SARS-CoV-2 Cellular Infection and Therapeutic Opportunities: Lessons Learned from Ebola Virus

Abstract

Viruses rely on the cellular machinery to replicate and propagate within newly infected individuals. Thus, viral entry into the host cell sets up the stage for productive infection and disease progression. Different viruses exploit distinct cellular receptors for viral entry; however, numerous viral internalization mechanisms are shared by very diverse viral families. Such is the case of Ebola virus (EBOV), which belongs to the filoviridae family, and the recently emerged coronavirus SARS-CoV-2. These two highly pathogenic viruses can exploit very similar endocytic routes to productively infect target cells. This convergence has sped up the experimental assessment of clinical therapies against SARS-CoV-2 previously found to be effective for EBOV, and facilitated their expedited clinical testing. Here we review how the viral entry processes and subsequent replication and egress strategies of EBOV and SARS-CoV-2 can overlap, and how our previous knowledge on antivirals, antibodies, and vaccines against EBOV has boosted the search for effective countermeasures against the new coronavirus. As preparedness is key to contain forthcoming pandemics, lessons learned over the years by combating life-threatening viruses should help us to quickly deploy effective tools against novel emerging viruses.

Keywords: Ebola virus; SARS-CoV-2; antibodies; antivirals; endocytosis; vaccines.

Figure 1

Viral and host factors involved in EBOV and SARS-CoV-2 infectious cycle. (A) EBOV entry into target cells is mediated by macropinocytosis, which directs surface-attached viral particles to the endosomal trafficking pathway. Within endosomes, host cathepsins cleave viral glycoprotein, facilitating interaction with the NPC1 receptor and viral membrane fusion. In the cytoplasm, the viral RNA genome undergoes transcription/replication, resulting in the synthesis of new viral particles that exit infected cells through membrane budding. (B) SARS-CoV-2 can enter target cells through an endosomal pathway that parallels EBOV internalization. Within endosomal compartments, cleavage of the Spike protein results in viral fusion and cytoplasmic entry, where viral replication occurs. (C) SARS-CoV-2 also enters target cells through an alternative mechanism in which Spike protein is cleaved at the cell surface, a process mediated by proteases such as TMPRSS2 and furin. In this case, the viral genome gains access to the cytoplasm through viral fusion with the plasma membrane. EBOV: Ebola virus; CLECs: C-type lectin receptors; TIM: T-cell immunoglobulin and mucin receptors; TAM: Tyro3-Axl-Mer receptors; Siglec-1: sialic acid-binding Ig-like lectin 1; NPC1: Niemann-Pick receptor C1; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; ACE2: angiotensin-converting enzyme 2; NRP1/2: neuropilin 1/2; TMPRSS2: transmembrane protease serine 2.

Figure 2

Antiviral strategies aimed at blocking EBOV and SARS-CoV-2 viral cycle. (A) Different antivirals tackle viral and host factors involved in EBOV replicative cycle. (B) Antivirals directed against the SARS-CoV-2 endocytic pathway. Several of these antivirals have also been proposed to block EBOV entry through similar mechanisms. (C) Antiviral strategies targeting SARS-CoV-2 cycle in cells undergoing viral fusion at the plasma membrane. nAbs: neutralizing antibodies. Immunological antiviral functions of neutralizing antibodies (NK- or complement-mediated infected cell lysis and macrophage phagocytosis) are highlighted in boxes.