Figure 1.
Mast cell–augmented immune responses to dengue virus infection.
(A) During localized infection of the skin, DENV triggers degranulation of MCs and release of de novo synthesized inflammatory mediators. MC-derived mediators, including proteases, leukotrienes, and histamine, promote edema within the site of infection as a result of increased microvascular permeability. MC products also stimulate the rolling of leukocytes along areas of activated endothelium and chemokines direct the recruitment of cytotoxic cells such as NK cells, NKT cells, and T cells into the infection site. The antiviral inflammatory program promoted by MCs at the site of infection aids viral clearance and limits spread beyond the site of initial infection to lymph nodes. (B) Systemic infection with DENV is characterized by widespread vascular leakage and virema coincides with elevated levels of MC products, such as the protease chymase, in the serum. Many MC products are vasoactive, including leukotrienes, TNF, VEGF, and others, and these are likely to act together to enhance the vascular leakage that occurs during viremia. (C) During secondary infection, pre-formed antibodies are hypothesized to cause ADE when they are non-neutralizing. For mast cells, ADE is also possible as a result of uptake of antibody virus complexes through the FcγR. MC degranulation responses can also be enhanced through crosslinking of FcεRs when bound to DENV-specific IgE. Although the influence of DENV-specific antibodies acting through MCs has not fully been investigated, augmented MC activation during secondary infection should also enhance immune responses, presumably including immune-mediated vascular injury.
Figure 2.
Multiple theories of dengue immune pathogenesis.
“Original antigenic sin” has the potential to occur during a DENV secondary infection with a heterologous serotype of DENV. For example, this begins when (1) primary infection occurs with Serotype 1 of DENV, resulting in adaptive immune responses where (2) Serotype 1–specific T cells are selected, activated, and (3) clonally expanded to combat infection. During the resolution of primary infection, memory Serotype 1–specific T cells are formed and are retained in higher frequency in the T cell repertoire than other T naïve cells. (4) A secondary challenge Serotype 1 would evoke a memory recall response and (5) effective containment of infection by highly specific T cells. (6) A secondary challenge with a heterologous strain, Serotype 2, has the potential to reactivate memory T cells that are of greater specificity for Serotype 1 than for Serotype 2. (7) These memory Serotype 1–specific T cells outcompete naïve T cells that would be more specific for Serotype 2, resulting in an expanded memory T cell pool that is low specificity for Serotype 2 and (8) poor viral clearance in vivo. Antibody-dependent enhanced replication also has the potential to occur during a secondary, heterologous infection. During primary infection (9), B cell selection occurs, promoting Serotype 1–specific antibody production. (10) These preexisting antibodies are present during the secondary challenge. (12) If the secondary challenge is with Serotype 1 again, (13) antibody-mediated neutralization of DENV occurs, (14) limiting infection. (15) If the secondary challenge is heterologous, as with Serotype 2, antibody specificity may be low (16) and weakly neutralizing antibodies can promote Fc receptor–mediated uptake of virus-antibody complexes. (17) Increased uptake of virus into the cell without efficient antibody-mediated neutralization results in production of higher viral titers and increases activation of pro-inflammatory intracellular signaling pathways. (18) Cytokine storm can occur during either primary or secondary infection when infected cells produce high levels of cytokines or (19) may also be derived from noninfected immune cells, such as activated T cells. (20) Cytokines act directly on the host vasculature and promote vascular leakage when they reach pathological levels. (21) MCs also release cytokines and additional de novo synthesized and pre-stored vasoactive mediators when they are activated by DENV. (22) Prior to secondary infection, MCs may also be sensitized by binding DENV-specific antibodies, which can also mediate MC activation in response to DENV. (23) MC-derived mediators act directly on the host vasculature to promote vascular leakage.