The World Health Organization reports the SARS-CoV-2 virus continues to infect thousands globally each month, listing omicron as the current “variant of concern.” Although loss of the sense of smell was widely seen in patients infected with the SARS-CoV-2 original strains through the subsequent delta strains, the more recent omicron variants much less frequently cause loss of smell function.

A new Johns Hopkins study published in the Journal of Clinical Investigation provides valuable insights into how evolving virus strains developed distinguishing clinical traits. Study findings emphasize that strains early in the pandemic specifically targeted cells in the sense of smell part of the nose, causing loss of smell function and potentially contributing to other long-lasting neurologic symptoms. Understanding how the course of COVID-19 was impacted by the initial site of infection in the nose may be important to predicting the severity of future variants and developing novel treatment approaches.

Through examining human tissue samples and animal models, researchers observed that the original WA-1 SARS-CoV-2 virus strain exhibited a strong preference for infecting the sense of smell portion of the nasal cavity, called the olfactory epithelium, suggesting that this area served as a critical initial site for virus replication. As with other respiratory viruses, the high viral load and immune cell accumulation detected in the study indicated that the nasal cavity is the principal initial site of viral infection and where the body’s immune response begins. The original WA-1 strain specifically targeted olfactory epithelium cells called sustentacular cells that express high levels of the protein ACE2, to which the virus binds. Early in the pandemic, the sudden loss of smell was highly predictive of infection, even in the absence of other symptoms.

“In contrast, the omicron strains that became the dominant variant and remain so to this day tend to infect the non-olfactory, or respiratory, epithelium, causing much milder damage and inflammatory reaction in the olfactory epithelium and symptoms more similar to a common cold,” says senior author Andrew Lane, director of the Johns Hopkins Sinus Center. “This shift in the characteristics of SARS-CoV-2 variant infection in the nose likely explains the lower incidence of smell loss in omicron-infected individuals and possibly relates to diminished development of brain symptoms in long COVID.”

Long COVID is estimated to affect 10% of infected individuals, which currently equates to about 65 million people around the world. The National Institutes of Health report many patients with long COVID experience olfactory dysfunction that lasts months to years.

Long COVID can also be associated with cognitive impairment known as brain fog. Infection with both the original strain and the delta strain, which evolved to spread more deeply into olfactory tissue, resulted in massive damage and inflammation of the olfactory epithelium by spreading the virus along olfactory nerves toward the brain. Researchers observed virus transport into the brain in the animal models, but the virus was not shown to have the capacity to infect brain cells and replicate.

Notably, no strain of the virus has been demonstrated to infect brain tissue, even in patients who developed long COVID.

“Our study provides evidence that early variants of SARS-CoV-2 that infected the olfactory epithelium could travel to the brain through infected olfactory neurons,” says lead author Mengfei Chen, who was a research associate in Lane’s lab at the time the work was performed. “Multiple factors may have been involved in the pathogenesis of cognitive impairment, including inflammation and cell damage in the brain.”

Although it is not fully understood how the immune system functions in the olfactory epithelium to fight viruses, researchers theorize the respiratory mucosa in the rest of the nose may be more capable of fighting viruses quickly, giving the infection less of a head start than in the olfactory epithelium.

Following infection of the olfactory epithelium with early SARS-CoV-2 strains, researchers observed rapid detachment of infected cells and severe damage and inflammation of the tissue structure. This shedding of infected olfactory epithelium not only explains smell dysfunction but also has implications for high aerosolized transmission of virus and spread to the lungs. Prior research suggests that ongoing inflammation suppresses regeneration of olfactory epithelium, which prevents regaining smell function but also preserves the ability to recover sense of smell once the inflammatory response has cleared the virus.

As the severity of COVID is known to be closely related to age, with older individuals being more vulnerable, researchers also examined age-related differences in viral clearance and immune response in animal models.

“Our immune function is largely affected by aging,” says Chen. “We observed that the process of clearing SARS-CoV-2-infected cells by nasal immune cells and the subsequent tissue repair are slower in older individuals. Mechanistically, the delayed viral clearance could be related to decreased function of local macrophages that ingest dead cells and debris.”

Although most children and adolescents are spared from severe COVID, it is reported that 22% experience neurologic involvement and 12% develop life-threatening neurologic sequelae. Study findings indicate that the original COVID strain traveled more prominently along olfactory neurons toward the brain in younger infected animals, leading to an inflammatory response that might result in neurological symptoms and complications if it also occurs in humans.

This finding underscores the importance of continued research into the neurological effects of olfactory system inflammation and possible long-term impact on brain health as a function of age. Researchers say the correlation between aging and the cellular damage and subsequent immune response to SARS-CoV-2 also requires further investigation.

Looking ahead, the demonstrated infection patterns of WA-1, delta and omicron strains and transition in tropism from olfactory to respiratory epithelium offer significant implications for understanding the severity of new variants as well as for novel respiratory viruses that may emerge in the future. Initial viral replication in the olfactory epithelium and the local olfactory immune defense could be potential targets for early intervention strategies in olfactory-directed strains to mitigate disease severity and complications such as neurologic sequela.

“Given what we have shown in the paper, if SARS-CoV-2 were to continue to evolve back in the direction of olfactory tropism, we theoretically might expect a more severe disease course again,” says Lane. “In general, understanding how respiratory viruses interact with target cells in the nose and how the body’s immune system responds to initial infection is paramount to developing therapeutic strategies and identifying at-risk populations.”

Other researchers involved in this study include Andrew Pekosz, Jason S. Villano, Wenjuan Shen, Ruifeng Zhou, Heather Kulaga, Zhexuan Li, Amy Smith, Asiana Gurung, Sarah E. Beck, Kenneth W. Witwer, Joseph L. Mankowski, Murugappan Ramanathan Jr. and Nicholas R. Rowan.

Funding from this study was supported by National Institutes of Health Grants R01 AI132590, R01 DC016106 (A.P.L), the Johns Hopkins Center of Excellence for Influenza Research and Surveillance, and the generosity of the collective community of donors to the Johns Hopkins University School of Medicine for COVID research.

No authors report conflicts of interest.