pathogenesis of dengue virus infection

1. Pathobiology of Dengue Virus
Infection
Fadel Muhammad Garishah
Pathobiology of Infectious Diseases
Faculty of Medicine DIPONEGORO UNIVERSITY
2014

2. Clinical Vignette
A 5 years-old boy was referred from a public health center
to general hospital due to a rapidly decreasing of platelets.
The previous 3 days he experienced fever up to 38,9 C, he
didn’t have any URT/LRT infection or Urinary tract
symptoms, no neurological deficits.
Currently his body temperature is 36,7 C, with cold
extremities.
Previous labwork showing a rapidly decreasing platelets
count from 102,000/mL and now 45,000/mL.
The GP in PHC referred the patient due to the prediction of
falling into severe shock.
Original Case from Emergency Department General Hospital

3. Vascular symptoms:
Hypovolaemia
Low blood pressure
Shock
Hepatic injury
Fluid pooling in
body cavities
Gall bladder
thickening
Haemorrhaging
within organs
Infrequent
complications:
Encephalitis
Acute pancreatitis
Renal failure
Myocarditis
Splenic rupture
Pulmonary haemorrhage
Vascular symptoms:
Leukopenia
Thrombocytopenia
Neutropenia
Late eosinophilia
Reduced coagulation
Skin symptoms:
Rash
Bruising
Petechiae
Purpura
Joint pain
Altered haematopoiesis
Bleeding gums,
nose and eyes
Headache,fever
Vomiting
Intestinal bleeding
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Clinical Manifestations of
DENV Infection
John ALS, Abraham SN, Gubler DJ.
Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis
Nature Reviews Microbiology 11, 420–426 (2013)
Available from: http://www.nature.com/nrmicro/journal/v11/n6/full/nrmicro3030.html

4. 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

5. 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

6. 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

7. What causes what?

8. 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).

9. 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 Infection
http://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106

10. 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 load
and 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

11. Mole BM. Bedeviled by Dengue/ The Scientist March 2013.
http://www.the-scientist.com/?articles.view/articleNo/34434/title/Bedeviled-by-Dengue/

12. 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

13. 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 Infection
http://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106