The article reviewed in this post is titled: "Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation" by Datan et al 2016. The article was released in March of 2016.
Threatening 40% of the
world’s population, dengue fever infection has doubled in the past 20 years,
(Datan et. al. 2016). A viral disease transmitted to humans by the mosquito genus
Aedes, dengue fever involves sudden
fever and acute pain in the muscles and joints, (Morens, 2009). Severe dengue
fever can turn into dengue hemorrhagic fever and dengue shock syndrome, which
can be fatal, (Rajapakse et. al. 2012). As a vector-borne illness, dengue
infection varies with seasonal climate changes, but as global warming begins to
alter region’s climates, the tropics are no longer the only locations with high
risk of dengue. Public health issues associated with the spread of dengue fever
make research involving viral mechanisms pertinent to understand how the virus
replicates for potential treatments and preventions. In a recent article,
investigation of dengue-2 virus reveals that infected cells require ER stress,
or PERK, pathway activation for dengue-induced autophagy, viral replication,
and protection from other cell stressors, (Datan et. al. 2016). New insight
into mechanisms of how dengue replicates can leads to possible treatments and
vaccinations as dengue infection advances on the world’s population.
In order to ensure the
virus’s own survival, dengue induces autophagy enabling the viral replication, (Datan et. al. 2016). Previously, dengue-2 was found to kill
mice macrophages, yet protect epithelial cells and fibroblasts creating an
optimal environment for viral survival. Induced autophagy increased viral
replication and viral gene NS4A is upregulated, (McLean et. al. 2011).
Inhibition of the NS4A gene limited viral replication indicating the NS4A is
sufficient and necessary to trigger PI3K-dependent autophagy, (McLean et. al.
2011).
Building off this concept,
researchers investigated the mechanism of dengue-induced
autophagy. Autophagy involved the transport of proteins, lipids, and organelles
to autophageosomes, and then they are targeted for lysosomes for degradation as
part of a cell’s normal homeostatic response, (Datan et. al. 2016). Typically,
the mediators of this process include sensors of cell energy, such as AMPK,
however, research has shown dengue virus mediates autophagy through activation
of ER, or PERK, pathway activation. Through tracking of calreticulin, a marker
of global ER stress, and markers of PERK pathway, ATF-4 (cyclic-AMP-dependent
transcription factor 4), and GADD34 (growth arrest and DNA damage-inducible
protein 34), ER stress is activated through signaling via the PERK pathway,
(Datan et al 2016). Levels of calreticulin, ATF-4, and GADD34 all increased in
host cells after infection with dengue virus indicating a strong correlation
between viral infection and induced ER stress and PERK pathway signaling, (Figure
1)(Datan et al 2016). Salubrinal, an inhibitor of PERK pathways, eliminates
dengue virus induced increases of calreticulin in host cells also strengthening
the correlation between ER stress and PERK pathway activation for mechanism of
autophagy in dengue-infected cells (Figure 1). The article also described the
importance of PERK pathway in viral replication and transcription by treating
cells with salubrinal and using specific primers for qPCR. Presence of the PERK
pathway inhibitor drastically reduced the transcription of NS4A, the gene
previously found to be responsible for autophagy and viral replication in
dengue infected cells (Figure 1). Since it is known dengue replication relies
on autophagy, the PERK pathway is necessary for viral replication. This
information was confirmed with testing in MDCK cells, (Datan et al 2016).
The study also reviewed how
an activated PERK pathway increases authophagy turnover in MEF cells. Using
PERK knock-outs and wild-type cells, they measured green puncta of p62, a
lysosomal protein and marker for autophagy turnover, via antibodies and
observed decreased p62 in PERK wild-types infected with dengue compared to the
control, yet not difference in p62 concentrations in PERK knock-outs, (Datan et
al, 2016). Since p62 degrades as a result of elevated rates of digestion of
autophagosome content in lysosomes, the final step of autophagy, the results
from this study further confirm PERK has a necessary role in dengue induced
autophagy and thus viral replication.
The researchers extended the
study to determine if ATM (ataxia telangiectasia mutated) signaling followed by
the production of ROS (reactive oxygen species), but the results revealed
little importance. While direct inhibition of ER stress causes decreases in
autophagy turnover, curtails production of ROS and suppresses viral
replication, ATM signaling inhibition does little to viral titers and ROS
accumulation, (Datan et al 2016). However, they were able to determine that ROS
regulates dengue-induced autophagy by implementing a ROS inhibitor linking
autophagy to ROS accumulation and then observed high levels of ROS in
dengue-infected cells, (Datan et al 2016). Cumulatively, the results
demonstrate that dengue virus induces and replicates through autophagy via ER
stress through ROS accumulation through a PERK dependent pathway.
Knowing this mechanism of
dengue replication opens up the possibility to treat with pharmaceuticals that
interfere with PERK pathway signaling during viral infection. It also poses the
possibility that other virus may work this way, providing basis for
investigation of other unknown viral mechanisms. For dengue, knowing the
mechanisms and inner workings of the virus can help medical professionals and
researchers attack the emerging and expanding outbreaks.
The threat of the reemergence
of Dengue Fever also exists for Australia. A 2004 study revealed that intense
El Niño Southern Oscillation (ENSO) events combined with surface temperature increases
of 0.3-0.6°C correlate with higher incidence rates of mosquitoes-borne
illnesses such as Malaria and Dengue Fever, (Zell 2004). Heavy precipitation
events lead to floods and development of stagnant water, especially in urban
environments, providing viable breeding grounds for mosquito vectors, (Khasnis
& Nettleman 2005). Periods of severe rainfall most likely result from
increased frequency and intensity of ENSO events due to climate change. Sea
level rise creates more extensive saltmarsh habitats along coastlines,
providing stagnant, moist environments for mosquitoes, (Russell, 1998). Urban
area are also prone to developing more area of stagnant water as heavy rains
pool water in tanks, trash bins, gutters and stray rubbish, co-inhabiting
locations where mosquitoes reproduce. Increases in temperatures enable
geographical shifts of species that carry Dengue Fever, such as Aedes albopictus and Aedes aegypti, further south in
Australia, (Russell et. al. 2009). Temperature increases also contribute to
quicker virus incubation and elevated rates of vector feeding, demonstrating
the potential of rapid transmission to humans.
A majority of Australia’s
population is concentrated in urban areas along the coast. High-density urban
areas combined with intense ENSO and QBO events and sea level rise leave the
country susceptible to Dengue Fever outbreaks. Present in Australia since the
1880’s, the disease was largely eliminated in the 1950’s, but reappeared in
1981, (Mackenzie et. al. 2006)(Russell, 2009).
Localized around the northern coastlines, dengue fever is expected to
move further south and inland, corresponding to climate zone shifts, (Figure
8). If average surface temperatures in
Australia increase by 2.0-3.0°C Dengue Fever could become a common occurrence
in Brisbane, (Russell, 2009). Temperature increases of 3.0-4.0°C could
stabilize the virus transmission as far south as Sydney. In absence of
mitigation strategies to address global warming, the spread of Dengue further
south in Australia could occur by 2100 based on warming trends, (Head et. al.,
2014).
Seeing the increased threat
of dengue on a global scale, understanding the mechanisms of how the virus
replicates initiates better intervention strategies and perhaps prevent the disease from emerging in area affected by climate change.
- Datan, E. Roy, S. G., Germain, G., Zali, N., McLean, J. E., Golshan, G., Harbajan, S. Lockshin, R. A. & Zaken, Z. (2016) Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation. Cell Death and Disease. 7: e2127
- Head, L., Adams, M., McGregor, H. V. & Toole, S. (2014) Climate Change and Australia. Wiley Interdisciplinary Reviews: Climate Change, 5, 2, 175-197.
- Khasnis, A. & Nettleman, M. (2005). Global Warming and Infectious Disease. Archives of Medical Research, 36, 689-696.
- Mackenzie, J., et.al. (2006). Emerging Viral Diseases of Southeast Asia. Issues in Infectious Diseases, 7, 3, 497-504.
- McLean JE, Wudzinska A, Datan E, Quaglino D, & Zakeri Z. (2011) Flavivirus NS4A-inducedautophagy protects cells against death and enhances virus replication. J Biol Chem. 286. 22147–22159.
- Morens, David M. MD. Dengue Fever and Dengue Hemorrhagic Fever. Pediatric Infectious Disease Journal. 28. 7. 635-636.
- Rajapakse, S., Rodrigo, C. & Rajapakse, A. (2012) Treatment of Dengue Fever. Infection and Drug Resistance. 5. 103-112.
- Russell, R. (1998). Mosquito-borne Arboviruses in Australia: The Current Scene and Implications of Climate Change for Human Health. International Journal for Parasitology, 28, 6, 955-969.
- Russell, R. (2009). Mosquito-borne Disease and Climate Change in Australia: Time for a Reality Check. Australian Journal of Entomology, 48, 1, 1-7.
- Zell, R. (2004). Global Climate Change and the Emergence/Re-emergence of Infectious Diseases. International Journal of Medical Microbiology Supplements, 293, 37, 16-26.
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