Viral pathogenesis

Viral pathogenesis is the study of the

process and mechanisms by which
viruses cause diseases in their target
hosts, often at the cellular or molecular
level. It is a specialized field of study in
virology.[1]

Pathogenesis is a qualitative description

of the process by which an initial
infection causes disease.[2] Viral disease
is the sum of the effects of viral
replication on the host and the host's
subsequent immune response against
the virus.[3] Viruses are able to initiate
infection, disperse throughout the body,
and replicate due to specific virulence
factors.[2]

There are several factors that affect

pathogenesis. Some of these factors
include virulence characteristics of the
virus that is infecting. In order to cause
disease, the virus must also overcome
several inhibitory effects present in the
host. Some of the inhibitory effects
include distance, physical barriers and
host defenses. These inhibitory effects
may differ among individuals due to the
inhibitory effects being genetically
controlled.

Viral pathogenesis is affected by various

factors: (1) transmission, entry and
spread within the host, (2) tropism, (3)
virus virulence and disease mechanisms,
(4) host factors and host defense.[4]
Mechanisms of infection
Viruses need to establish infections in
host cells in order to multiply. For
infections to occur, the virus has to hijack
host factors and evade the host immune
response for efficient replication. Viral
replication frequently requires complex
interactions between the virus and host
factors that may result in deleterious
effects in the host, which confers the
virus its pathogenicity.[5]

Important steps of a virus life …

cycle that shape pathogenesis

Typical sites of virus entry into the body: The first

steps of viral infection is determined by the site at
which the virus implants into the body. This would
subsequently dictate the mechanisms of viral
pathogenesis.
Transmission from a host with an
infection to a second host
Entry of the virus into the body
Local replication in susceptible cells
Dissemination and spread to
secondary tissues and target organs
Secondary replication in susceptible
cells
Shedding of the virus into the
environment
Onward transmission to third host
Overview of the main manifestations of viral
infection[6]

Primary transmission …

Three requirements must be satisfied to

ensure successful infection of a host.
Firstly, there must be sufficient quantity
of virus available to initiate infection.
Cells at the site of infection must be
accessible, in that their cell membranes
display host-encoded receptors that the
virus can exploit for entry into the cell,
and the host anti-viral defense systems
must be ineffective or absent.[3][5]

Entry to host …

Viruses causing disease in humans often

enter through the mouth, nose, genital
tract, or through damaged areas of skin,
so cells of the respiratory,
gastrointestinal, skin and genital tissues
are often the primary site of
infection.[2][7][4] Some viruses are capable
of transmission to a mammalian fetus
through infected germ cells at the time of
fertilization, later in pregnancy via the
placenta, and by infection at birth.[2]

Local replication and spread …

Following initial entry to the host, the

virus hijacks the host cell machinery to
undergo viral amplification. Here, the
virus must modulate the host innate
immune response to prevent its
elimination by the body while facilitating
its replication. Replicated virus from the
initially infected cell then disperse to
infect neighbouring susceptible cells,
possibly with spread to different cell
types like leukocytes. This results in a
localised infection, in which the virus
mainly spreads and infects adjacent cells
to the site of entry.[5][7] Otherwise, the
virus can be released into extracellular
fluids. Examples of localised infections
include: common cold (rhinovirus), flu
(parainfluenza), gastrointestinal
infections (rotavirus) or skin infections
(papillomavirus).[2]

Dissemination and secondary

replication
…

In other cases, the virus can cause

systemic disease through a
disseminated infection spread
throughout the body. The predominant
mode of viral dissemination occurs
through the blood or lymphatic system,
some of which include viruses
responsible for chickenpox (varicella
zoster virus), smallpox (variola), HIV
(human immunodeficiency virus). A
minority of viruses can disseminate via
the nervous system.[2][7] Notably, the
poliovirus can be transmitted via the
fecal-oral route, where it initially
replicates in its site of entry, the small
intestine and spread to regional lymph
nodes. Then, the virus disseminates via
the bloodstream into different organs in
the body (e.g. liver, spleen), followed by a
secondary round of replication and
dissemination into the central nervous
system to damage motor neurons.[4]

Shedding and secondary

transmission
…

Finally, the viruses spread to sites where

shedding into the environment can occur.
The respiratory, alimentary and
urogenital tracts and the blood are the
most frequent sites of shedding in the
form of bodily fluids, aerosols, skin,
excrement. The virus would then go on to
be transmitted to another person, and
establish the infection cycle all over
again.[2][4][7]

Factors affecting
pathogenesis
There are a few main overarching factors
affecting viral diseases:

Virus tropism
Virus factors
Host factors

Molecular basis of virus tropism …

Virus tropism refers to the virus’
preferential site of replication in discrete
cell types within an organ. In most cases,
tropism is determined by the ability of
the viral surface proteins to fuse or bind
to surface receptors of specific target
cells to establish infection. Thus, the
binding specificity of viral surface
proteins dictates tropism as well as the
destruction of particular cell populations,
and is therefore a major determinant of
virus pathogenesis.[2][7] However, co-
receptors are sometimes required in
addition to the binding of cellular
receptors on host cells to viral proteins in
order to establish infection. For instance,
HIV-1 requires target cells to express co-
receptors CCR5 or CXCR4, on top of the
CD4 receptor for productive viral
attachment.[8] Interestingly, HIV-1 can
undergo a tropism switch, where the
virus glycoprotein gp120 initially uses
CCR5 (mainly on macrophages) as the
primary co-receptor for entering the host
cell. Subsequently, HIV-1 switches to
bind to CXCR4 (mainly on T cells) as the
infection progresses, in doing so
transitions the viral pathogenicity to a
different stage.[8][9]

Apart from cellular receptors, viral

tropism can also governed by other
intracellular factors, such as tissue-
specific transcription factors. An
example would be the JC polyomavirus,
in which its tropism is limited to glial
cells since its enhancer is only active in
glial cells,[2] and JC viral gene expression
requires host transcription factors
expressed exclusively in glial cells.[9]
The accessibility of host tissues and
organs to the virus also regulates
tropism. Accessibility is affected by
physical barriers,[2][7] such as in
enteroviruses, which replicate in the
intestine since they are able to withstand
bile, digestive enzymes and acidic
environments.[9]

Virus factors …

Viral genetics encoding viral factors will

determine the degree of viral
pathogenesis. This can be measured as
virulence, which can be used to compare
the quantitative degree of pathology
between related viruses. In other words,
different virus strains possessing
different virus factors can lead to
different degrees of virulence, which in
turn can be exploited to study the
differences in pathogenesis of viral
variants with different virulence.[10][11]

Virus factors are largely influenced by

viral genetics, which is the virulence
determinant of structural or non-
structural proteins and non-coding
sequences. For a virus to successfully
infect and cause disease in the host, it
has to encode specific virus factors in its
genome to overcome the preventive
effects of physical barriers, and
modulate host inhibition of virus
replication.[2][10] In the case of poliovirus,
all vaccine strains found in the oral polio
vaccine contain attenuating point
mutations in the 5' untranslated region
(5' UTR). Conversely, the virulent strain
responsible for causing polio disease
does not contain these 5’ UTR point
mutations and thus display greater viral
pathogenicity in hosts.[1][12]

Virus factors encoded in the genome

often control the tropism, routes of virus
entry, shedding and transmission. In
polioviruses, the attenuating point
mutations are thought to induce a
replication and translation defect to
reduce the virus’ ability of cross-linking to
host cells and replicate within the
nervous system.[12]
Viruses have also developed a variety of
immunomodulation mechanisms to
subvert the host immune response. This
tend to feature virus-encoded decoy
receptors that target cytokines and
chemokines produced as part of the host
immune response, or homologues of
host cytokines.[13][14] As such, viruses
capable of manipulating the host cell
response to infection as an immune
evasion strategy exhibit greater
pathogenicity.
Host factors …

Viral pathogenesis is also largely

dependent on host factors. Several viral
infections have displayed a variety of
effects, ranging from asymptomatic to
symptomatic or even critical infection,
solely based of differing host factors
alone. In particular, genetic factors, age
and immunocompetence play an
important role is dictating whether the
viral infection can be modulated by the
host.[11][15] Mice that possess functional
Mx genes encode an Mx1 protein which
can selectively inhibit influenza
replication. Therefore, mice carrying a
non-functional Mx allele fail to
synthesise the Mx protein and are more
susceptible to influenza infection.[16]
Alternatively, immunocompromised
individuals due to existing illnesses may
have a defective immune system which
makes them more vulnerable to damage
by the virus. Furthermore, a number of
viruses display variable pathogenicity
depending on the age of the host.
Mumps, polio, and Epstein-Barr virus
cause more severe disease in adults,
while others like rotavirus cause more
severe infection in infants. It is therefore
hypothesized that the host immune
system and defense mechanisms might
differ with age.[10]

Disease mechanisms: How

do viral infections cause
disease?
A viral infection does not always cause
disease. A viral infection simply involves
viral replication in the host, but disease is
the damage caused by viral
multiplication.[5] An individual who has a
viral infection but does not display
disease symptoms is known as a
carrier.[17]

Mechanisms by which viruses cause damage and

disease to host cells
Damage caused by the virus …

Once inside host cells, viruses can

destroy cells through a variety of
mechanisms. Viruses often induce direct
cytopathic effects to disrupt cellular
functions.[11][18] This could be through
releasing enzymes to degrade host
metabolic precursors, or releasing
proteins that inhibit the synthesis of
important host factors, proteins, DNA
and/or RNA.[13] Namely, viral proteins of
herpes simplex virus can degrade host
DNA and inhibit host cell DNA replication
and mRNA transcription.[9] Poliovirus can
inactivate proteins involved in host
mRNA translation without affecting
poliovirus mRNA translation. In some
cases, expression of viral fusion proteins
on the surface of the host cells can
cause host cell fusion to form
multinucleated cells. Notable examples
include measles virus, HIV, respiratory
syncytial virus.[2][13]
The "lifestyle" strategies of viruses in host cells.

Acute infections tend to occur for a relatively short

duration, while persistent infections are when the
virus is not completely cleared from the body. In
latent infections, reactivation of disease may occur
a long time after the initial infection.

Importantly, viral infections can differ by

the “lifestyle strategy”. Persistent
infections happen when cells continue to
survive despite a viral infection and can
be further classified into latent (only the
viral genome is present, there is no
replication occurring) and chronic (basal
levels of viral replication without
stimulating an immune response). In
acute infections, lytic viruses are shed at
high titres for rapid infection to a
secondary tissue/host, whereas
persistent viruses undergo shedding at
lower titres for a longer duration of
transmission (months to years).[1][2][19]

Lytic viruses are capable of destroying

host cells by incurring and/or interfering
with the specialised functions of host
cells. An example would be the triggering
of necrosis in host cells infected with the
virus.[18] Otherwise, signatures of viral
infection, like the binding of HIV to co-
receptors CCR5 or CXCR4, can also
trigger cell death via apoptosis through
host signalling cascades by immune
cells.[20] However, many viruses encode
proteins that can modulate apoptosis
depending on whether the infection is
acute or persistent. Induction of
apoptosis, such as through interaction
with caspases, will promote viral
shedding for lytic viruses to facilitate
transmission, while viral inhibition of
apoptosis could prolong the production
of virus in cells, or allow the virus to
remain hidden from the immune system
in chronic, persistent infections.[9][11][18]
Nevertheless, induction of apoptosis in
major immune cells or antigen-
presenting cells may also act as a
mechanism of immunosuppression in
persistent infections like HIV. The
primary cause of immunosuppression in
HIV patients is due to the depletion of
CD4+ T helper cells.[4]

Interestingly, adenovirus has an E1A

protein to induce apoptosis by initiating
the cell cycle, and an E1B protein to block
the apoptotic pathway through inhibition
of caspase interaction.[21]

Persistent viruses can sometimes

transform host cells into cancer
cells.[15][22][18] Viruses such as the human
papillomavirus (HPV), human T-
lymphotropic virus (HTLV) etc, can
stimulate growth of tumours in infected
hosts, either by disrupting tumour
suppressor gene expression (HPV) or
upregulating proto-oncogene expression
(HTLV).[15]

Damage caused by host immune

system
…

Sometimes, instead of cell death or

cellular dysfunction caused by the virus,
the host immune response can mediate
disease and excessive inflammation. The
stimulation of the innate and adaptive
immune system in response to viral
infections destroys infected cells, which
may lead to severe pathological
consequences to the host. This damage
caused by the immune system is known
as virus-induced immunopathology.[23][24]

Specifically, immunopathology is caused

by the excessive release of antibodies,
interferons and pro-inflammatory
cytokines, activation of the complement
system, or hyperactivity of cytotoxic T
cells. Secretion of interferons and other
cytokines can trigger cell damage, fever
and flu-like symptoms.[23][24] In severe
cases of certain viral infections, as in
avian H5N1 influenza in 2005, aberrant
induction of the host immune response
can elicit a flaring release of cytokines
known as a cytokine storm.[25]

In some instances, viral infection can

initiate an autoimmune response, which
occurs via different proposed
mechanisms: molecular mimicry and
bystander mechanism.[26] Molecular
mimicry refers to an overlap in structural
similarity between a viral antigen and a
self-antigen.[26] The bystander
mechanism hypothesizes the initiation of
a non-specific and overreactive antiviral
response that tackles self-antigens in the
process.[26] Damage caused by the host
itself due to autoimmunity was observed
in the West Nile virus.[27]

Incubation Period
Viruses display variable incubation
periods upon virus entry into the host.
The incubation period refers to the time
taken for the onset of disease after first
contact with the virus.[2][7] In Rabiesvirus,
the incubation period varies with the
distance traversed by the virus to the
target organ; but in most viruses the
length of incubation depends on many
factors.[7][28] Surprisingly, generalised
infections by togaviruses have a short
incubation period due to the direct entry
of the virus into target cells through
insect bites.[7]

There are several other factors that

affect the incubation period. The
mechanisms behind long incubation
periods, months or years for example, are
not completely understood yet.[28]

Evolution of virulence
Some relatively avirulent viruses in their
natural host show increased virulence
upon transfer to a new host species.
When an emerging virus first invades a
new host species, the hosts have little or
no immunity against the virus and often
suffer high mortality. Over time, a
decrease in virulence in the predominant
strain can sometimes be observed. A
successful pathogen needs to spread to
at least one other host, and lower
virulence can result in higher
transmission rates under some
circumstances. Likewise, genetic
resistance against the virus can develop
in a host population over time.[2][29]

An example of the evolution of virulence

in emerging virus is the case of
myxomatosis in rabbits. The release of
wild European rabbits in 1859 into
Victoria, Australia for sport resulted in a
rabbit plague. In order to curb with rabbit
overpopulation, myxoma virus, a lethal
species-specific poxvirus responsible for
myxomatosis in rabbits, was deliberately
released in South Australia in 1950. This
led to a 90% decrease in rabbit
populations, and the disease became
endemic in a span of five years.
Significantly, severely attenuated strains
of the myxoma virus were detected in
merely 2 years of its release, and genetic
resistance in rabbits emerged within
seven years.[30]
See also
Virology
Glossary of virology
Pathogen
Pathogenesis
List of human diseases associated
with infectious pathogens

References
1. Nathanson, Neal (2016-01-04). Viral
pathogenesis . Lippincott-Raven.
p. 2016 . ISBN 9780128011744.
2. Albrecht, Thomas; Fons, Michael;
Boldogh, Istvan; Rabson, Alan S.
(1996-01-01). Baron, Samuel (ed.).
Medical Microbiology (4th ed.).
Galveston (TX): University of Texas
Medical Branch at Galveston.
ISBN 0963117211. PMID 21413282 .
3. Racaniello, Vincent. "Viral
Pathogenesis" (PDF). Retrieved
8 February 2014.
4. Kenneth J Ryan; C George Ray, eds.
(2014). "Chapter 7 Viral
Pathogenesis". Sherris Medical
Microbiology (6 ed.).
5. Stephen A. Morse, Stefan Riedel,
Timothy A. Mietzner, Steve Miller
(2019-08-25). Jawetz Melnick &
Adelbergs Medical Microbiology 28E.
McGraw-Hill Education.
ISBN 9781260012033.
 . Chapter 33 (Disease summaries), pp.
367–92 in:Lippincott's Illustrated
Reviews: Microbiology. Hagerstwon,
MD: Lippincott Williams & Wilkins;
2007. (Lippincott's Illustrated
Reviews Series). ISBN 978-0-7817-
8215-9. p. 367–92.
7. Mitchell, Maika G. (2010-04-16).
Molecular Pathology and the
Dynamics of Disease . Academic
Press. ISBN 978-0-12-814610-1.
 . Shen, H., Yin, J., Leng, F. (2016). "HIV
coreceptor tropism determination
and mutational pattern
identification" . Scientific Reports. 6.
9. Kumar, Vinay; Abbas, Abul K.; Aster,
Jon C., eds. (2014). Robbins & Cotran
Pathologic Basis of Disease (9 ed.).
Elsevier. ISBN 9780323313094.
10. Cann, Alan (2016-01-04). Jawetz,
Melnick, & Adelberg’s Medical
Microbiology (28 ed.). Elsevier.
p. [1] . ISBN 9780128011744.
11. Fuentes-González AM, Contreras-
Paredes A, Manzo-Merino J, Lizano
M (2013). "The modulation of
apoptosis by oncogenic viruses".
Virology Journal. 10.
doi:10.1186/1743-422X-10-182 .
12. Gutiérrez AL (1997). "Attenuating
Mutations in the Poliovirus 5"
Untranslated Region Alter Its
Interaction with Polypyrimidine Tract-
Binding Protein" (PDF). Journal of
Virology. 71: 3826–3833.
13. MacLachlan, James; Dubovi, Edward
(2011). Fenner's Veterinary Virology
(4th ed.). Elsevier.
ISBN 9780123751584.
14. Felix, J., Savvides, S. (2017).
"Mechanisms of immunomodulation
by mammalian and viral decoy
receptors: insights from structures" .
Nature Reviews Immunology. 17:
112–129.
15. Nigel J. Dimmock; Andrew J. Easton;
Keith N. Leppard, eds. (2016).
Introduction to modern virology (7
ed.). John Wiley & Sons Ltd.
ISBN 9781119978107.
1 . Staeheli P, Grob R, Meier E, Sutcliffe
JG, Haller O (1988). "Influenza virus-
susceptible mice carry Mx genes
with a large deletion or a nonsense
mutation". Molecular Cell Biology. 8.
doi:10.1128/mcb.8.10.4518 .
17. Furuya-Kanamori L, Cox M, Milinovich
GJ, Magalhaes RJ, Mackay IM, Yakob
L (June 2016). "Heterogeneous and
Dynamic Prevalence of
Asymptomatic Influenza Virus
Infections" . Emerging Infectious
Diseases. 22 (6): 1052–6.
doi:10.3201/eid2206.151080 .
PMC 4880086 . PMID 27191967 .
1 . Alan Cann (2015). Principles of
Molecular Virology (6 ed.). Academic
Press. ISBN 9780128019559.
19. S. Jane Flint, Vincent R. Racaniello,
Glenn F. Rall, Anna Marie Skalka,
Lynn W. Enquist (2015). Principles of
Virology, 4th Edition (4th ed.). ASM
Press. ISBN 978-1-555-81933-0.
20. Barbara Ahr, Véronique Robert-
Hebmann, Christian Devaux &
Martine Biard-Piechaczyk (2004).
"Apoptosis of uninfected cells
induced by HIV envelope
glycoproteins" . Retrovirology. 12.
21. Eileen White (1998). "Regulation of
Apoptosis by Adenovirus E1A and
E1B Oncogenes" . Seminars in
Virology. 8: 505–513.
22. Walther Mothes; Nathan M. Sherer
(2010). "Virus Cell-to-Cell
Transmission". Journal of Virology.
17. doi:10.1128/JVI.00443-10 .
23. Barry T.Rouse (1996). "Virus-Induced
Immunopathology" . Advances in
Viral Research. 47: 353–376.
24. Barry T.Rouse, Sharvan Sehrawat
(2010). "Immunity and
immunopathology to viruses: what
decides the outcome?" . Nature
Reviews Immunology. 10: 514–526.
doi:10.1038/nri2802 .
PMC 3899649 .
25. Tisoncik JR, Korth MJ, Simmons CP,
Farrar J, Martin TR, Katze MG (2012).
"Into the Eye of the Cytokine Storm".
Microbiology and Molecular Biology
Reviews. 76: 3826–3833.
doi:10.1128/MMBR.05015-11 .
2 . Smatti MK, Cyprian FS, Nasrallah GK,
Al Thani AA, Almishal RO, Yassine
HM (2019). "Viruses and
Autoimmunity: A Review on the
Potential Interaction and Molecular
Mechanisms". Viruses. 8.
doi:10.3390/v11080762 .
27. Hawkes Maximiliano A., Hocker Sara
E., Leis A. Arturo (2018). "West Nile
virus induces a post-infectious pro-
inflammatory state that explains
transformation of stable ocular
myasthenia gravis to myasthenic
crises" . Journal of the Neurological
Sciences. 395: 1–3.
2 . Nelson Kenrad E., Williams Carolyn
Masters (2013). Infectious Disease
Epidemiology: Theory and Practice (3
ed.). Jones & Bartlett Learning.
ISBN 978-1-44-968379-5.
 29. Benjamin M Bolker, Dharmini Shah
(2010). "Transient virulence of
emerging pathogens" . Journal of the
Royal Society Interface. 7: 811–822.
doi:10.1098/rsif.2009.0384 .
PMC 2874237 .
30. Peter J Kerr (2012). "Myxomatosis in
Australia and Europe: A model for
emerging infectious diseases" .
Antiviral Research. 93: 387–415.

Retrieved from
"https://en.wikipedia.org/w/index.php?
title=Viral_pathogenesis&oldid=966246227"

Last edited 3 days ago by JCW-CleanerBot

Content is available under CC BY-SA 3.0 unless

otherwise noted.