Host Manipulation Mechanisms of SARS-CoV-2

Abstract

Viruses are the simplest of pathogens, but possess sophisticated molecular mechanisms to manipulate host behavior, frequently utilizing molecular mimicry. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to bind to the host receptor neuropilin-1 in order to gain entry into the cell. To do this, the virus utilizes its spike protein polybasic cleavage site (PCS), which mimics the CendR motif of neuropilin-1's endogenous ligands. In addition to facilitating cell entry, binding to neuropilin-1 has analgesic effects. We discuss the potential impact of neuropilin-1 binding by SARS-CoV-2 in ameliorating sickness behavior of the host, and identify a convergent evolutionary strategy of PCS cleavage and subsequent neuropilin binding in other human viruses. In addition, we discuss the evolutionary leap of the ancestor of SARS-COV-2, which involved acquisition of the PCS thus faciliting binding to the neuropilin-1 receptor. Acquisition of the PCS by the ancestor of SARS-CoV-2 appears to have led to pleiotropic beneficial effects including enhancement of cell entry via binding to ACE2, facilitation of cell entry via binding to neuropilin-1, promotion of analgesia, and potentially the formation of decoy epitopes via enhanced shedding of the S1 subunit. Lastly, other potential neuromanipulation strategies employed by SARS-CoV-2 are discussed, including interferon suppression and the resulting reduction in sickness behavior, enhanced transmission through neurally mediated cough induction, and reduction in sense of smell.

Keywords: CendR motif; Host manipulation; Mimicry; Neuropilin; Polybasic cleavage site; SARS-CoV-2.

Fig. 1

Müllerian molecular mimicry ring consisting of neuropilin-1 and its ligands, with SARS-CoV-2 spike protein as a Batesian invader. Neuropilin-1 and its endogenous ligands comprise a Müllerian molecular mimicry ring. The ring is formed by the host genes (the senders) that code for endogenous ligands which share a common signal, the CendR motif. The common signal is recognized and bound by neuropilin-1 (the receiver). This is part of normal host physiology and results in a common benefit to all participants of the ring as they have perfect common interest. The cleaved PCS of virus spike protein is a Batesian mimic of the CendR motif, deceiving neuropilin-1 into binding to it. This facilitates entry of the virus into the cell, which is beneficial to the virus, but harmful to the host, hence host and virus have a conflict of interest. Spike protein binding has analgesic effects, which may positively influence the mood of the infected person, promoting transmission of the virus. Given that neuropilin-1 and its endogenous ligands are found throughout the vertebrates, the ring appears to have been stable over hundreds of millions of years, despite the likelihood of repeated invasions by viral Batesian molecular mimics over time. These are indicated by the existence of several human viruses which target neuropilins using molecular mimicry of the CendR motif (Table 2), and may be attributed to the simple nature of the CendR motif, which makes it easy to mimic. A detailed signaling games definition of Müllerian molecular mimicry rings and Batesian molecular mimics is described in (Massey and Mishra ; Casey et al. 2021). The PDB identifier for the neuropilin-1 structure is 4GZ9, and the amino acid recognition motifs for each ligand were obtained from the following references: Vesicular Epithelial Growth Factor A165 (Vander Kooi et al. 2007), Platelet Derived Growth Factor (Siegfried et al. 2003), Transforming Growth Factor 1β (Dubois 1995) and semaphorin 3A/B/C/D (Parker et al. 2013)