Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects

Abstract

Olfactory perception is an important physiological function for human well-being and health. Loss of olfaction, or anosmia, caused by viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received considerable attention, especially in persistent cases that take a long time to recover. This review discusses the integration of different components of the olfactory epithelium to serve as a structural and functional unit and explores how they are affected during viral infections, leading to the development of olfactory dysfunction. The review mainly focused on the role of receptors mediating the disruption of olfactory signal transduction pathways such as angiotensin converting enzyme 2 (ACE2), transmembrane protease serine type 2 (TMPRSS2), neuropilin 1 (NRP1), basigin (CD147), olfactory, transient receptor potential vanilloid 1 (TRPV1), purinergic, and interferon gamma receptors. Furthermore, the compromised function of the epithelial sodium channel (ENaC) induced by SARS-CoV-2 infection and its contribution to olfactory dysfunction are also discussed. Collectively, this review provides fundamental information about the many types of receptors that may modulate olfaction and participate in olfactory dysfunction. It will help to understand the underlying pathophysiology of virus-induced anosmia, which may help in finding and designing effective therapies targeting molecules involved in viral invasion and olfaction. To the best of our knowledge, this is the only review that covered all the receptors potentially involved in, or mediating, the disruption of olfactory signal transduction pathways during COVID-19 infection. This wide and complex spectrum of receptors that mediates the pathophysiology of olfactory dysfunction reflects the many ways in which anosmia can be therapeutically managed.

Keywords: ACE2 receptor; COVID-19; TRPV1; anosmia; basigin; neuropilin 1; sustentacular cells.

Figure 2

(A) Entry of SARS-CoV-2 into the sustentacular cell and the molecular interaction of the virus spike protein and the host cellular receptor ACE2, which depends on spike protein activation by TMPRSS2 and/or furin [46,49,53,59]. (B) Viral invasion activates Panx1, promoting the release of ATP from the cell [60]. (C) Extracellular ATP binds to P2 receptors, causing an increase in intracellular Ca²⁺ and ROS, which in turn results in DNA damage and cell death. The elevated intracellular Ca²⁺ and DNA damage collectively stimulate inflammatory responses, including the synthesis of cytokines like TNF-α and IL-1ß [61]. (D) Intercellular communication of SC with OSN through gap junctions, creating Ca²⁺ waves in the OSN. (E) Increasing intracellular Ca²⁺ in OSN activates Ca²⁺-dependent K⁺ channels that may mediate a hyperpolarization and subsequently inhibit the odor response or activate Cl⁻ channels, reducing the negativity in the cell and causing a depolarization. ACE2, angiotensin-converting enzyme 2 receptor; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD147, basigin; CNG, cyclic nucleotide-gated channel; IL-1ß, interleukin 1 ß; NRP-1, neuropilin-1; OR, olfactory receptor; OSN, olfactory sensory neuron; PANX1, pannexin 1; P2X4, P2X7, purinergic receptors; ROS, reactive oxygen species; SC, sustentacular cell; TMPRSS 2, transmembrane protease serine type 2; TNF-α, tumor necrosis factor-alpha. This figure was created with http://Biorender.com.

Figure 1

Organization of the olfactory epithelium and its communication with the olfactory bulb (prepared with http://Biorender.com).

Figure 3

TRPV1 participates in anosmia associated with SARS-CoV-2 infection. (1) SARS-CoV-2 infection activates the immune response; (2) inflammatory cells produce proinflammatory cytokines, such as TNF-α, which binds to its receptor (TNF-αR) expressed on the trigeminal ganglion neuron in the OE; (3) TNF-α activates intracellular cascades, including MAPK, p38, and other translational factors, to increase CGRP synthesis and increases the expression and trafficking of TRPV1 to the plasma membrane, thus triggering CGRP release. (4) CGRP binds to its receptor (CGRPR) expressed on OSN. (5) CGRPR activates adenylyl cyclase, which in turn converts ATP to cAMP; (6) cAMP activates a CNG channel, allowing Ca²⁺ influx; and (7) Ca²⁺ activates a Ca²⁺-dependent K⁺ channel (K_Ca), leading to (8) hyperpolarization and inhibition of odor detection. TGN: trigeminal neuron. AC: adenylyl cyclase; CGRP: calcitonin-related gene peptide; CNG: cyclic nucleotide gated channel; TRPV: transient receptor potential vanilloid; TNFR: TNF-α receptor. TGN: trigeminal nerve ending; OSN: olfactory sensory neuron.