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Pathobiology of Dengue Virus Infection
Fadel Muhammad Garishah
Pathobiology of Infectious Diseases
Faculty of Medicine DIPONEGORO UNIVERSITY
2014
Clinical Vignette
A 5 years-old boy was referred from a public health centerto general hospital due to a rapidly decreasing of platelets.
The previous 3 days he experienced fever up to 38,9 C, hedidn’t have any URT/LRT infection or Urinary tractsymptoms, no neurological deficits.
Currently his body temperature is 36,7 C, with coldextremities.
Previous labwork showing a rapidly decreasing plateletscount from 102,000/mL and now 45,000/mL.
The GP in PHC referred the patient due to the prediction offalling into severe shock.
Original Case from Emergency Department General Hospital
Nature Reviews | Microbiology
Vascular symptoms:HypovolaemiaLow blood pressureShock
Hepatic injuryFluid pooling in body cavitiesGall bladder thickeningHaemorrhaging within organs
Infrequent complications:EncephalitisAcute pancreatitisRenal failureMyocarditisSplenic rupturePulmonary haemorrhage
Vascular symptoms:LeukopeniaThrombocytopeniaNeutropeniaLate eosinophiliaReduced coagulation
Skin symptoms:RashBruisingPetechiaePurpura
Joint pain
Altered haematopoiesis
Bleeding gums, nose and eyes
Headache, fever
VomitingIntestinal bleeding
pro-inflammatory response that is detectable
in the serum of patients with dengue32, it has
been postulated that immune factors act as
intermediaries in the response of endothe-
lial cells to DENV. In particular, cytokine
storm (elevated levels of many cytokines in
the serum) has been identified as a poten-
tial underlying mechanism of vascular
pathology21.
During DENV infection, copious amounts
of certain pro-inflammatory and vaso active
cytokines, including TNF and vascular
endothelial growth factor A (VEGFA), are
produced32. However, although these fac-
tors are frequently elevated in the serum
of patients with dengue, some studies have
raised questions about their direct role in
dengue pathology. For example, in spite of
the well-established role of TNF in promot-
ing vascular leakage in other diseases and
experimental contexts33,34, there has been no
clear correlation shown between levels of
TNF and the manifestation of dengue fever
versus DHF–DSS in humans. Some evidence
has been obtained for there being both lower
expression of TNF receptors on granulo-
cytes during DHF–DSS35 and an association
between DHF–DSS and certain TNF poly-
morphisms12. In one study, serum TNF
was elevated during both DHF–DSS and
dengue fever compared with levels in healthy
controls, but a significant difference in TNF
levels between DHF–DSS and dengue fever
groups was not detected36. Thus, it is possible
that TNF has a role in DENV infection, but
whether it is (or can be, in some instances)
a significant cause of DHF–DSS in humans
is still unclear. Multiple pro-inflammatory
factors might act in concert to promote
vasculopathy.
Drawbacks of in vitro analysis. Ultimately,
the mechanisms of many of the immune
changes that occur in response to DENV
infection, and the roles of these immune
changes in protection versus pathology, are
not yet explained. Unfortunately, the com-
plexity of the interactions between DENV
and the host cannot be adequately modelled
by in vitro manipulation of human cells and
biological products outside the organs and
systems that govern their responses to infec-
tion. Not only are the specific target cells of
DENV not clearly known, but also in vitro
analysis does not capture the responses
of cells that do not become infected but
might nonetheless respond to DENV and
to the inflammatory products in their
microenviron ment in vivo. As a further
complication, interactions between DENV
and host cells can change over the course of
infection, which begins as a localized cuta-
neous infection with innate immune activa-
tion and develops into a systemic infection
characterized by viral replication in target
organs (including the lymphoid system) and
high viral titres in the blood19. The most
severe pathologies associated with DENV
infection frequently manifest in patients
as viraemia resolves and fever begins to
subside27, but it is unclear at what stage of
infection these pathological processes are
initiated.
The role of immunological memory
Primary DENV infection results in long-
lasting immunity to the infecting serotype
and, potentially, partial immunity to subse-
quent infection with other serotypes. Many
individuals in dengue-endemic countries
have experienced DENV infection previ-
ously. Re-infection with the same serotype
as that which caused the primary infection
has not been documented, demonstrating
that immunity to a homologous DENV
strain can be highly protective and lifelong5.
Pre-existing neutralizing antibodies must
have a major role in preventing subsequent
infection with the same DENV serotype.
Secondary infection with a heterologous
serotype can cause a broad spectrum of
illnesses, ranging from asymptomatic infec-
tion to severe haemorrhagic disease. For
example, some epidemiological studies have
shown that patients with a secondary DENV
infection and babies born to mothers who
have previously been infected with DENV
are more likely to develop severe disease37,38.
One theory for why this occurs was first
described in reference to other flaviviruses
(Murray Valley encephalitis virus, West Nile
virus and Japanese encephalitis viruses)39
and is termed antibody-dependent enhance-
ment of infection (ADE). ADE involves
the binding of immune complexes of non-
neutralizing antibody and infectious virus
to the Fc receptors of immune cells29,40,41
Figure 1 | Dengue virus pathogenesis in humans. Systemic infection with dengue virus (DENV)
affects multiple organ systems. This diagram depicts the clinical symptoms and pathogenesis of
dengue in humans, across the spectrum of mild to severe disease. Clinical manifestations associated
with dengue fever are listed in blue boxes, those associated with dengue haemorrhagic fever are listed
in purple boxes, and more rare complications of DENV infection are listed in the green box.
PERSPECTIVES
NATURE REVIEWS | MICROBIOLOGY ADVANCE ONLI NE PUBLI CATI ON | 3
© 2013 Macmillan Publishers Limited. All rights reserved
Clinical Manifestations ofDENV Infection
John ALS, Abraham SN, Gubler DJ.Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesisNature Reviews Microbiology 11, 420–426 (2013)
Available from: http://www.nature.com/nrmicro/journal/v11/n6/full/nrmicro3030.html
Geographical Distribution of Dengue Virus Infection
Distributed in the tropics and subtropics, data shown as dengue infection (DF, and DHF) cases
Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine. Nature Reviews Microbiology 5, 518-528 (1 July 2007)
Available from: http://www.nature.com/nrmicro/journal/v5/n7/full/nrmicro1690.html
How dengue is transmitted?
Because of the high level of viraemia resulting from dengue virus (DENV) infection of humans, the viruses are efficiently transmitted between mosquitoes and humans without the need for an enzootic amplification host.
Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine. Nature Reviews Microbiology 5, 518-528 (1 July 2007)
Available from: http://www.nature.com/nrmicro/journal/v5/n7/full/nrmicro1690.html
Key of pathophysiology
What causes the vascular leakage?• Direct platelet/endothelial damage?• Immune mediated platelet/endothelial damage?
Picture taken from Kumar V et al. Robbin’s Pathologic Basis of Disease 8th Edition. 2011. Philadelphia: Elsevier Saunders
What causes what?
How DENV enter patient’s body?
Diamond, M. S. Evasion of innate and adaptive immunity by flaviviruses. Immunology and Cell Biology 81, 196–206 (2003).
What is the role of secondary infection of DENV?
• In the 1960s, Dr. Scott Halstead and his colleagues were studying the dengue virus in Thailand.
• They noticed that people who had been exposed to dengue a second time had an increased risk of severe dengue compared with those who had not been previously exposed.
• They wondered what makes a second dengue infection worse than the first.
Host Response to Dengue Infectionhttp://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106
The dengue virus tricks the immune system to get around its defenses and
infect more cells.
Non-neutralizing antibodies bind to FcGR of monocytes, inducing a large amount of viral ingestion in MO. Causing higher intraMacrophage multiplication, increasing viral loadand cytokines production, affecting the immune mediated storms.
Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine. Nature Reviews Microbiology 5, 518-528 (1 July 2007)Available from: http://www.nature.com/nrmicro/journal/v5/n7/full/nrmicro1690.html
Mole BM. Bedeviled by Dengue/ The Scientist March 2013. http://www.the-scientist.com/?articles.view/articleNo/34434/title/Bedeviled-by-Dengue/
Vascular Leakage
A large infected cell mass results in elevated concentrations of acute-phase response proteins, cytokines, and chemokines; generation of immune complexes; and consumption of complement and release of split products.
Interactions between dengue nonstructural protein 1 (NS1) and the surface glycocalyx layer may result in release of heparan sulfate into the circulation, thereby altering the filtration characteristics of the layer and resulting in leakage of proteins.
Simmons CP, Farrar JJ, van Vinh Chau N, Wills B. Current Concepts: Dengue. N Engl J Med
2012;366:1423-32
Conclusion
“B cells produce antibodies that specifically recognize and neutralize the foreign viral particles, and cytotoxic T cells recognize and kill cells that are infected with the dengue virus.
People who are infected a subsequent time with a different type of the dengue virus may experience something called "antibody-dependent enhancement."
Host Response to Dengue Infectionhttp://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106