What Is the Portal of Entry for COVID-19?

The primary portal of entry for SARS-CoV-2, the virus that causes COVID-19, is the lining of the nose. Ciliated cells in the nasal epithelium are the first and most important targets for viral infection, largely because they are rich in the two surface molecules the virus needs to get inside: ACE2 and TMPRSS2. But the nose is not the only door. The virus can also reach the body through the mouth, the eyes, and possibly the gut, with each route offering a slightly different pathway to infection and influencing which symptoms develop.

Why the Nose Is the Main Entry Point

SARS-CoV-2 is an airborne virus, and the nose is the first stretch of airway that inhaled particles encounter. That alone would make it important, but biology stacks the odds further. The cells lining the inside of the nose express the highest levels of ACE2, the receptor the virus latches onto, of any tissue in the entire respiratory tract.¹ Those same cells also produce TMPRSS2, a surface enzyme the virus exploits to complete its entry. The combination of high ACE2 and high TMPRSS2 in the nasal epithelium makes ciliated nasal cells the primary site where SARS-CoV-2 lands, replicates, and begins spreading.²

Research on nasal tissue samples has confirmed this at the protein level, not just the gene-expression level. One study showed that the virus’s preference for ciliated cells in the nose matches where the entry-related proteins are actually present on cell surfaces, rather than simply where the genes for those proteins are turned on.³ This distinction matters because gene activity and protein availability do not always line up, and it is the protein on the cell surface that the virus grabs hold of.

Mapping studies looking further down the respiratory tract found that ACE2 and TMPRSS2 are also present in small-airway epithelium, but the nasal epithelium consistently shows the highest combined expression of both.⁴ In practical terms, the nose acts as the beachhead: the virus establishes itself there first, then spreads downward into the throat, bronchi, and lungs as infection progresses.

How the Virus Actually Gets Inside a Cell

Once SARS-CoV-2 reaches a cell that carries ACE2 on its surface, it has two distinct routes to slip inside, and which one it takes depends on what other equipment the cell has. If the cell also has TMPRSS2, the virus can fuse directly with the cell’s outer membrane in a fast process that takes roughly ten minutes. If the cell lacks TMPRSS2, the virus gets swallowed into the cell through a slower process called endocytosis, ending up in an acidic internal compartment where a different enzyme, cathepsin L, does the job of cracking the virus open so it can release its genetic material. These two pathways are mutually exclusive on a given cell.⁵

This dual-pathway setup is one reason SARS-CoV-2 is so effective at spreading through different tissues. The nasal lining, rich in TMPRSS2, favors the fast membrane-fusion route. Cells deeper in the lungs or in other organs may rely more on the slower endosomal pathway. The virus is not locked into a single strategy.

Beyond ACE2 Alone

ACE2 gets most of the attention, but the virus does not rely on it in isolation. Several co-receptors and attachment factors help the spike protein stick to cells and facilitate entry. These include heparan sulfate proteoglycans on the cell surface, neuropilin-1, sialic acids, and others.⁶ Neuropilin-1 is especially interesting because a cleavage product of the spike protein fits neatly into one of its binding pockets, the same site normally used by a growth factor involved in blood vessel formation.⁷

Heparan sulfate, a sugar-chain molecule coating most cell surfaces, appears to serve as an initial docking station. The virus first grabs onto heparan sulfate, which concentrates it near the cell membrane and increases the chances of encountering ACE2. Lab experiments have shown that blocking heparan sulfate can inhibit viral entry, and that different blocking agents may work through distinct mechanisms, some competing with the virus at the cell surface and others binding directly to the spike protein.⁸

The Eyes as a Secondary Door

Touching your eyes with contaminated hands or being hit by respiratory droplets near the face can introduce the virus to the ocular surface. The cornea and conjunctiva carry ACE2 receptors, so direct infection of eye tissue is at least theoretically possible.⁹ But the more likely scenario is that the eyes act as a relay station rather than a final destination. The nasolacrimal duct, the small channel that drains tears from your eyes into your nasal cavity, provides a direct anatomical bridge. Virus landing on the eye surface can be washed down into the nose by normal tear drainage, where it then encounters the receptor-rich nasal lining.¹⁰

This is part of why eye protection was recommended for healthcare workers during the height of the pandemic. The eyes are a large exposed surface area, and hand-to-eye contact is one of the most common unconscious habits people have. Even if the ocular route accounts for a small fraction of infections overall, it is a plausible one, and the tear-drainage pathway means an eye exposure effectively becomes a nasal exposure within minutes.

The Mouth and Salivary Glands

The oral cavity is another significant entry zone. ACE2 and TMPRSS2 are present across the oral mucosa and in salivary gland tissue, and research has confirmed that the virus can actively infect cells in both locations.¹¹ Saliva from infected people can carry high viral loads, which is one reason talking, singing, and coughing are such effective transmission routes. Saliva is also why the virus can spread through close-range conversation even without a full-blown cough or sneeze.¹²

Receptor expression has also been found in taste buds, which may help explain the distinctive loss of taste that many COVID-19 patients experience.¹³ While taste and smell loss often get lumped together as a single symptom, they appear to involve different tissues and different mechanisms.

Why COVID-19 Causes Loss of Smell

Loss of smell was one of the most recognizable early symptoms of COVID-19 and generated a lot of public curiosity. The mechanism turned out to be indirect. The virus does not infect the olfactory neurons themselves, the nerve cells responsible for detecting odors. Instead, it infects the sustentacular cells, the support cells that surround and nourish the olfactory neurons.¹⁴ When these support cells become infected and inflamed, they disrupt the chemical environment that the olfactory neurons need to function properly, effectively shutting down smell signaling without directly damaging the neurons.

A comprehensive review of the evidence concluded that direct neuronal infection in the olfactory system is extremely rare, both at the nerve endings in the nose and in the brain. The widespread loss of smell in COVID-19 patients is better explained by these indirect effects on supporting cells than by the virus invading neurons.¹⁵ This is encouraging, because damage to support cells is typically more reversible than damage to neurons, which helps explain why most people eventually regain their sense of smell.

The Gut as an Entry Point

Gastrointestinal symptoms like diarrhea and nausea are common in COVID-19, and that is not a coincidence. The enterocytes that line the small intestine express high levels of ACE2, and lab studies using organoids, miniature lab-grown versions of intestinal tissue, have demonstrated that SARS-CoV-2 can productively infect these cells and generate new infectious viral particles.¹⁶ Whether the gut can serve as a primary portal of entry through swallowed virus, or whether intestinal infection mainly results from virus spreading internally after a respiratory infection begins, remains debated. But the gut is clearly a tissue the virus can exploit.

How Aerosol Size Determines Where the Virus Lands

Not all inhaled particles end up in the same place. The size of the droplet carrying the virus plays a major role in determining how deep into the respiratory tract it travels. Modeling of cough-generated particles found that droplets in the two-to-three micrometer range dominate the mass of exhaled particles. More than half of particles in this size range get filtered out in the upper airways, mainly the nose and throat, through inertial impaction. Particles that slip past can travel deep into the acinar airways of the lungs. Very small particles under one micrometer can also reach the deep lung, but most of them are simply exhaled back out without depositing. Larger particles, above three micrometers, overwhelmingly land in the upper airways.¹⁷

This physics helps explain the typical course of COVID-19. Most virus-laden particles deposit in the nose and throat, which is where infection begins. Only a fraction penetrates to the deep lung, but when it does, it can trigger pneumonia and more severe disease. Situations that generate finer aerosols, like prolonged loud talking or certain medical procedures, may shift the balance toward deeper deposition.

Children Have Fewer Entry Points

One of the persistent puzzles of the pandemic was why children generally had milder disease than adults. Part of the answer appears to lie at the portal of entry itself. Studies measuring ACE2 gene expression in nasal tissue found that it increases with age. Younger children had the lowest nasal ACE2 expression, with levels rising through older children, young adults, and adults.¹⁸ A separate analysis confirmed that children had lower expression of both ACE2 and TMPRSS2 in nasal and bronchial tissue compared to adults, and that smoking and chronic lung disease further increased expression in adults.¹⁹

Fewer receptors may mean less efficient viral entry and a smaller initial viral load, giving the immune system more time to mount a response before the infection takes hold. This is not the whole story, since children also differ from adults in immune function and other factors, but the reduced portal-of-entry availability is a contributing piece of the puzzle.

How Variants Changed the Entry Strategy

As SARS-CoV-2 evolved, its variants altered how the virus gets into cells in subtle but consequential ways. The Omicron variant, which became dominant in late 2021, showed a reduced ability to use the fast TMPRSS2-dependent membrane fusion pathway compared to earlier strains like Delta. Lab studies demonstrated that Omicron’s spike protein inefficiently uses TMPRSS2 and relies more heavily on the slower endosomal pathway involving cathepsin L.²⁰ Additional research found that Omicron favors this cathepsin-dependent route while Delta favored the TMPRSS2-dependent route.²¹

This shift in entry preference helps explain why Omicron tended to replicate more efficiently in the upper airways and less efficiently in the deep lung compared to Delta. The deep lung cells are rich in TMPRSS2 and favor the fast-fusion pathway, while upper airway cells offer both pathways. The result was a variant that spread more readily (upper airway replication means more virus in exhaled air) but caused less severe pneumonia on average. However, when researchers tested Omicron in human airway epithelial cultures that closely mimic real tissue, they found that serine proteases, the TMPRSS2 family, still played a role in entry, suggesting the picture is more nuanced than pure cell-line experiments implied.²²

Can the Virus Reach the Brain?

Neurological symptoms in COVID-19, including brain fog, headaches, and cognitive impairment, raised the question of whether SARS-CoV-2 can cross into the brain. Several potential routes have been identified. The olfactory nerve, the trigeminal nerve, and the vagus nerve could each theoretically carry the virus from infected peripheral tissues toward the brain through retrograde transport along nerve fibers.²³ The virus might also reach the brain through the bloodstream, particularly if the blood-brain barrier has been weakened by inflammation.²⁴

That said, the evidence for large-scale direct viral invasion of the brain remains thin. Many of the neurological effects of COVID-19 are likely driven by inflammation and immune-mediated damage rather than the virus physically infecting neurons in large numbers. The brain-entry question is relevant to understanding long COVID and persistent cognitive symptoms, but distinguishing between direct viral damage and indirect inflammatory damage is an area where research is still catching up.

Mucosal Immunity at the Gateway

The tissues lining the nose, mouth, and throat are not passive targets. They come equipped with mucosal immune defenses that act as the first barrier the virus has to overcome. Secretory IgA antibodies produced at mucosal surfaces can neutralize the virus before it ever reaches a cell, and this mucosal immunity likely plays a significant role in the large number of infections that remain asymptomatic or mild.²⁵ This is one reason researchers have been interested in developing nasal vaccines: they could potentially stimulate immunity right at the portal of entry, stopping infection before it starts rather than limiting it after the virus has already spread.

Environmental conditions at the portal of entry also matter. The nasal passages normally warm and humidify inhaled air, and innate immune responses in the upper airway epithelium work best under optimal temperature and humidity conditions. When inhaled air is cold and dry, both the conditioning function and the local immune response are weakened, which may contribute to the seasonal patterns of respiratory virus transmission.

Smoking Makes the Door Wider

If the nasal and oral epithelium is the main gateway, then anything that increases receptor density on those cells effectively widens the door. Cigarette smoke does exactly that. Experiments on gingival epithelial cells, the cells lining the gums, showed that exposure to cigarette smoke condensate increased both ACE2 and TMPRSS2 expression. The same exposure increased the cells’ uptake of SARS-CoV-2 pseudovirus, and the effect was tied to activation of a specific signaling pathway triggered by chemicals in cigarette smoke.²⁶ This is consistent with the broader finding that smoking and chronic lung disease are associated with higher receptor expression in the airways.

Nasal Sprays That Target the Portal

Because the nasal epithelium is the primary entry site, researchers have explored whether topical nasal treatments could block infection right at the source. A phase 2 clinical trial of azelastine nasal spray, an antihistamine commonly used for allergies, found that it significantly reduced SARS-CoV-2 infections and upper respiratory infections overall when used regularly.²⁷ Another approach uses astodrimer sodium, a branched molecule formulated in a nasal spray that works by binding to the spike protein and blocking its interaction with heparan sulfate on the cell surface, preventing the virus from ever reaching ACE2.²⁸

These strategies reflect a simple logic: if you can block the virus at the first tissue it contacts, you may prevent infection entirely rather than trying to fight it once it has spread. Neither approach has replaced vaccines or standard prevention, but they represent a promising line of defense for future respiratory virus threats.

Vertical Transmission During Pregnancy

A less common but clinically important portal of entry is the placenta. Syncytiotrophoblasts, the outer layer of placental tissue that sits at the boundary between the mother’s blood and the fetus, carry ACE2 receptors and can be infected by SARS-CoV-2.²⁹ Some studies of third-trimester placentas from COVID-positive pregnancies found that the spike protein co-localized with ACE2 at this maternal-fetal interface, although ACE2 expression appeared to be downregulated compared to uninfected placentas.³⁰ Confirmed cases of vertical transmission from mother to fetus have been documented but remain relatively rare.

Cross-Species Entry and the Broad Host Range

The portal of entry is not unique to humans. SARS-CoV-2’s ability to bind ACE2 gives it access to a remarkably wide range of host species. A functional analysis of ACE2 from dozens of mammals found that 44 out of 48 tested orthologs could bind the spike protein and support viral entry, including domestic animals, pets, livestock, and animals found in zoos and aquariums.³¹ The key binding site on ACE2 can tolerate up to seven amino acid substitutions out of the twenty residues that contact the spike protein and still function as a receptor, which explains the broad susceptibility.³² Old World primates fall into the highest risk category based on ACE2 similarity, while New World monkeys have sequence differences that prevent binding entirely.³³

Receptor availability alone does not determine the full picture of susceptibility. Animal species also differ in the additional proteases needed for viral entry and in their immune responses, so high ACE2 expression does not automatically mean severe disease.³⁴ Still, the breadth of the virus’s potential host range underscores why spillover events into animal populations have been a persistent concern throughout the pandemic, and why monitoring wildlife reservoirs remains relevant for future preparedness.