Dendritic Cells (DCs) as “Fire Accelerants” of Hantaviral Pathogenesis

Abstract

Hantaviruses are widespread zoonotic pathogens found around the globe. Depending on their geographical location, hantaviruses can cause two human syndromes, haemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). HPS and HFRS have many commonalities amongst which excessive activation of immune cells is a prominent feature. Hantaviruses replicate in endothelial cells (ECs), the major battlefield of hantavirus-induced pathogenesis, without causing cytopathic effects. This indicates that a misdirected response of human immune cells to hantaviruses is causing damage. As dendritic cells (DCs) orchestrate antiviral immune responses, they are in the focus of research analysing hantavirus-induced immunopathogenesis. In this review, we discuss the interplay between hantaviruses and DCs and the immunological consequences thereof.

Replication in the Mononuclear Phagocyte System (MPS) as a Determinant of Hantavirus Pathogenicity

“…This suggests that hantaviral pathogenicity is linked to the MPS and β2 integrins. In accordance, several pathogenic hantavirus species (HTNV, PUUV, and ANDV) have previously been demonstrated to productively infect human DCs in vitro (Raftery et al, 2002a;Marsac et al, 2011;Scholz et al, 2017;Schonrich and Raftery, 2019). Previous studies also reported in vitro infection of primary monocytes (Nagai et al, 1985;Temonen et al, 1993;Scholz et al, 2017) or a monocytic cell line (Markotic et al, 2007) with pathogenic hantavirus species.…”

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design

“…47 These findings indicate that the activation of the immune response mediated by infected DCs could contribute to the pathogenesis during viral infection. 34 Moreover, analyses of human tissue samples from ANDV fatal cases and infected wild Oligoryzomys longicaudatus rodents identified ANDV in alveolar macrophages and submandibular glands. 91 It has been proposed that replication in human salivary glands and expectoration of alveolar macrophages could contribute to personto-person transmission.…”

“…64 The upregulation of these chemo-attractant cytokines might be responsible for the recruitment of hantavirus-specific immune cells and extensive bystander activation of innate and cytotoxic cells that destroy ECs. 34 This scenario, combined with the cell-to-cell junction disruption, could promote platelet migration at the injury site, with the consequent thrombocytopenia commonly found in hantavirus disease. 56,66 Additionally, alterations between platelets and their ligands are reported during hantavirus infection, with high levels of fibrinogen and von Willebrand factor (VWF) in the acute stage of NE, 67 both directly involved in the initial steps of clot formation.…”

“…[28][29][30] It has been proposed that hantavirus-specific CD4 + T cells and CD8 + T cells contribute to the cytokine storm observed and capillary leak, with the consequent pulmonary oedema and cardiogenic shock during HCPS. 2,31 Several features of hantavirus pathogenesis and immunity, [32][33][34] as well as advances in vaccines and therapeutics, 35,36 have been recently reviewed and discussed elsewhere. Here, we summarize the main findings relative to the immune response in humans and animal models for both HFRS and HCPS, emphasizing the similarities and differences among both syndromes, and discussing the immunological basis for the rational design of vaccines and immunotherapeutic interventions.…”

“…Several features of hantavirus pathogenesis and immunity, 32–34 as well as advances in vaccines and therapeutics, 35,36 have been recently reviewed and discussed elsewhere. Here, we summarize the main findings relative to the immune response in humans and animal models for both HFRS and HCPS, emphasizing the similarities and differences among both syndromes, and discussing the immunological basis for the rational design of vaccines and immunotherapeutic interventions.…”