Tropism of Dengue Virus in Mice and Humans Defined by Viral Nonstructural Protein 3-Specific Immunostaining

Abstract

Previous attempts to define dengue virus (DENV) tropism in human autopsy tissues have detected DENV antigens that are abundant in circulation during severe dengue, and thus may be present in uninfected cells. To better define DENV tropism, we performed immunostaining for the DENV2 nonstructural protein 3 (NS3) in humans and in a mouse model of DENV infection. In mice, NS3 was detected in phagocytes of the spleen and lymph node, hepatocytes in liver, and myeloid cells in bone marrow. In human autopsy tissues, NS3 was present in phagocytes in lymph node and spleen, alveolar macrophages in lung, and perivascular cells in brain. This protein was also found in hepatocytes in liver and endothelial cells in spleen, although NS3 was not present in endothelium in any other tissue. Thus, NS3-specific immunostaining supports roles for infected phagocytes, hepatocytes, and, to a limited degree, endothelial cells in the pathogenesis of severe dengue.

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

“…2A). These kinetic data support previous observations that immune compartments are primary sites of DENV infection (26)(27)(28), and highlight the dynamic nature of DENV infection in living mice. Our data suggest a model in which virus administered i.p.…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…13,14 However, M are heterogeneous throughout the body, 15 and the phenotypic and functional diversities of M are influenced by cytokines, which regulate their differentiation, tissue distribution, and defense to invaded pathogens. 16 Among these mediators, M-CSF and GM-CSF are the most important factors that contribute to M differentiation.…”

Dengue Virus Cellular Receptors and Tropism

“…Although hematopoietic lineage cells are major sites of DENV replication, some other cells of non-hematopoietic origin such as hepatocytes and Kupffer cells or neurons and microglia can be permissive to DENV during natural infection [5,11]. Furthermore, autopsies have documented infection of endothelial cells (ECs), a finding that has been reproduced in a mouse model of DENV infection [4,12]. Infection of ECs can contribute to the pathogenesis of the disease by increasing viremia, cytokine secretion, and modulating host's immune responses [13•].…”

“…Infection of ECs can contribute to the pathogenesis of the disease by increasing viremia, cytokine secretion, and modulating host's immune responses [13•]. In this respect, it is not clear if the tropism observed in fatal cases of DENV infection or in the mice model is the same that the one detected in patients with dengue fever [4,14,15].…”

“…Samples from patients traditionally come from complicated, severe cases and not from initial phases of infection. In consequence, histopathological studies from patients' biopsies documenting the localization of DENV proteins might be confused with cells that can actively replicate the virus with those cells that acquire dengue antigens by endocytic or phagocytic uptake of viral particles or proteins [4,5]. The initial steps following an infected mosquito inoculation have been studied ex vivo, where a skin explant is infected transcutaneusly [6].…”