Revealing the mystery of persistent smell loss in Long COVID patients

Abstract

COVID-19 is hopefully approaching its end in many countries as herd immunity develops and weaker strains of SARS-CoV-2 dominate. However, a new concern occurs over the long-term effects of COVID-19, collectively called "Long COVID", as some symptoms of the nervous system last even after patients recover from COVID-19. This review focuses on studies of anosmia, i.e., impairment of smell, which is the most common sensory defect during the disease course and is caused by olfactory dysfunctions. It remains mysterious how the olfactory functions are affected since the virus can't invade olfactory receptor neurons. We describe several leading hypotheses about the mystery in hope to provide insights into the pathophysiology and treatment strategies for anosmia.

Keywords: COVID-19; long COVID; olfactory dysfunction.

Figure 1

Schematic to illustrate the expression of ACE2 encoding a receptor for SARS-CoV-2 and detection of SARS-CoV-2 in the olfactory mucosa. A. Cells expressing ACE2 in the olfactory mucosa, which are labeled in green, including SCs, MCs, a subset of BGDCs, and HBCs. B. Cells infected by SARS-CoV-2 in the olfactory mucosa, which are labeled in red, including SCs, MCs, HBCs, BGDCs, a subset of ORNs, and cells in the outer layers of OB (the mitral and glomerular neurons), based on the detection of the viral RNA and antigens.

Figure 2

Schematic to illustrate mechanisms for persistent OD associated with COVID-19. A. Infection of the mitral and glomerular cells by SARS-CoV-2 through ACE2-mediated cell entry and low neurogenesis potential of OBNs manifested in permanent smell loss. B. Massive damage and cell death of SCs and ciliated apical side of the OE by SARS-CoV-2 invading through ACE2, illustrated as “Y” shape. The extensive damage to the OE due to the SC cell death affects the ORN structures and functions, leading to permanent smell loss. C. Infiltrated IBA⁺ neutrophils and macrophages produce inflammatory cytokines, including CXCL10, IL-6, IL-1β, IFNβ, and IFNγ, and affects ORN functions. The persistent presence of the virus results in the prolonged inhibitory activity against the ORNs. D. SARS-CoV-2 infection of the HBCs disrupts ORN differentiation and maturation as well as the restoration of the ORN after the OE damage. Ultimately, the ORN functions are inhibited or damaged for an extended period. E. The exposure to TNFα triggers differential NFκB signaling in the HBCs. The early or chronic inflammation in the OE promotes differentiation and proliferation of HBCs by upregulating the expression of differentiation genes and p63, respectively. imORN and mORN stand for immature and mature ORNs, respectively. F. SARS-CoV-2 infection of SC causes chromatin re-organization such that the OR cluster no longer interacts with the enhancer sequence, thereby downregulating the expressions of OR and ORN signaling genes and disrupting the functions of ORN in the long term. The red dots, black dots, and the half-moon or crescent-moon-shaped objects inside the cells represent SARS-CoV-2, apoptotic granules, and dying nuclei, respectively.