Expected Learning Outcomes

• At the end of this lecture, you should be able to:

a) Name routes of transmission of various human viruses.
Introduction to viral pathogenesis b) Describe basic steps involved in human virus infection
process.
c) Link a human virus with the organ it replicates and
Topic 17 disease it causes.
d) Describe and give an example of an acute viral infection,
a late complication following an acute infection, a latent
viral infection, a chronic viral infection, and a slow viral
infection.
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Virus-Host Interactions: Terms Iceberg concept of infection:

Types of host and cellular responses to virus infection
• Viral disease: Is some harmful abnormality that
results from viral infection of the host organism
• Clinical disease: Consists of overt signs and
symptoms.
• Syndrome: Is a specific group of signs and
symptoms
• Inapparent/subclinical: Viral infections that fail
to produce any symptoms in the host
• Viral pathogenesis: Is the process by which a
virus interacts with its host in a discrete series of
stages to produce disease
• Viral virulence: Is the capacity of a virus to
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produce disease in a susceptible host.

Viral disease Viral pathogenesis

The susceptibility of an individual to a virus
and severity of the disease depends on:
• Nature of exposure
• Immune status, age, occupation, lifestyle,
travel history and health of an individual
• Viral dose
• Genetics of both the virus and host
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Fundamental questions of viral pathogenesis:
• How does a virus particle enter the host?
• What is the initial host response?
• Where does primary replication occur?
• How does the infection spread in the host?
• What organs and tissues are infected?
• Is the infection cleared from the host or is a
persistent infection established?
• How is the virus transmitted to other hosts?

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 Viral pathogenesis 1. Entry into body or Acquisition
Stages in virus-host interaction
• For host infection to occur, a virus must
1) Entry into the host first transmitted into the body
2) Adsorption to host cells • Portals of entry/Transmission:
3) Primary replication at site of entry
4) Spread
5) Cell and tissue tropism
6) Secondary replication in the target tissue
7) Human immune response
8) Resolution or persistent infection/chronic
disease 7 8

a) Direct transmission from person to person by contact

b)
• Respiratory transmission: Include droplet or aerosol
infection (eg, influenza, measles, smallpox)
• Indirect transmission by the fecal–oral route
• Sexual contact (eg, papillomavirus, hepatitis B, herpes (eg, enteroviruses, rotaviruses, infectious
simplex type 2, human immunodeficiency virus)
hepatitis A) or by fomites (eg, Norwalk
• Hand–mouth, hand–eye, or mouth–mouth contact (eg, virus, rhinovirus).
herpes simplex, rhinovirus, Epstein-Barr virus)

• Transmission via blood: Exchange of contaminated blood

(eg, hepatitis B, human immunodeficiency virus).

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c) d)

• Transmission from animal to animal, with • Transmission by means of an arthropod

humans an accidental host.
• Spread may be by bite (rabies) or by droplet
or aerosol infection from rodent-
contaminated quarters (eg, arenaviruses,
hantaviruses).
vector (eg, arboviruses, now classified
primarily as togaviruses, flaviviruses, and
bunyaviruses).

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 Routes of virus entry into the host
Virus transmission routes

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2. Attachment to cells at site of entry

• The second step in the infection process is
adsorption to the host cell surface.
• This occurs through a random collision of
the virion with a plasma membrane receptor
site protein, frequently a glycoprotein
Examples
• Poliovirus receptors are found only in the
human nasopharynx, gut, and spinal cord
anterior horn cells
• Measles virus receptors are present in most
tissues 15 16

3. Initiation of infection: Replication at Localized viral infections

the primary site of entry
Examples of localized infections in which viral entry and
replication occur at the same anatomic site include:
• Viruses usually replicate at the primary site of
• Respiratory infections caused by:
entry. - influenza virus
• Some, such as influenza viruses (respiratory - respiratory syncytial virus
infections) and noroviruses (gastrointestinal - rhinovirus
infections), produce disease at the portal of entry • Enteric infections produced by:
and likely have no necessity for further systemic - astrovirus
- calicivirus
spread.
- rotavirus
• Dermatologic infections caused by:
- HPV (warts)
- paravaccinia virus (milker’s nodules)
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 4. Spread Spread

Entry and spread of • Many viruses produce disease at sites distant

viruses in human hosts.
from their point of entry (eg, enteroviruses, which
This scheme illustrates
entry, primary enter through the gastrointestinal tract but may
replication, secondary produce central nervous system [CNS] disease).
replication, and • After primary replication at the site of entry, these
invasion of target viruses then spread within the host
organs.
• Mechanisms of viral spread vary, but the most
common route is via the bloodstream or
lymphatics.

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Other Examples
• Poliovirus spreads from the GI tract to the
central nervous system (CNS) to produce
meningitis, encephalitis or poliomyelitis.
• Measles virus and varicella-zoster virus enter the
host through the respiratory tract and then
spread to lymph nodes, skin, and viscera.
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a) Hematogenous spread
• Viruses that produce disseminated infection often do so by
entering the blood.
• Viruses may enter blood directly through capillaries, by
replicating in endothelial cells, or through vector bite.
• Virus in the extracellular fluids is taken up by lymphatic
capillaries, which are more permeable than circulatory
capillaries, then spread to blood.
• Once in blood, virus has access to almost every tissue.
• In lymph nodes, viruses encounter lymphocytes and other
immune cells, and may replicate in them; may also spread
infection to distant tissues.
• Other viruses spread freely in the blood.
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• Examples of viruses that travel freely in the Viremia

plasma:
- picornaviruses and togaviruses
• Examples of viruses spread by macrophages:
(CMV, HIV, and measles virus).
• Examples of viruses spread by lymphocytes:
{CMV, EBV, HIV and human T-cell
lymphotrophic virus (HTLV)}
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• Presence of infectious virus in the blood.
• Active viremia: results from virus
replication.
• Passive viremia: results from virus
introduced into the blood without
replication.
• Has a big diagnostic value.
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b) Neural spread
• Many viruses spread from primary site of
infection to CNS through nerves.
• Examples: bornavirus, coronavirus, HSV,
poliovirus, rabies virus and reovirus.
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c) Multiple routes of spread
• Viruses are not limited to a single route of
spread
• Varcella-zoster virus enters the host by the
respiratory route and then spreads from
respiratory epithelium to the
reticuloendothelial system and skin via the
blood stream
• Poliovirus spreads by both hematogenous
and neutral routes.
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5. Cell and tissue tropism

• Tropism: The ability of a virus to infect a

distant group of host cells from site of entry.
• The spectrum of tissues infected by a virus.
• The cells have virus receptors on the surface.
• Examples: Enterotropic, neurotropic,
hepatotropic.
• Ranges from limited to pantropic.

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Factors that influence tropism:

• Route of entry
• The pathway of spread
• Polymorphism in the expression of
• Host factors
chemokine receptor CCR5, which serves as
(i) Age e.g. respiratory syncytial virus and
a coreceptor of HIV, are associated with
rotavirus mainly infect young children
alterations in susceptibility to HIV
(ii) Nutritional status e.g. persons with
infections in human
vitamin A deficiency have enhanced
susceptibility to measles virus infection.
(iii) Immune status
(iv) Genetics e.g.
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 6. Replication in target tissue, immune Mechanism Examples
a Inhibition of cellular protein synthesis Poliovirus, HSV
response, cell injury and clinical illness b Inhibition and degradation of cellular DNA Herpesviruses
c Toxicity of virion components Adenovirus fibers, reovirus
NSP4 protein
• Destruction of virus-infected cells in the target d Alteration of cell membrane structure
tissues and physiologic alterations produced in the (i) Glycoprotein insertation All enveloped viruses
host by the tissue injury are partly responsible for (ii) Syncytial formation HSV, VZV, HIV
the development of disease (iii) Disruption of cytoskeleton Non-enveloped viruses, HSV
(iv) Disruption of permeability Togavirus, herpesviruses

e Inclusion bodies
Negri bodies (intracytoplasmic) Rabies
Owl’s eye (intranuclear) CMV
Intranuclear basophilic Adenoviruses
Perinuclear cytoplasmic acidophilic Reoviruses

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• General symptoms associated with many

viral infections, such as malaise and
anorexia, may result from host response
functions such as cytokine production

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Immunopathogenesis Immune mediators Examples

Flulike symptoms Interferon and Respiratory viruses,

(fever, running nose, cytokines arboviruses (viremia
malaise, headache) inducing viruses)
Stages of viral infection
Delayed-type T-cells, Enveloped viruses
hypersensitivity and macrophages, and
inflammation polymorphonuclear
leukocytes
Immune complex Antibody, Hepatitis B virus,
disease complement rubella
Hemorrhagic disease T cell, antibody, Yellow fever,
complement dengue, Lassa fever,
Ebola virus
Postinfection cytolysis T cells Enveloped viruses
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Immunosuppression Unknown HIV, CMV, measles

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 How do viruses evade the human immune system?
a) Some viruses have developed strategies to evade the
action of IFN – α/β e.g. hepatitis C virus.
b) Inhibition of antigen presentation by infected host cells
e.g. herpes simplex viruses (HSV) expresses ICP47
which very effectively inhibits the human TAP.
c) A number of viruses have strategies for evading
complement-mediated destruction e.g. vaccinia virus.
d) A number of viruses escape immune attack by
constantly changing their antigens e.g. influenza virus.
e) A large number of viruses evade the immune response
by causing generalized immunosuppression e.g. EBV
and HIV. 37
In apparent infection occurs if:
a) If the infected tissue is undamaged
b) The infection is controlled before the virus
reaches its target tissue
c) The target tissue is expendable
d) The damaged tissue is rapidly repaired
e) The extent of the damage is below a
functional threshold for that particular
tissue
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Assignment:
• Define the following viral infections. Give an example
for each.
• Acute viral infections
• Sub acute viral infections
• Chronic viral infections
• Persistent viral infections
• Latent viral infections
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Outcomes of a viral infection
• At incubation period, the virus is replicating but
has not reached the target tissue or induced
sufficient damage to cause the disease
• If primary site of infection is the target tissue, the
characteristic symptoms of the disease are
experienced
• Three outcomes are possible:
a) In apparent infections
b) Acute infections
c) Persistent or chronic infection
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Outcome of a viral infection
(ii) Acute infection
• Antiviral and immune system controls and resolves a viral infection
• Recovery with no residue effects
• Recovery with residue effects e.g. acute viral encephalitis leading to
neurological sequelae.
• Death
• Proceed to chronic infection
(iii) Chronic infection
• Silent subclinical infection for life e.g. CMV, EBV
• A long silent period before disease e.g. HIV, SSPE, PML
• Reactivation to cause acute disease e.g. herpes and shingles.
• Chronic disease with relapses and excerbations e.g. HBV, HCV.
• Cancers e.g. EBV, HTLV-1, HPV, HBV, HCV, HHV-8
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7. Recovery from Infection
• The host either succumbs or recovers from
viral infection
• Recovery mechanisms include both innate
and adaptive immune responses.
• The genetic basis of host susceptibility
remains to be determined for most
infections.
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 8. Virus Shedding

• The last stage in pathogenesis is the

shedding of infectious virus into the
environment.
• This is a necessary step to maintain a viral
infection in populations of hosts
• Shedding usually occurs from the body
surfaces involved in viral entry

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Oncogenic viruses and cancer

• Oncogenic viruses cause cancer Oncogenic DNA
• Cancers are not contagious in the sense that they are not viruses Oncogenic RNA viruses
transmitted from patients to close contacts • EBV • Hepatitis C virus (HCV)
• In cancers, viral replication is either diminished or absent; • Hepatitis B virus (HBV) • Human T-cell lymphotropic
active replication would lyse the host cell and prevent
• Human papillomavirus virus-1 (HTLV-1)
tumorigenesis
(HPV)
• The virus exists intracellularly as naked nucleic acid in the
form of a plasmid, episome, or cellular-integrated genome • Human herpesvirus-8
(HHV-8)
• DNA virus genomes can integrate directly into the host
genome • Merkel cell polyomavirus
(MCPyV)
• RNA virus genomes must undergo reverse transcription to
DNA before integration can occur
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Virus Type of cancer

EBV
Human papillomavirus (HPV)
White et al., clinical microbiology reviews, 2014
Burkitt lymphoma, Hodgkin
lymphoma, post-transplant
lymphoproliferative
disorder
(i) Malignant manifestations:
cervical, penile, vulvar, vaginal,
anal, and oropharyngeal carcinoma
(ii) Benign cutaneous manifestations:
common warts (verruca vulgaris),
plantar warts, plane warts,
anogenital warts, and
epidermodysplasia verruciformis
(iii) Benign mucosal manifestations:
oral warts, condylomata, focal
epithelial hyperplasia (Heck’s
disease), nasal and conjunctival
papillomas, laryngeal papillomas,
and cervical lesions
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 Virus
Human herpesvirus-8 (HHV-8)
Merkel cell polyomavirus (MCPyV)
Hepatitis B virus (HBV)
Hepatitis C virus (HCV)
Human T-cell lymphotropic virus-1
(HTLV-1)
Type of cancer
Kaposi sarcoma, multicentric Castleman
disease, primary effusion lymphoma
Merkel cell carcinoma
Liver cancer (hepatocellular carcinoma)
Carcinomas of the head and neck,
biliary duct, bladder, renal, pancreas,
thyroid, breast, and prostate
Peripheral T cell neoplasm adult
T-cell lymphoma (ATLL), polymyositis,
HTLV-1-associated
myelopathy/tropical spastic paraparesis
(HAM/TSP), infective dermatitis
associated with
HTLV-1 (IDH), arthropathy, Sjögren’s
syndrome, facial nerve paralysis
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Targeted and Inhibited pathways
• Tumor suppressor pathways, such as p53 and
retinoblastoma (Rb)
• Tumor necrosis-associated factors (TRAFs)
• Telomerase reverse transcriptase (TERT)
• Cytoplasmic PI3K-AKT-mTOR
• Nuclear factor-B (NF-B)
• β-catenin
• Interferon signaling pathways
• Major histocompatibility class-1 (MHC-1)
• Janus kinase/signal transducer and activator of
transcription (JAK/STAT)
• DNA damage response pathway (DDR)
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How do oncogenic viruses escape the immune

system?
1) Downregulation of the major histocompatibility complex
class I or associated functions: 3) Molecular Mimicry
- MHC presents viral epitopes to cytotoxic CD8+ T cells - virus can elaborate proteins that can evade host immune
for destruction. responses by mimicking aspects of host immune function.
- Many human oncoviruses have evolved mechanisms to
4) Generation of escape mutants
subvert this process.
- Viruses that have an RNA genome or have an RNA
2) Interfering with interferon action replicative intermediate and employ a low-fidelity
- Interferons (IFNs) are cytokines produced and secreted polymerase may generate mutants that are antigenically
by host cells in response to foreign pathogens such as different and thereby evade the immune system
viruses, and they function to communicate between cells
5) Expressing proteins at a very low level
to trigger protective immune defenses.
- Many oncoviruses have adapted mechanisms to escape
the effects of interferon. 51 52

Viral specimens
System Specimen
For Isolation
Respiratory Throat swab, Throat
washings, Aspirates
Central Nervous system Stool, Blood, CSF
Cardio Vascular System Stool, Macular popular
scrapings, ulcer scrapings,
throat swab
Required
For direct examination
Nasopharygeal aspirate
Brain biopsy, CSF
Vesicular/pustular fluid,
Ulcer scraping.

Eye Conjuctival scraping and Conjuctival

swabs scraping/swabs
Gastrointestinal tract Stool, vomit Stool, vomit
Liver Blood Serum
Congenital infections Throat swab, product of NIL
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 Further Reading
• Jawetz, Melnick & Adelberg’s Medical
Microbiology, 26th Edition, chapter 30,
page 431 – 445

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