Hantavirus entry: Perspectives and recent advances

Abstract

Hantaviruses are important zoonotic pathogens of public health importance that are found on all continents except Antarctica and are associated with hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. Despite the significant disease burden they cause, no FDA-approved specific therapeutics or vaccines exist against these lethal viruses. The lack of available interventions is largely due to an incomplete understanding of hantavirus pathogenesis and molecular mechanisms of virus replication, including cellular entry. Hantavirus Gn/Gc glycoproteins are the only viral proteins exposed on the surface of virions and are necessary and sufficient to orchestrate virus attachment and entry. In vitro studies have implicated integrins (β1–3), DAF/CD55, and gC1qR as candidate receptors that mediate viral attachment for both Old World and New World hantaviruses. Recently, protocadherin-1 (PCDH1) was demonstrated as a requirement for cellular attachment and entry of New World hantaviruses In vitro and lethal HPS in vivo, making it the first clade-specific host factor to be identified. Attachment of hantavirus particles to cellular receptors induces their internalization by clathrin-mediated, dynamin-independent, or macropinocytosis-like mechanisms, followed by particle trafficking to an endosomal compartment where the fusion of viral and endosomal membranes can occur. Following membrane fusion, which requires cholesterol and acid pH, viral nucleocapsids escape into the cytoplasm and launch genome replication. In this review, we discuss the current mechanistic understanding of hantavirus entry, highlight gaps in our existing knowledge, and suggest areas for future inquiry.

Predictive value of pentraxin-3 on disease severity and prognosis in patients with hemorrhagic fever with renal syndrome

“…After infection with Hantavirus, the human body could develop a strong and rapid immune response characterized by the hyperactivity of immune cells and the ooding of cytokines, so as to the damage of vascular endothelium and visceral organs [1][2][3][4][5][6]. As one of the most important immune cells in innate immunity, neutrophils play a crucial part in resisting bacterial infection.…”

“…Hemorrhagic fever with renal syndrome (HFRS) is a kind of natural focus disease caused by Hantavirus infection, which is characterized by fever, hemorrhage and renal impairment [1]. Hantavirus infection could induce the destruction of vascular endothelial cells [2], the diffuse damage of systemic microvessels, the increase of capillary permeability, and the decrease of platelets [3]. Patients with intemperate immunoreaction may further develop "capillary leakage syndrome", which could result in secondary edema, hypovolemic shock, acute kidney injury (AKI), coagulation disorder, and even multiple organ dysfunction syndrome (MODS) [4].…”

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

“…MPS cells strongly express integrin β1, the only receptor described for low pathogenic/apathogenic hantavirus species (Gavrilovskaya et al, 1998(Gavrilovskaya et al, , 1999) as well as receptors described for pathogenic hantavirus species (integrin β2, integrin β3, gC1qR, and CD55) ( Figure S2) (Gavrilovskaya et al, 1998(Gavrilovskaya et al, , 1999Choi et al, 2008;Krautkramer and Zeier, 2008;Raftery et al, 2014). After receptor binding hantaviruses enter target cells by an endocytic pathway and are finally released from endosomes into the cytoplasm (Albornoz et al, 2016;Mittler et al, 2019). The latter process requires acidification FIGURE 3 | Post-entry block of TULV replication in myeloid cells.…”

Biodefense Implications of New-World Hantaviruses

“…NIAID's categories refer to documented priority pathogens A, B, and C, and emerging infectious diseases defined as those that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range (NIAID, 2018). There is much categorical confusion though for hantaviruses, and specifically New-World Hantaviruses such as Sin Nombre orthohantavirus (SNV), as to what priority of a bioagent and subsequent threat they pose (Mir, 2010;Mittler et al, 2019). Hantaviruses as a whole are categorized as emerging viruses along with Nipah Virus in the CDC as Category C Pathogens; whereas NIAID places hantaviruses as part of the Category A Pathogens (CDC, 2018;NIAID, 2018).…”

“…Hantaviruses are emerging zoonotic viruses that are responsible for two human diseases: Hantavirus Cardiopulmonary Syndrome (HCPS) associated with New-World Hantaviruses found in the western hemisphere; and Hemorrhagic Fever with Renal Syndrome (HFRS) associated with Old-World Hantaviruses in the eastern hemisphere (Mittler et al, 2019). Collectively, 150,000 -200,000 cases of hantavirus disease are reported annually with the majority of HFRS cases occurring in Asia, specifically in the People's Republic of China which constitutes upwards of 90% of cases (Schmaljohn, 2009;Iannetta et al, 2019;Liu et al, 2019).…”