Female mosquito taking a blood meal
If you're a creationists who follows the latest science (if there is such a thing), you must be bursting with admiration for the ingenuity of your beloved intelligent designer for the way its brilliance at making us sick and spreading more suffering in the world is being revealed by science.
In the last few days, I've reported on how HIV, the virus that causes AIDS, is designed to hijack our cell's metabolic processes to ensure its own survival, and how the zika virus that cause the serious birth defect, microcephaly, in children if their mothers become infected during pregnancy, is brilliantly designed to make our skin produce more of the scent that attracts mosquitoes, so ensuring it is spread as widely as possible.
Now we have a superb example of this skill in malevolent design revealed by researchers from the National University of Singapore (NUS) who have discovered how the dengue virus is designed to make sure as many people as possible are infected by it. And this is breath-taking in its ingenuity. It is spread by the divine malevolence's favourite insect vector - the mosquito.
Tell me all about dengue, please. Dengue is a mosquito-borne viral infection that poses a significant public health threat in many tropical and subtropical regions of the world. It is caused by the dengue virus (DENV), which belongs to the Flavivirus genus and has four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). Infection with one serotype does not provide lifelong immunity against the others, meaning a person can get dengue multiple times, with severe illness more likely upon reinfection.When a mosquito takes a blood meal it first injects some anti-coagulant-containing saliva into the wound to keep the blood flowing. The saliva contains the dengue virus and any other nasty little pathogens for making us sick. It also takes any circulating viruses and other pathogens that are already in the blood into its stomach. The problem the dengue virus then faces is how to get from the mosquito's gut to its salivary glands, ready to infect its next victim. This is where an ingenious piece of design comes in, if you believe what creationists tell you.
Transmission
Dengue is primarily transmitted to humans through the bite of infected female mosquitoes, mainly Aedes aegypti and, to a lesser extent, Aedes albopictus. These mosquitoes are most active during the day, especially in the early morning and late afternoon.
Humans are the main hosts of the virus. When a mosquito bites an infected person, it picks up the virus and can transmit it to another person through subsequent bites. Rare cases of transmission through blood transfusion, organ transplantation, and from mother to child during pregnancy or childbirth have been reported.
Symptoms
Dengue symptoms usually appear 4–10 days after infection and can range from mild to severe. The illness typically lasts 2–7 days and can be classified into three forms:
Diagnosis
- Mild Dengue Fever
- High fever (40°C/104°F)
- Severe headache
- Pain behind the eyes
- Muscle, bone, and joint pain (sometimes called "breakbone fever")
- Nausea and vomiting
- Skin rash (appears a few days after fever starts)
- Mild bleeding (nosebleeds, gum bleeding, or easy bruising)
- Severe Dengue (Dengue Haemorrhagic Fever)
- Persistent vomiting
- Severe abdominal pain
- Bleeding from the nose, gums, or under the skin
- Blood in vomit or stool (black, tarry stools)
- Difficulty breathing due to fluid accumulation
- Organ dysfunction (liver, heart, brain complications)
- Dengue Shock Syndrome (DSS)
- Sudden drop in blood pressure (shock)
- Weak and rapid pulse
- Cold, clammy skin
- Restlessness or loss of consciousness
- This is a medical emergency with a high fatality rate if untreated.
Dengue is diagnosed through clinical symptoms and laboratory tests:Treatment
- PCR (Polymerase Chain Reaction): Detects viral RNA in the blood.
- NS1 Antigen Test: Identifies dengue virus early in infection.
- IgM and IgG Antibody Tests: Detect the body’s immune response to the virus.
There is no specific antiviral treatment for dengue. Care is supportive:Prevention
- Hydration: Drinking fluids is crucial to prevent dehydration.
- Pain relief: Paracetamol (acetaminophen) is recommended. Aspirin and NSAIDs (e.g., ibuprofen) should be avoided as they can increase bleeding risks.
- Hospital care: Severe cases require intravenous fluids, blood transfusions, and intensive monitoring.
There is no universal cure for dengue, so prevention focuses on mosquito control and personal protection:
Vaccination
- Eliminate breeding sites: Mosquitoes lay eggs in stagnant water, so regularly empty or cover water containers.
- Use mosquito nets and screens: Especially important for infants, the elderly, and those with weakened immunity.
- Wear protective clothing: Long sleeves and trousers reduce exposure.
- Use insect repellents: Products containing DEET, picaridin, or oil of lemon eucalyptus are effective.
- Community mosquito control efforts: Spraying insecticides, introducing mosquito predators (like certain fish), and genetic modification of mosquitoes are strategies used in some regions.
A dengue vaccine, Dengvaxia, is available but is only recommended for people who have had a previous dengue infection. If given to someone without prior exposure, it may increase the risk of severe dengue upon a future infection. Other dengue vaccines are in development, including Qdenga, which is approved in some countries for broader use.
Global Impact
Dengue is endemic in over 100 countries, particularly in Southeast Asia, the Pacific Islands, the Americas, Africa, and parts of the Middle East. The disease has surged due to urbanization, climate change, and increased global travel, with an estimated 390 million infections annually, of which 96 million are symptomatic.
Conclusion
Dengue remains a serious global health issue, particularly in tropical and subtropical regions. Since no specific treatment or universally recommended vaccine exists, mosquito control and public health awareness are the best defences. Early recognition of severe symptoms and prompt medical care significantly reduce fatalities.
In the blood the mosquito ingested is a protease enzyme known as plasmin. This enzyme has two functions - digesting and breaking down blood clots and breaking down the extracellular matrix to enable cell movement within tissues. However, the enzyme also binds to two binding sites on the dengue virus protein coat and then to the lining of the mosquito mid-gut wall, making it more permeable so the virus can pass out of the mosquito's digestive system into it body, and from there to the salivary glands.
So, ingeniously, the dengue virus gets into the mosquito complete with its own tool kit, stolen from its last victim, to help it get into its next victim!
This discovery is the subject of an open access research paper in the journal Protein Science and a blog post in the NUS blog:
Hijacking of plasmin by dengue virus for infection
Biological scientists from the National University of Singapore (NUS) have uncovered how the dengue virus uses its envelope protein to capture human plasmin from a blood meal to enhance the permeability of the mosquito midgut for infection.
Plasmin is a protease that contains five kringle-domains (KR1-5) responsible for substrate binding. In addition to digesting blood clots, plasmin is also used for the breakdown of the extracellular matrix to enable cell movement in tissues. While bacteria are known to capture human plasmin to digest host tissue for metastasis, the hijacking of plasmin by viruses for infection is not well studied.
The dengue virus is transmitted to humans through mosquito bites. Once ingested in a blood meal, the virus needs to pass through the mosquito midgut to infect the salivary glands before being transmitted to the next human host. However, the mechanism enabling this midgut traversal is not well understood. The acidic motifs on both the KR-4 and KR-5 domains of plasmin are found to bind synergistically to two lysine-containing regions (basic) located on the domain I of the dengue virus envelope protein. This interaction enhances the permeability of the mosquito midgut, facilitating viral infection. The identification of the exact binding sites between plasmin and dengue virus provides a potential way to interfere with this interaction and prevent dengue virus transmission.
A research team led by Associate Professor MOK Yu Keung from the Department of Biological Science at NUS expressed individual domains of human plasmin and the dengue virus envelope protein using an insect cell system. Kinetic binding experiments show that both KR-4 and KR-5 domains are needed to bind synergistically to the dengue virus. In addition, hydrogen-deuterium mass spectrometry experiments showed that two lysine-containing regions on domain I of the dengue virus envelope protein are found to interact with plasmin. These findings corrected earlier reports in the literature, which suggested that KR1-3 domains are involved in binding with domain III of the dengue virus envelope protein.
The research findings were published in the journal Protein Science.
We are glad to have clarified inaccuracies in the literature. Our findings reveal new mechanisms of dengue virus pathogenesis, which could pave the way for innovative approaches to tackle vector-borne viruses.
Professor Yu Keung Mok, lead author
Department of Biological Sciences
National University of Singapore, Singapore.
In the future, the group plans to study the interaction of other arboviruses, such as Zika and Chikungunya viruses, with plasmin. They also aim to determine the crystal structure of the protein complex formed between plasmin kringle-domains and the envelope protein of the dengue virus.
Diagram showing how the dengue virus captures plasmin using its envelope protein. The hijacked plasmin is used to enhance the permeability of the mosquito midgut to allow the dengue virus to escape and infect the salivary glands of the mosquito. Note that the diagram is not drawn to scale, and there will be more than one molecule of bound plasmin per viral particle.
Images of dengue virus and plasmin taken from Protein Data Bank https://www.rcsb.org, PDB ID: 3J35 and 4A5T, respectively.
Diagram of mosquito taken from Ruckert, C. et al., 2018, Trends in Parasitology, 34, 310-321.
AbstractAccording to Discovery Institute fellow, William A Dembski, the virus' ability to use plasmin this way must be due to genetic 'specified complexity' using 'specified information' that must have been supplied by creationism's intelligent designer.
Dengue fever is a serious health issue, particularly in tropical countries like Singapore. We have previously found that dengue virus (DENV) recruits human plasmin in blood meal to enhance the permeability of the mosquito midgut for infection. Here, using biolayer interferometry, we found that neither kringle-4 nor kringle-5 plasmin domains alone binds well to dengue virus. However, the domains together lead to a synergistic effect, with both kringle-4 and -5 domains required and sufficient for binding. Site-directed mutagenesis experiments showed that the N-terminal and C-terminal aspartic acid residues in the “DXD” acidic motifs of the kringle-4 and -5 domains likely have different roles when engaged with DENV. Hydrogen deuterium exchange mass spectrometry experiments on the plasmin:DENV complex led to the identification of two Lys-containing regions on domain I of the E-protein of DENV that are buried by plasmin and could be potential plasmin binding sites. These findings contradict with published literature that domain III of the DENV E-protein interacts with the kringle-1–3 domains of plasmin. We provide a plausible explanation for the observed discrepancies.
1 INTRODUCTION
Dengue virus (DENV) is a single-stranded RNA flavivirus. Its outermost shell comprises an icosahedral scaffold consisting of 90 copies of the glycoprotein E (E-protein) dimer (Kuhn et al., 2002). DENV is an arbovirus, transmitted via hematophagy between human hosts by vector insects, particularly mosquitoes of the Aedes species, such as Aedes aegypti and Aedes albopictus (Ross, 2010). The mosquito first acquires DENV from the blood meal of an infected individual. The virus then invades, proliferates, and eventually passes through the mosquito midgut barrier to enter is hemolymph. Once there, the virus spreads to and infects the salivary gland, whereafter the mosquito then unintentionally transmits the virus to another individual via subsequent blood feeding (Guzman et al., 2016). In Singapore, there have been two recent outbreaks of dengue infection in 2020 and 2022, with 35,315 and 32,325 cases, respectively (National Environment Agency, Singapore). In 2013, the worldwide number of annual infections was estimated to be 390 million, with 96 million manifesting clinically (Bhatt et al., 2013). Despite these extraordinarily high counts, to date, there is still no effective vaccine or drug against DENV.
Plasmin is a fibrinolytic enzyme expressed in its zymogen form, plasminogen. Plasminogen is globular and contains seven domains: an N-terminal plasminogen-apple-nematode (PAN) domain, five kringle (KR1-5) domains, and a C-terminal serine protease (SP) domain. KR1, KR2, KR4, and KR5 domains of human plasminogen contain an acidic “DXD” motif for substrate binding (Chang et al., 1998; Law et al., 2012, 2013.1; Mulichak et al., 1991). Upon binding to its substrate, plasminogen opens up to allow activators, such as tissue plasminogen activator (tPA) or urokinase (uPA), to activate and convert plasminogen into plasmin. This is achieved by cleaving a loop at residues Arg561-Val562 between the KR-5 and SP domains. Activated plasmin then provides local protease activity on the bound substrate, and is subsequently inhibited by α2-antiplasmin and α2-macroglobulin quickly after its action (Wu et al., 2019). Although plasmin is known to play a significant role in catalyzing fibrinolysis, it is also involved in extracellular matrix degradation, growth factor activation, and cell migration (Law et al., 2013.1).
Numerous pathogens can recruit plasmin to aid their infection and metastasis within host tissues. Plasmodium ookinetes capture plasmin to invade the midgut wall of malaria mosquito vectors for infection through enolases on their surface (Ghosh et al., 2011). Bacteria such as Borrelia burgdorferi, Helicobacter pylori, Yersinia pestis, and Streptococci, also recruit plasmin to increase their mobilities across host tissues (Lähteenmäki et al., 2005). The complex crystal structure of the a1a2 repeats of Streptococcus M protein and the KR2 domain of human plasmin has previously been solved (Quek et al., 2019.1). Moreover, activation of coagulation and fibrinolysis, which are characteristics associated to plasmin, were observed during DENV infection (Huang et al., 2001). However, it is unclear how DENV recruits plasminogen. One study suggests that plasmin KR1-3 may interact with domain III of the DENV E-protein based on western blotting of elastase-digested fragments of plasmin with DENV E-protein (Monroy & Ruiz, 2000).
Previously, we found that a Kazal-type protease inhibitor from Aedes aegypti, AaTI, interacts with plasmin and DENV to form a tripartite complex. We also showed that DENV recruits plasmin to enhance the permeability of the mosquito midgut barrier for infection, an activity that could be suppressed by AaTI (Ramesh et al., 2019.2). Here, we sought to examine the detailed interaction between plasmin with DENV using biolayer interferometry and site-directed mutagenesis to map the exact residues on plasmin involved with binding to the DENV E-protein. We found that two acidic “DXD” motifs on KR4 and KR5 of human plasmin are needed for the protein to interact with DENV; albeit, with different modes of binding. Using HDX-mass spectrometry analysis, we mapped two proximally located lysine-containing regions on domain I of DENV E-protein as the region buried by plasmin and likely employed by DENV to hijack plasmin for mosquito infection.
Yuen YJ, Sabitha T, Li LJ, Walvekar VA, Ramesh K, Kini RM, et al.
Hijacking of plasminogen by dengue virus: The kringle-4 and -5 domains of plasminogen binds synergistically to the domain I of envelope protein. Protein Science. 2025; 34(2):e70035. https://doi.org/10.1002/pro.70035
Copyright: © 2025 The authors.
Published by John Wiley & Sons, Inc. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
And even Michael Behe, with his convoluted gobbledygook, would be hard-pressed to explain away mutations in the dengue virus protein coat that gave it the ability to bind to plasmin and take it into the mosquito's gut, the better to escape from there and find its way to the salivary glands ready to infect a new victim, as 'devolutionary'. Since the mutations can only have been beneficial there is no way that make biological sense that they can be dismissed as 'devolution' due to 'genetic entropy'.
So, following the logic of creationism, the dengue virus, like so many other nasty pathogens that cause suffering, can only be ascribed to the 'intelligent [sic] designer', since cult dogma precludes them being ascribed to a mindless natural process in which gods played no part.
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