by defective virus or lack the ability to ever produce virus
Latent = retain ability to re-initiate transcription / replication to produce new virus (reactivation / recrudescence)
Slow type of chronic infection
- No symptoms on initial infection
- Long incubation period
- May or may not induce an immune response
- Eventual disease is followed by progressive deterioration and death
Chronic viral infection types
Persistant
Latent
Dead-end
Slow
Transforming viral infections
= contribute in various ways to tumorigenesis
- Some retroviruses integrate into host genome & activate viral or host oncogene.
- Other viruses may or may not integrate to cause host DNA breakage & oncogene activation / inactivation of tumor suppressor genes.
- Some viral infections (esp,. persistent infections) may cause ongoing inflammation and thus contribute to tumorgenesis.
Types of viral disease & examples
Acute Local - Colds, diarrhea Acute Systemic - Smallpox, measles Chronic - Rubella in neonates Latent - VZV in nerves (varicella zoster virus) Slow/Progressive - AIDS, cancer
Epidemics vs. Endemics
Epidemics refers to…
- local outbreaks of disease
- pandemics to global outbreaks
Endemics referes to…
- outbreaks occuring commonly & frequently in a given population
Factors influencing epidemiology of viral diseases:
- spread / transmission
- susceptibility to re-infection
- age dependence
- group / population effects
- seasonality
- immune status of host
- animal reservoirs
Viral control methods:
Involve understanding viruses:
- animal reservoirs
- susceptibility factors
- modes of transmission
- methods to inactivate the virus
- vaccines
- anti-viral drugs
- development of drug resistance
Virulence (& virulence genes)
= capacity of the infection to cause disease
= range from avirulent to attenuated to virulent
Four types of virulent genes:
1. affect ability of virus to replicate
2. modify host defense mechanisms
3. facilitate virus spread in / among hosts
4. direct toxicity to host cells
