Evaluating the role of memory B and T cells during secondary dengue infection

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Felipe Rubio

"Evaluating the role of memory B and T cells during secondary dengue infection"
Dengue viruses (DENV) are transmitted by Aedes mosquito bite that causes mild dengue fever (DF) or dengue severe (DS). There are more than 50 million DF cases each year. There are four serotypes of dengue virus, DENV1 - DENV4, which has only 20%-35% divergence to each other. The cross-reactive immune response contributes to increased disease severity following heterologous infections. In general, primary infections result in either asymptomatic or mild DF disease. Secondary infections with different serotypes are either cleared or can induce dengue severe. Mechanisms responsible for the severity of secondary dengue infections are not entirely understood. One of them is the cross-reactive antibodies can enhance the disease, which is called antibody-dependent enhancement (ADE). ADE is explained as follows. When a person is first infected with one dengue strain, the host produces neutralizing antibodies specific against this strain. After the primary infection is eliminated, due to the immunological memory plasma cells produce specific antibodies for the first dengue strain, which persist in the body. If this person is secondly infected with a different dengue strain, antibodies from the primary infection bind the second virus but do not neutralize it. Besides that, macrophages recruited to clear the immune complex; they internalize this non-neutralized virus and become infected in the process of clearance. There is evidence that Fc receptors, which are proteins on the surface of some cells like macrophages and monocytes that bind to the antigen-antibody complex, might facilitate viral entry in cells and increase dengue viral replication. We propose a mathematical model composed of seven non-linear differential equations to describe the ADE phenomenon in secondary dengue infection, considering that partial cross-immunity takes place due to primary dengue infection. We consider that the immune system has not yet performed a complete response against the secondary infection. During this time, the circulating antibodies against the primary virus can facilitate heterologous secondary infection. Here we consider target cells - macrophages, a specific antibody against the primary infection, memory B cells, memory T cells, the formation of the immune complex, and dengue virus. We focus on the role of memory B and T cells during the secondary dengue infection. It is possible to determine the basic reproduction number parameter, R0, and B and T cell cloning during the secondary dengue infection. In the impossibility of cloning these cells, we find that if R0<1, there will be no possibility of ADE's appearance. However, when we introduced the possibility of memory B cell cloning, we saw that an infectious state could arise even when the basal reproduction number is less than one. Analogously, when we analyzed only the effect of memory T cell cloning, we saw that ADE's emergence is not possible. These cells only act to decrease viral concentration.
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