Insight into the Tropism of Dengue Virus in Humans

Abstract

In tropical and subtropical zones, arboviruses are among the major threats to human life, affecting a large number of populations with serious diseases. Worldwide, over three hundred million people are infected with dengue virus (DENV) every year as per the World Health Organization (WHO). DENV-mediated disease severity ranges from a mild fever to hemorrhagic fever and shock syndrome. Patients suffering from severe infection might experience multi-organ failure, cardiomyopathy and even encephalopathy, further complicating the disease pathogenesis. In life-threatening cases, DENV has been reported to affect almost all organs of the human body. In this review, we discuss the organ tropism of DENV in humans in depth as detected in various autopsy studies. Keeping in mind the fact that there is currently no DENV-specific antiviral, it is of utmost importance to achieve a vivid picture of the susceptible cells in humans which might help in designing antivirals against DENV, especially targeting those tissues in which infection might lead to life-threatening conditions.

Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines

“…Next, the virus spreads to the lymph nodes, followed by the dissemination to other tissues and organs. Tropism for cells from the liver, immune system, endothelium (blood vessels), and retinal cells has been described for DENV [ 101 , 102 , 103 ]. Additionally, at autopsy, DENV was detected in the human brain, thymus, lung, bone marrow, kidney, lymph nodes, spleen, liver, gastrointestinal tract, heart, and skin ( Figure 4 a) [ 101 ].…”

Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II - DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis

“…Controversially, DENV-ADE for other considered immune cells such as endothelial cells [116,117] have been also described in vitro and in vivo [118][119][120][121]. However, histochemistry of autopsy samples from fatal dengue cases and in vitro assays using peripheral blood cells revealed that macrophages/monocytes are primary targets for DENV infection and not endothelial cells [122][123][124][125][126][127].…”

Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: Part I - Dengue Virus Tropism, Host Innate Immune Responses, and Subversion of Antiviral Responses

“…Despite this, the single definitive receptor mediating this critical step in the DENV replication cycle continues to be elusive. So far, numerous candidates have been described in the mammalian and mosquito cells, including glycosaminoglycans such as heparan sulfate and lectins, the adhesion molecule of dendritic cells (DC-SIGN), the mannose receptor (MR) of macrophages, the lipopolysaccharide (LPS) receptor CD14, and stress-induced proteins such as the heat-shock proteins 70 and 90 and the endoplasmic reticulum (ER) chaperonin GRP78 [64][65][66][67][68]. This suggests that DENV may not use a unique, specific receptor to enter cells, but recognizes diverse molecules, both in the vertebrate and mosquito hosts, which can potentially explain the broad tissue range that defines DENV tropism and infection.…”

“…Numerous in vitro studies have shown that DENV is able to infect a variety of cell types including epithelial cells, endothelial cells, hepatocytes, muscle cells, dendritic cells, monocytes, B cells, and mast cells [65,66,[111][112][113][114][115][116][117]. Several autopsies and ex vivo studies have found the presence of DENV antigens (e.g., envelope protein, NS3) in some tissues such as the skin, liver, spleen, lymph node, kidney, bone marrow, lung, thymus, and brain [56,67,68,[118][119][120][121][122]. However, infectious virus particles have not always been isolated from all these organs but only from the liver and peripheral blood mononuclear cells (PBMCs), suggesting that: (a) the presence of DENV antigens such as the structural proteins E, pre-M, and C in several organs may not always be associated with the evidence of productive viral infection and severe organ pathology and (b) the immune cells and liver may be the main targets for DENV replication during the dengue disease [67].…”

“…Additionally, B cells and T cells have been studied to test permissiveness to DENV, but these studies have resulted in contradictory results [154][155][156]. In vitro studies using B cell and T cell lines (e.g., Raji cells, Daudi, and Jurkat) and primary B cells derived from healthy human peripheral blood mononuclear cells (PBMCs) have revealed the potential role of these cells in DENV replication, both in presence and absence of heterologous antibodies [67,155,[157][158][159]. Additional studies using a humanized mouse model found that DENV infected both B and T cells accompanied by an important production of pro-inflammatory cytokines such as IL-6 and TNF-α, like monocytes and macrophages [160].…”