Pink Eye: Is Covid Even Still Covid-19?

LET’S DIVE INTO THE FASCINATING AND COMPLEX WORLD OF VIROLOGY TO FIND OUT.

Shin Jie Yong

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Image by kjpargeter on Freepik

When Covid-19 first shook the world in late 2019 and 2020, an eerie disappearance of the sense of smell and taste plagued about half of the infected. This then became the tell-tale sign of Covid-19. One famous man even engulfed raw onions and garlic paste to prove his taste had indeed been robbed by SARS-CoV-2, the Covid-19 virus.

But what’s a formidable foe if it’s too predictable? For SARS-CoV-2, it was anything but predictable. As SARS-CoV-2 mutates and evolves over time, its Covid-19 symptoms began to change as well:

• In 2021, the more virulent and transmissible Delta variant of SARS-CoV-2 took over, and more infected people experienced runny noses and sore throats instead — like a bad cold. Smell and taste loss was not even listed in the top 10 most common symptoms of Delta.
• In 2022, the milder but more immune-evasive Omicron outcompeted Delta and remained the prevailing variant to this day. Instead of runny noses, sore throats and hoarse voices began to occur more often.
• In 2023, a sub-variant of Omicron dubbed Arcturus gained another level of immune evasiveness and began to dominate the landscape, and patients started getting ocular symptoms like pink eyes.

How did SARS-CoV-2 morph biologically over the years? Let’s dive into the intriguing and complex world of virology to find out.

From smell/taste loss to runny noses

What’s unique about the Covid-19 smell loss was it wasn’t accompanied by a blocked nose, suggesting that the smell loss could be neurological in origin, such as damaged olfactory neurons. (As smell and taste are intertwined, smell loss often results in taste loss as well.)

But a landmark 2020 study showed that human olfactory neurons are devoid of the ACE2 and TMPRSS2 receptors required for SARS-CoV-2 infection. Rather, the study uncovered an abundance of these receptors on sustentacular cells, i.e., cells that support the metabolism and structural integrity of olfactory neurons. Later, a brain autopsy study of Covid-19 victims affirmed that their olfactory neurons were intact but were structurally disorganized and lost their smell-sensing receptors.

These findings show that the original SARS-CoV-2 variant (aka Wuhan-2019) had a strong predilection to infect the olfactory sustentacular cells (Figure 1), resulting in smell and taste impairments.

Figure 1. A schematic representation of the olfactory epithelium connecting to the olfactory bulb in the brain. Supporting sustentacular cells are depicted in green. Source: Narayanan et al. (2020).

But as the SARS-CoV-2 evolved into the Alpha, Beta, Delta, and finally, Omicron variant, fewer and fewer infected patients had smell loss.

Did Delta and Omicron lose their predilection for sustentacular cells?

Yes, according to a 2022 study involving a human nasal tissue model — sourced from Covid-negative individuals who underwent surgery — and a hamster model. Using these models, the study showed that:

• The original SARS-CoV-2 variant readily infected sustentacular cells, causing widespread cell death. But fewer sustentacular cells got destroyed with Delta and even fewer with Omicron infection. This explains why fewer and fewer infectees had smell loss when the waves transitioned to Delta and then Omicron.
• Instead, Delta infected 21-fold more Bowman’s glands — responsible for nasal mucus production —than the original variant, explaining the deviation from smell loss to runny noses.
• For Omicron, it barely infected any cells in the olfactory system, not even the Bowman’s glands, further explaining the deviation from smell loss to other symptoms like sore throats (Figure 2).

Figure 2. Gradual loss of olfactory epithelium (OE) tropism from the original Wuhan (WA1) to Delta to Omicron variant. Red dots denote SARS-CoV-2’s nucleocapsid protein (NP), a proxy for infection. Green dots denote neuronal cells while blue dots denote normal cells. Left: In WA1, infection was mostly localized to the sustentacular cells situated near olfactory neurons (green). Middle: In Delta, infection was mostly localized to the Bowman’s glands. Right: In Omicron, barely any infection was seen in the OE. (RE is the respiratory epithelium, btw). Source: Chen et al. (2022).

More sore throats

As SARS-CoV-2 evolved into Delta and then Omicron, more and more infected patients reported having sore throats. Specifically, sore throats were about 30% more common in Delta than Alpha infection, and about 20% more common in Omicron than Delta infection.

Now, what explains the predilection towards sore throats in Covid-19? While the research is less clear-cut on this, we can speculate a few theories.

For one, runny noses and sore throats often co-occur, likely due to the close proximity of inflammatory responses. More immune cells may also be situated around the lower nose-throat area (i.e., infection site for Delta and Omicron) compared to the upper nose-brain area (i.e., infection site for the original variant), given that the brain is an immune-privilege organ with restricted immune responses. In the upper nose, the olfactory neurons directly innervate the olfactory bulb in the brain (Figure 1).

Second, Omicron is known to produce milder Covid-19 than Delta, resulting in fewer hospitalizations and deaths. A reason for this is that Omicron preferentially infects the upper airways and doesn't infect the lower airways (where the delicate lungs reside) as much as Delta.

This is because Omicron is more efficient at using the ACE2-cathepsin L endocytic route of cell infection rather than the usual ACE2-TMPSSR2 cell fusion route. And the upper airways have less TMPSSR2 than the lower airways. What’s the difference between the two routes?

• In the ACE2-TMPSSR2 infection route, the viral envelope and cell membrane fuse. But this process also causes fusion between cells, resulting in syncytium formation that kills cells. And dead cells are a dead-end to virus replication.
• But in the shift towards the ACE2-cathepsin L route in Omicron, the virus gets taken in via cell vesicles instead. And this process forms less syncytium as the cells are not forcing their way in (Figure 3).
• As such, Omicron maximizes its replication by not killing the host cells excessively — a fine balance, indeed.

The preferential use of the ACE2-cathepsin L route also explains why Omicron could not infect olfactory sustentacular cells (Figure 2). These sustentacular cells express IFITM3 (interferon-induced transmembrane protein 3), which inhibits cathepsin L-mediated endosomal entry.

The greater viral loads concentrated in the upper airways are also suspected to give Omicron an advantage over Delta in transmissibility. As follows, inflammatory immune responses directed towards Omicron would also be localized more in the upper airways, i.e., the throat.

Figure 3. SARS-CoV-2 infection via the TMPSSR2 or cathepsin L route. Right: Upon ACE2 binding, SARS-CoV-2 is activated by TMPRSS2 and the viral envelope fuses with the cell membrane. Left: Upon ACE2 binding, SARS-CoV-2 enters cells by endocytosis and the spike protein is cleaved by cathepsin L to drive fusion between viral and endosomal membranes. Source: Hoffmann & Pöhlmann (2022).

Added pink eyes/conjunctivitis

At present, the latest rising variant is the Omicron subvariant, Arcturus XBB.1.16. Arcturus has spread to over 30 countries since its emergence earlier this year, and it’s outcompeting other Omicron subvariants, even the infamous Kraken XBB.1.5 subvariant.

It’s still unclear if Arcturus is more virulent or immune evasive than other variants. But multiple reports have noted that those infected with Arcturus have one usual symptom — i.e., itchy pink eyes or conjunctivitis.

This is especially true among children, per the American Academy of Opthalmology. According to Dr. Ronald Benner, OD, an optometrist and president of the American Optometric Association, people infected with Arcturus might only have pink eyes as the only symptom of Covid.

However, such reports are brd on the anecdotal experiences of eye and infectious disease specialists. Due to its novelty, no formal studies or data analyses have been done on this matter, so caution is best exercised before attributing pink eyes as a novel symptom of Arcturus.

If true, however, it means that SARS-CoV-2 has morphed phenotypically again, this time targeting the ocular system. (Phenotype means an observable trait, such as that of a disease.)

This is not far-fetched given that cases of ocular signs as the presenting symptom of Covid-19 have been documented with older variants.

In fact, many parts of the eyes, such as the cornea, limbus, retina, and conjunctiva, have been shown to express ACE2 in several studies, laying the necessary landscape for SARS-CoV-2 infection.

This is confirmed in a 2020 study showing that SARS-CoV-2 isolated from the human nose could infect conjunctival cells of the eye as easily as respiratory cells. Another 2020 study successfully infected monkeys with SARS-CoV-2 via the eyes. As a result, the monkeys developed mild Covid-19 and shed viruses through the nose and throat. Notably, a high viral load was also found in the monkeys’ nasolacrimal system.

The nasolacrimal system drains tear fluid from the eye into the nasal cavity and then the throat (Figure 4). It’s no wonder that crying leads to sobbing. So, the nasolacrimal system may serve “as a conduit for virus-containing fluid exchange between these sites,” stated a 2013 research review.

Figure 4. Nasolacrimal system. The nasolacrimal duct (top left box) connects the tear duct to the nasal cavity, which may also serve as a conduit for infectious agents. Source: Belser et al. (2013).

Viruses infecting the respiratory system through the eyes, presumably via the nasolacrimal system, are not unheard of. The respiratory syncytial virus could replicate efficiently in the eyes and then migrate into the lungs to cause respiratory disease in mice. Certain subtypes of adenoviruses and influenza viruses can also infect the eyes to reach the respiratory system.

But we still don’t know if Arcturus has actually evolved an ability to infect individuals via the nasolacrimal system. Studies are severely scarce on this issue. If true, however, it may be wise to bring back eye shields if cases spike beyond what our healthcare system can handle.

In the end, SARS-CoV-2 has proven to be far from predictable, morphing Covid-19 from its trademark smell and taste loss to runny noses and sore throats and then to pink eyes. We can only wait and see what unexpected developments SARS-CoV-2 has in store for us in the future.

Some scientists have even proposed classifying SARS-CoV-2 into serotypes, given how far in the evolutionary genetic tree has Omicron diverged from its ancestral SARS-CoV-2 variants (Figure 5).

Is Covid-19 even the same as Covid-19 back in 2019? No, it’s vastly distinct now, in terms of both the disease phenotype and genetics.

Figure 5. A genetic phylogeny of SARS-CoV-2 global evolution and Omicron divergence. Source: Simon-Loriere and Schwartz (2022).