MICROBIOLOGY PATHOGENESIS AND CONTROL OF VIRAL DISEASES

AY 2019-2020 Josefina C. Chua, MD

2nd Sem Prelim February 24, 2020

PRINCIPLE OF VIRAL DISEASES • Entry and Primary Replication

● The fundamental process of viral infection is the viral • Viral Spread and Cell Tropism
replicative cycle • Cell Injury and Clinical Illness
● Viral disease
→ Viral infection of host organism • Recovery from Infection
● Clinical disease • Virus Shedding
→ Overt signs and symptoms ENTRY AND PRIMARY REPLICATION
● Syndrome
→ Specific group of signs and symptoms

● Inapparent (subclinical)

→ Viral infections that fail to produce any symptoms in

the host.

Principles that pertain to viral disease

1. Many viral infections are subclinical
2. The same disease may be produced by variety of
viruses
3. The same viruses may produce variety of diseases
4. The disease produced bears no relationship to viral
morphology
5. The outcome in any particular case is determined
by both viral and host factors and is influenced by the
genetics of each • Virus must first attach to and enter cells of one of the
body surfaces
Viral pathogenesis ® Exception HIV and arbovirus
® Process that occurs when virus infects the host. • Viruses usually replicate at the primary site of entry,
produce disease at the portal of entry and likely
Disease pathogenesis have no necessity for further systemic spread
® Subset of events during an infection that results in ® Example influenza viruses (respiratory infections)
disease manifestation in the host. and noroviruses (gastrointestinal infections),
• They spread locally over epithelial surfaces but there are
A virus is pathogenic for a particular host if it can infect no spread to distant sites.
and cause signs of disease in that host.
A strain of a certain virus is more virulent than another
strain if it commonly produces more severe disease in
a susceptible host.

PATHOGENESIS OF VIRAL DISEASES

Steps in Viral Pathogenesis VIRAL SPREAD AND TROPHISM

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• Many viruses produce disease at site distant from their
point of entry.
• After primary replication at the site of entry, these viruses
then spread within the host.
• MECHANISM OF VIRAL SPREAD MY VARY
® Most common- Bloodstream or lymphatics.
• VIREMIA
® The presence of virus in the blood.
• Viremic phase is short in many viral infections
• VIRIONS MAYBE:
® free in the plasma (eg, enteroviruses,
togaviruses)
® associated with particular cell types (eg,
measles virus)
• NEURONAL SPREAD:
® Rabies and herpes simplex virus ( latent
infection)
• Viruses tend to exhibit organ and cell specificities
® Tropism determines the pattern of systemic
illness produced during a viral infection (hepatitis
b virus with liver hepatocytes)
• Tissue and cell tropism by a given virus usually reflect the
presence of specific cell surface receptors for that virus
• Receptors are components of the cell surface with which
a region of the viral surface (capsid or envelope) can
specifically interact and initiate infection
Necessary step to maintain a viral infection in populations
of hosts
Usually occurs from body surfaces involved in viral entry
It represents the time at which an infected individual is
infectious to contacts
 Shedding does not occur dead-end infections such as
rabies
HOST IMMUNE RESPONSE
• The most prominent among the innate immune
responses is the induction of IFN
• These responses help inhibit viral growth during the time
it takes to induce specific humoral and cell-mediated
immunity
• Both humoral and cellular components of the immune
responses are involved in control of viral infections
• Virus-encoded proteins serve as targets for the immune
response
• Virus infected cells may be lysed by cytotoxic T
lymphocytes as a result of recognition of viral
polypeptides on the cell surface
• Humoral immunity protects the host against reinfection of
the same virus
• Neutralizing antibody directed against capsid proteins
blocks the initiation of viral infection
• Secretory IgA antibody is important in protecting against
infection of viruses through the respiratory or GI tracts
• Some viruses infect and damage the cells of the immune
system
• Host susceptibility and response to infection are
genetically determined

CELL INJURY AND CLINICAL ILLNESS

• Destruction of virus-infected cells in the target tissues and
physiologic alterations produced in the host by the tissue
injury are partly responsible for the development of
disease
® Some tissues can rapidly regenerate and
withstand extensive damage than others
® Some physiologic effect may result from
nonlethal impairment of specialized functions of
cells
• Clinical illness from viral infection is the result of a
complex series of events and many of the factors that
determine degree of illness is unknown
• Clinical illness is an insensitive indicator of viral infection

RECOVERY FROM INFECTION

• Host either succumbs or recovers
• Recovery mechanism (innate and adaptive immune
response)
 IFN, other cytokines, humoral and cell-
mediated immunity
• The genetic basis of host susceptibility remains to be
determined for most infections
• In acute infections, recovery is associated with viral
clearance

Virus Shedding
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• Viruses have evolved a variety of ways that serve to  demonstration of a rise in

suppress or evade the host immune response and thus antibody titer
avoid being eradicated • The specific viral disease can be deduced by
 Major symptoms

VIRAL PERSISTENCE: CHRONIC AND LATENT

INFECTION
• CHRONIC (PERSISTENT) INFECTIONS
 Those in which replicating virus can be continuously
detected, often at low levels.
 Mild or no clinical symptoms
 Rubella, CMV, hepatitis B
 Cancer, degenerative disease of CNS
 Spongiform encephalitis
• LATENT INFECTIONS
 Virus persists in an occult form most of the time when
no new virus is produced
 Intermittent flare-ups of clinical disease
 herpesvirus

LATENT INFECTION BY HERPES SIMPLEX VIRUS

 patient’s age
 Time of year
 Pattern of illness in the community

OVERIVIEW OF VIRAL INFECTIONS OF THE

GI TRACT
• HSV and EBV infect cells in the mouth.
• Viruses able to initiate infection are all resistant to acid and
bile salts.
• AGE (rotavirus, noroviruses and caliciviruses)
• Enteroviruses, coronaviruses, adenoviruses
 Often asymptomatic
• Polioviruses and hepatitis A
 Systemic disease but no intestinal symptoms

OVERVIEW OF VIRAL INFECTIONS OF THE SKIN

Route of Entry
• Abrasions of the skin
 Poxvirus
 Papillomaviruses
 HSV
• Bite of arthropod or infected host
 Arbovirus
 Rabies virus
OVERVIEW OF ACUTE RESPIRATORY INFECTIONS  Hepatitis B
• Successful infection occurs despite normal host protective • Injected through blood transfusion or through
mechanism ( mucus covering most surfaces, ciliary action, contaminated needles
collection of lymphoid cells, alveolar macrophages,  Hepatitis B
secretory IgA)  HIV
• Definitive diagnosis • A few agents remain localized and produced lesions at
 isolation of the virus the site of entry (papillomavirus and molluscum
 identification of viral gene contagiosum).
sequence • Most spread to other site.
• Viruses that infect the epidermis cells tend to localize.
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• Viruses introduced into the dermis usually spread and • SUBACUTE SPONGIFORM ENCEPHALOPATHIES
cause systemic infections.  Scrapie
 Characteristic neuropathologic changes occur but no
inflammatory of immune response is elicited
• Skin rashes with viral infections develop because virus
spreads to the skin via the bloodstream after replication OVERVIEW OF CONGENITAL VIRAL INFECTIONS
at some other site. Principles in the production of congenital defects
 Macules – local dilatation of dermal blood vessels • The ability of the virus to infect the pregnant woman and
 Papule – with edema and cellular infiltration be transmitted to the fetus
 Vesicles – epidermis is involved • The stage of gestation at which the infection occurs
 Pustules – inflammatory reaction delivers PMN to the • The ability of the virus to cause damage to the fetus
lesion. directly (by infection of the fetus) or indirectly(by infection
 Ulceration and Scabbing of the mother), resulting in altered fetal environment .
 Hemorrhagic and petechial rash – severe
involvement of the dermal vessels
• Skin lesions frequently play no role in viral transmission.
(measles and arbovirus)
• Skin lesions are important in the spread of poxvirus and
HSV
 Infectious virus particles are present in high titers in
the fluid of these vesiculopustular rashes and they are
able to initiate infection by direct contact with other
hosts

OVERVIEW OF VIRAL INFECTIONS OF THE

CNS
• HEMATOGENOUS SPREAD
 growth through the endothelium of small cerebral Figure 2 Acquision of significant perinatal infections
vessels
 passive transport across the vascular endothelium,
 passage through the choroid plexus to the CSF VIRAL INFECTION OF THE FETUS
 transport within infected monocyte, leukocyte or
lymphocyte
• NEURONAL SPREAD (VIA PERIPHERAL NERVES)
 Virus can be taken up by sensory nerve or motor
endings and be moved within axons, through
endoneural spaces, or by Schwann cell infection
 Herpesvirus travel in axons to be delivered to dorsal
root ganglia neurons
• Encephalitis caused by HSV is the most common cause of
sporadic encephalitis in humans
• Pathologic reactions to cytocidal viral infection of the CNS
 Necrosis
 Inflammation
 Phagocytosis by glial cells
• Cause of symptoms for rabies is unclear
• Postinfectious encephalitis – characterized by
demyelination without neuronal degeneration and is
probably autoimmune.

• SLOW VIRUS INFECTION

 Long incubation period followed by onset of clinical
illness and progressive deterioration resulting on
death in weeks to months.
 Progressive multifocal leukoencephalopathy (JC
polyomavirus). EFFECTS OF THE HOST
 Causes common, asymptomatic, chronic • More severe disease – NB
infections that are normally controlled by an • Age-related changes in susceptibility of certain cell types
intact immune system. to infection
 Subacute panencephalitis (measles virus) • Rubella – most serious during gestation
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• Rotavirus – infants • AMANTADINE AND RIMANTADINE

• St. Louis encephalitis – elderly adults  Specifically inhibit influenza A viruses by blocking viral
uncoating

• Viruses are obligate intracellular parasite PREVENTION AND TREATMENT OF VIRAL

 Antiviral agents must be capable of INFECTION
selectively inhibiting viral functions without damaging the  Administered prophylactically
host • FOSCARNET
 Many rounds of virus replication occur during the  Selectively inhibits viral DNA polymerase and reverse
incubation period and the virus has spread before the transcriptase at the pyrophosphate binding site
symptoms appear, making the drug relatively
ineffective.
• METHISAZONE
ANTIVIRALS  Inhibitor of poxvirus
• Used to treat established infections when vaccines would  Blocked a late stage in viral replication,
not be effective resulting in the formation of immature noninfectious virus
• Needed to reduce morbidity and economic loss caused by particles
viral infection
• Treat increasing numbers of immunosuppressed patients INTERFERONS
wo are at risk of infection • Host-coded proteins that are members of the large
cytokine family and that inhibit viral replication.
TARGETS OF ANTIVIRAL THERAPY • Produced very quickly in response to a viral
• Attachment of virus to host cells infection
• Uncoating of the viral genome
• One of the body’s first responders in the defense
• Viral nucleic acid synthesis
against viral infection.
• Translation of viral proteins
• Assembly and release of progeny virus particles
• In reality, it has been very difficult to develop antivirals that
can distinguish viral from host replicative processes

ANTIVIRAL CHEMOTHERAPY
• Nucleoside and Nucleotide Analogs
• Reverse Transcriptase Inhibitors
• Protease Inhibitors
• Other types of Antiviral Agents

NUCLEOSIDE AND NUCLEOTIDE ANALOGS

• Inhibit nucleic acid replication by inhibition of polymerases
essential for nucleic acid replication
• Some analogs can be incorporated into the nucleic acid
and block further synthesis or alter its function
• The most effective analogs are those that are able to
significantly inhibit virus-encoded enzymes, with minimal
inhibition of analogous
• The use of combinations of antiviral drugs can delay the
emergence of resistant variants
• Acyclovir, lamivudine, ribavirine, vidarabine,zidovudine
• Nucleotide analogs
 attached phosphate group
• Central to the innate antiviral immune response
 Ability to persist in cells for long periods of time
• Modulate humoral and cellular immunity and have
increases their potency
broad cell growth regulatory activities.
 Cidofovir
Properties of Interferons
REVERSE TRANSCRIPTASE
• NEVIRAPINE SYNTHESIS OF INTERFERON
 It acts by binding directly to reverse transcriptase and • Normal cells do not generally synthesize IFN until they are
disrupting the enzyme’s catalytic site induced to do so.
 Resistant mutant emerge rapidly • Infection with viruses is a potent insult leading to induction
(RNA > DNA).
OTHER TYPES • IFN-γ not produced in response to most viruses but is
• FUZEON induced by mitogen stimulation.
 large peptide that blocks the virus and cellular membrane • IFN-γ is produced mainly by lymphocytes (T and NK cell).
fusion step involved in entry of HIV-1 into cells
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ANTIVIRAL ACTIVITY AND OTHER BIOLOGIC

EFFECTS
• IFNs were first recognized by their ability to interfere with
viral infection in cultured cells
• IFN plays a primary role in the nonspecific defense of the
host against viral infections
 Agammaglobulinemic individuals usually
recover from primary viral infections about as well as
normal people
• IFN does not protect the virus-infected cell that produces it
• IFN is not the antiviral agent
• IFN moves to other cells, where it induces an antiviral
state by prompting the synthesis of other proteins that
actually inhibit viral replication
• Receptor binding triggers tyrosine phosphorylation and
activation of transcription factors (STAT [signal transducer
and activator of transcription] proteins) in the cytoplasm
which translocate into the nucleus and mediate
transcription of IFN-inducible genes.
• Results in the synthesis of several enzymes believed to be
instrumental in the development of antiviral state.

ANTIVIRAL ACTIVITY AND OTHER BIOLOGIC

EFFECTS
Pathways
1. A dsRNA-dependent protein kinase (PKR) which
phosphorylates and inactivates cellular initiation factor eIF-
2 and thus prevents formation of the initiation complex
needed from viral synthesis
2. An oligonucleotide synthetase (2-5A synthetase) which
activates a cellular endonuclease(Rnase L) which in turn
degrade mRNA
3. A phosphodiesterase which inhibits peptide chain
elongation
4. Nitric oxide synthetase which is induced by IFN-γ
 Fail to reveal why the antiviral state acts
selectively against viral mRNA and not cellular
mRNA

VIRUS MECHANISM TO COUNTERACT INTERFERON

• Specific viral proteins may block induction of expression of
IFN (herpesvirus, papillomavirus, filovirus, hepatitis C
virus, rotavirus)
• May block the activation of the key PKR protein kinase
( adenovirus, herpesvirus)
• May activate cellular inhibitor of PKR (infuenza, poliovirus)
• May block IFN-induced signal transduction(adenovirus,
herpesvirus, hepatitis B virus)
• May neutralize IFN-γ by acting as a soluble IFN receptor
(myxoma virus)

CLINICAL STUDIES
• Recombinant IFN-α is beneficial in controlling hepatitis B
and hepatitis C viral infections of the liver although relapse
after cessation of treatment is common.
• Topical IFN in the eye may suppress herpetic keratitis and
accelerate healing.

VACCINES
• Serum and secretory antibody response to orally
administered, live attenuated polio vaccine to
intramuscular inoculation of killed polio vaccine
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TABLE CHARACTERISTICS OF VACCINE

Figure 3 MECHANISM OF SPREAD OF VIRUS

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Figure 4 DIAGNOSIS OF VIRAL INFECTION