Lecture 24: patterns of
infection
See Flint et al, Chapter 16
General points:
•Infection can be
–Acute
–Persistent
•Effects can range from
–Unnoticeable
–Deadly
Viral life cycles
• Cytopathic: rapidly kill the cell while
producing a burst of new particles
• Non-cytopathic: infection yields virions
without causing immediate cell death
• Incubation
period:
The time
between
initial
infection
and onset
of
symptoms
Stages of viral infection
1. Primary infection- Infection of cells in the
general location where virus enters.
– Common with cold viruses and Diarrhea causing
viruses. Many viruses including HIV initially infect
cells in the infected area.
2. Viremia- Virus enters the blood system and
can be detected in the blood stream.
– Not all viruses do this. Some remain only localized.
3. Secondary infection- Infection of other organ of
cell types by the virus.
– Many viruses have high affinity for specific organs
due to the presence of receptors or specific cell
metabolic functions. Examples are infection of
salivary glands by mumps virus, brain tissue by
encephalitis virus, and liver tissue by hepatitis virus.
Stages of
viral
infection –
Varicella
zoster
infection
Virulence
• The ability of an infectious agent to cause
disease. A relative term in the sense that it
depends on the particular host that is infected
and the state of that host as well as the site of
infection.
– Rabies and Ebola are highly virulent.
– Some viruses infect animals but are virulent only
when the host immune response is suppressed.
Examples are certain herpes and hepatitis B virus
that become virulent when human hosts are treated
with immunosuppressant drugs after organ transplant.
General patterns of infection
Fig. 16.1
Acute Infections
• Acute infections only detected by
clinical symptoms.
• Can be acutely infected but
assymptomatic…subclincal.
• Large amounts of progeny virus usually
produced
• Rapid onset of symptoms
Defense against acute infections
• Most acute infections are rapidly resolved
• Limited by the intrinsic and innate immune
responses
– Localization to the immediate site of infection
– Clearance by macrophages, NK cells,
polymorphonuclear cells, complement.
• Adaptive immune response provides memory
against subsequent infection.
– Virus-specific humoral and cellular responses
• If not quickly limited, acute infections are
resolved by host death
– e.g. many haemorragic viruses, severely
immunocompromised patients
The course of an acute infection
Fig. 16.2
Antigenic variation – the viral
response
• Survival of acute infection  lifelong immunity to that
specific virus
• How is it that we get sick from other acute viruses over
and over?
– e.g. common cold, influenza
• Answer: viruses capitalize on high rates of mutation to
evolve around immune response
• Structural plasticity: virions that can tolerate many amino
acid substitutions yet remain infections.
– Rhinoviruses and Influenzaviruses are incredibly structurally
plastic.
– Limits ability to make effective vaccines
• Many viruses are not structurally plastic: e.g. poliovirus.
One vaccination can confer lifelong immunity
Structural plasticity: Antigenic variation
• The immune system detects “epitopes” on “antigens”:
structural features of molecules
• Antigenic variation:
– Changes in the epitopes of viral proteins that are presented to the
immune system.
• Antigenic drift:
– Appearance of virions with slightly altered surface proteins following
passage in the natural host.
– An evolutionary process where natural selection is driven by the host
immune response
• Antigenic shift:
– A major change in a surface protein as a gene encoding a completely
new surface protein is acquired.
– Results from coinfection of one host with two different viral serotypes.
– Due to reassortment of genes among two or more viruses.
– Very commonly seen with viruses having segmented genomes.
– Reassortment and recombination of blocks of genetic information result
in viral hybrids that are immunologically new to the host.
Acute infections and Public
Health
• Acute infections are commonly associated with
epidemics
– e.g. polio, influenza, measles, common cold
• Main problem: by the time symptoms emerge,
the patient has passed on the infection
• Difficult to control in large populations and
crowded environments
– e.g. work, daycare, dorms
• Effective antiviral drug therapy requires early
intervention, safe drugs with few side
effects…..not really practical for acute infections.
• Cost: 90% of outpatient visits due to self-limiting
acute viral infections.
Persistent infections
• Infection by viruses which actively produce large
amounts of progeny
• 4 classes of Persistent infections
1) Infection by viruses which actively produce large amounts of
progeny, but which cause little cytopathology.
2) Infection by normally lytic virus but in which the extent of
virus multiplication is somehow limited, so that the yield of
virus is small.
3) Limitation of reinfection by various viral and cellular factors,
so that the proportion of infected cells in the total cell
population remains small but constant.
4) Chromosomal integration of proviral genomes can result in
“silent” infections, infrequent or constant rounds of low level,
only slightly cytopathic virus production.
Some persistent viral infections of humans
VIRUS
SITE OF PERSISTENCE
CONSEQUENCE
Adenovirus
Adenoids, tonsils, lymphocytes
None known
Epstein-Barr
B-cells, nasophayngial epithelia
Lynphoma, carcinoma
H.Cytomegalovirus
Kidney, salivary gland, WBCs?
Pneumonia, retinitis
Hepatitis B virus
Liver, lymphocytes
Cirrhosis, liver cancer
Hepatitis C virus
Liver
Cirrhosis, liver cancer
HIV
CD4+ T-cells, macrophates, microglia
AIDS
HSV 1 and 2
Sensory and autonomic ganglia
Cold sore, genital herpes
HTLV 1 and 2
T-cells
Leukemia, brain infections
Papillomaviruses
Skin, epithelial cells
Papillomas, carcinomas
Polyomavirus BK
Kidney
Hemorrhagic cystitis
Polyomavirus JC
Kidney, CNS
Progressive multifocal
leukoencephalopathy
Measles
CNS
Subacute sclerosing
panencephalitis
Rubella virus
CNS
Progressive rubella panencephalitis
Varicella-Zoster
Sensory ganglia
Shingles, postherpetic neuralgia
Perpetuating a persistent infection by modulating the
adaptive immune response: Blocking display of viral
antigen in context of MHC class I
MHC Class II modulation after
infection
• Antigen presenting cells – Macrophages,
dendritic cells, B-cells.
• Gobble up antigens from outside
• process them, presents them to CD4 T-cells in
the context of MHC class II
• Presentation of viral antigen in this contact
activates T-helper cells, activating specific
immune response.
• Any viral proteins that can modulate the MHC
class II antigen presentation pathway would
therefore interfere with T-helper cell activation.
Any viral protein that can modulate the MHC class II antigen presentation
pathway would therefore interfere with T-helper cell activation.
HIV Nef
EBV
BZLF2
Fig. 15.20
Killing activated CTLs
• Activated CTLs express
the membrane-bound Fas
receptor: related to TNF
receptor
• Fas binds the Fas-Ligand
(FasL)
• Binding of FasL on target
cells by Fas on activated
CTLs activates T-cell
aptosis.
• Many viruses, e.g. HIV-1
increase expression of
FasL on the surfaces of
infected cells.
CTL
Target cell
From Fig. 15.1
Direct infection of cells of the
immune system
• Allows viruses to suppress the immune
response, e.g. HIV
• Mobility of immune cells allows viruses to
disseminate through host – e.g. CMV
Infections of tissues with
reduced immune surveillance
Tissues with surfaces exposed to environment
• Higher thresholds of immune activation,
• e.g. skin, glands, bile ducts, kidney tubules.
– Cytomegalovirus infects cells on the surfaces of glands and ducts
(kidney, salivary, mammary), ensuring constant shedding of new virus
into environment.
– Papillomaviruses: Productive replication of only occurs in the outer,
terminally differentiated skin cells. The result is skin warts.
Other compartments of the body can’t mount inflammatory
responses
• To do so would be to severely damage them.
• e.g. CNS, eye, areas of lymphoid drainage.
• Persistent infection of these tissues by viruses is common.