Sendai Virus Induces Persistent Olfactory Dysfunction in a Murine Model of PVOD via Effects on Apoptosis, Cell Proliferation, and Response to Odorants

Abstract

BackgroundViral infection is a common cause of olfactory dysfunction. The complexities of studying post-viral olfactory loss in humans have impaired further progress in understanding the underlying mechanism. Recently, evidence from clinical studies has implicated Parainfluenza virus 3 as a causal agent. An animal model of post viral olfactory disorders (PVOD) would allow better understanding of disease pathogenesis and represent a major advance in the field.ObjectiveTo develop a mouse model of PVOD by evaluating the effects of Sendai virus (SeV), the murine counterpart of Parainfluenza virus, on olfactory function and regenerative ability of the olfactory epithelium.MethodsC57BL/6 mice (6–8 months old) were inoculated intranasally with SeV or ultraviolet (UV)-inactivated virus (UV-SeV). On days 3, 10, 15, 30 and 60 post-infection, olfactory epithelium was harvested and analyzed by histopathology and immunohistochemical detection of S-phase nuclei. We also measured apoptosis by TUNEL assay and viral load by real-time PCR. The buried food test (BFT) was used to measure olfactory function of mice at day 60. In parallel, cultured murine olfactory sensory neurons (OSNs) infected with SeV or UV-SeV were tested for odorant-mixture response by measuring changes in intracellular calcium concentrations indicated by fura-4 AM assay.ResultsMice infected with SeV suffered from olfactory dysfunction, peaking on day 15, with no loss observed with UV-SeV. At 60 days, four out of 12 mice infected with SeV still had not recovered, with continued normal function in controls. Viral copies of SeV persisted in both the olfactory epithelium (OE) and the olfactory bulb (OB) for at least 60 days. At day 10 and after, both unit length labeling index (ULLI) of apoptosis and ULLI of proliferation in the SeV group was markedly less than the UV-SeV group. In primary cultured OSNs infected by SeV, the percentage of cells responding to mixed odors was markedly lower in the SeV group compared to UV-SeV (P = 0.007).ConclusionWe demonstrate that SeV impairs olfaction, persists in OE and OB tissue, reduces their regenerative ability, and impairs the normal physiological function of OSNs without gross cytopathology. This mouse model shares key features of human post-viral olfactory loss, supporting its future use in studies of PVOD. Further testing and development of this model should allow us to clarify the pathophysiology of PVOD.

A Systematic Review of the Neuropathologic Findings of Post-Viral Olfactory Dysfunction: Implications and Novel Insight for the COVID-19 Pandemic

“…This may account for the prolonged presence of viral protein and viral RNA within the OB. 41,45 Studies demonstrated high neurovirulence of HSV for the CNS. In vivo studies of HSV-1 and HSV-2 consistently showed high degree of neuroinvasion within the olfactory pathway as well as in higher cortical centers, resulting in encephalitis and cell death.…”

Obesity and COVID-19: Oro-Naso-Sensory Perception

“…We propose that SARS-CoV-2 might affect the integrity or regeneration/renewal of the olfactory epithelium, impacting the physiological function of olfactory sensory neurons (Figure 2). Hence, we can cite the example of Sendai virus which has been shown to impair olfaction by reducing the regeneration of the olfactory epithelium and olfactory bulb in the mouse [51]. In in vitro experiments on murine olfactory neurons infected with this virus, the number of odorant-responsive cells were decreased.…”

Psychophysical evaluation of chemosensory functions 5 weeks after olfactory loss due to COVID-19: a prospective cohort study on 72 patients

“…However, it has been hypothesized that odor detection thresholds represent the function of the peripheral olfactory system to a higher degree than the central nervous processing of olfactory information. Although central nervous damage has also been described, respiratory viruses are expected to produce major damage at the level of the olfactory epithelium [ 6 , 7 ]. Hence, evaluating detection thresholds may provide specific information on the olfactory loss due to SARS-CoV-2.…”