Hello. My name is Zayan and our topic today is Antibody Dependent Enhancement in Dengue Infection We will be answering three questions. What is dengue? What do antibodies do? And what’s different about antibodies in antibody dependent enhancement that actually makes the infection worse. So – antibodies making the infection worse. To answer the first question, we have with us today – The man, or rather, the mosquito himself – Mr. Mosquito. Don’t worry he doesn’t bite. It’s only the female mosquito that bites. So, thank you for being with us today. Dengue is a mosquito borne illness. Oh, he brought some family slideshows. So that’s Aedes Aegypticus. The most common vector for dengue transmission. It is also the vector for yellow fever, chikungunya, and Zika. Baby pictures… Dengue larvae are laid in stagnant water. So the big public health problem is clearing up ponds and garbage dumps. And he likes to show off his travel selfies… Aedes Aegypticus is found in every continent except Antarctica. It is a neglected tropical disease. And it is mostly a problem in developing countries. But if we think it is a topic we can ignore, let’s remember Zika… Which is also a flavivirus and also carried by the same vector… To remind us how easily irrelevant man made borders can be. So thank you Mr. Mosquito. But I have my own family slideshow to show now. So this is back in Sri Lanka… … which is currently battling the worst recorded outbreak of dengue fever. That’s me and those are my brothers. We are only separated by one and two years apart but notice the difference in height. In countries like Sri Lanka with many neglected tropical diseases… …usually the child stuck in the cycle of infection, leading to poor growth, leading back to infection… You would expect that person to be the one to get the disease… But it was actually my oldest brother, who ended up with a severe case of dengue. Indeed something about a strong immune response suggests a worse outcome. That’s my middle brother, he didn’t get dengue… Just ignore him for the example. He’s the middle brother, so he’s used to being ignored. So what happens when someone like my brother gets dengue. The first is dengue fever… …which is known for fever and bone pain. A step above is dengue hemorrhagic fever. Which is known for capillary leak and hemorrhage. Which in turn can lead to the worst outcome… … dengue shock syndrome. So let’s find out what antibodies normally do… …before we learn what goes wrong in antibody dependent enhancement. So this is an antibody. It has variable regions that are specific to an antigen. It is also made by B cells and can be in the extra-cellular space… … or membrane bound to the B cell as part of the B cell receptor complex. To activate the B cell, you need two signals. The first is simply the foreign antigen, or virus, attaching to the B cell receptor. This is then taken up by endocytosis… …and then presented on MHC class II… … to a T helper which provides the second signal. Now this specific B cell can multiply and start producing antibodies. A specific antigen and a specific antibody can come together… … to form the immune complex, or antibody-antigen complex. Now there are three tricks it has to fight infection. The first is neutralization. Where the antibody antigen complex simply has more antibodies recruited to surround it and block it off from infecting. The second is opsonization. So a plain antigen is not very appetizing to a macrophage. But attach the antibody to it… .. and suddenly it is so much more palatable. It will now eat it and digest it. The third trick is complement activation. So you have an antibody. But meet C1. It’s very innocent looking. It likes to hug the antibody. It looks innocent but this leads to a chain reaction. And on the other end… … you get things like lysis, cell death, and scary sounding things like membrane attack complex. So those are the three things that antibodies do. So what do antibodies do differently in antibody dependent enhancement of the infection. So you are actually having antibodies making the infection worse. The first reason is dengue comes in different serotypes. This is dengue. You can identify dengue because it likes to wear different hats. Each serotype wears a different kind of hat. So they all have their own preferred hat. The second reason is that dengue infects the macrophages that phagocytize it. So let’s run through the antibody response again, this time noting the differences. So you form the complex. This time the antibody specific to the top hat wearing serotype. And neutralization is specific so it is effective. Then you have phagocytosis after opsonization. But this is a bad idea, because remember dengue can survive in the macrophage and infect it. But you have other mechanisms in place to fight the infection. So you clear the first infection, and your immune system has some memory. But it is not aware that different serotypes exist. All it knows is that someone wearing a hat caused a lot of trouble. And then a while later you can be exposed to the next serotype. And that’s the third reason. A second infection with a different serotype – or a different hat – generates a memory antibody response that is large and rapid… … but is actually ineffective at neutralizing the new serotype. You can tell it’s dengue again because it is wearing a hat. But it is a different serotype because it is wearing a turban instead of a top hat. So like what might happen to you if you walked into airline security wearing a turban… … it gets stopped. Because the antibody is generalizing from its previous bad experience with a headwear wearing foreigner. Then we have neutralization. The antibodies are not as effective because it is a different kind of hat. So you can make the attachment but not the neutralization. Then you have opsonization. But remember dengue actually infects these macrophages. And this is a memory response so you are having more antibodies causing more macrophages to get infected. So with those three things combined… … you are having more ineffective antibodies causing increased viremia… … and as the macrophages travel around the body they are spreading the infection. So in summary… You have a lot of memory antibodies… … that form antibody antigen complexes… … that are not specific because it is a new serotype. And more antibody antigen complexes that are weakly neutralized because it is a different serotype. … and more weakly neutralized antibody-antigen complexes leads to more macrophages getting infected. And more macrophages getting infected leads to macrophages spreading the viremia and having a more severe outcome. And that’s what antibody dependent enhancement is. It’s antibodies from a first infection… … responding and binding to a new serotype in a second infection… … but are only weakly and ineffectively neutralizing… … and this causes increased viral infection of macrophages… … which leads to increased viremia and a more severe infection. And that’s my talk. Thank you.