The concept of a “portal of entry” describes the route an infectious agent uses to gain initial access to a host’s body and begin the process of infection. For Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, this portal is defined by the mucosal surfaces of the head, throat, and eyes. As a highly transmissible respiratory pathogen, the virus is primarily contained within respiratory droplets and aerosols expelled by an infected person. These airborne particles are then either inhaled or directly deposited onto susceptible mucosal tissue in a new host.
The Anatomical Entry Points
The primary and most efficient anatomical site for SARS-CoV-2 entry is the nasal cavity, particularly the tissue lining the superior and middle nasal turbinates. The epithelial cells within this region possess a high concentration of the specific cellular receptors the virus requires for attachment. Studies show that a nasal infection is highly likely to be established within one to two days of minimal exposure due to this high receptor density.
The oral cavity is recognized as a secondary, yet still significant, portal of entry, especially the mucosa of the tongue and the gingival sulcus. These tissues also express the necessary cellular receptors, allowing the virus to establish an infection or to be harbored as a reservoir. Viral presence in the mouth creates a potential route for the virus to spread both downward into the respiratory tract and into the gastrointestinal system. The throat and upper pharynx, which receive drainage from the nasal cavity, also present susceptible mucosal surfaces that contribute to the initial colonization.
The conjunctiva, the thin membrane covering the eye, is another potential, though less common, site of initial contact. While the eye surface does express the necessary entry factors, the high volume of tear production makes it a less favorable environment for viral attachment compared to the nasal lining. Virus deposited on the ocular surface can drain through the nasolacrimal duct, providing a direct pathway for the viral particles to reach the highly susceptible nasal mucosa. Thus, the eye can facilitate the virus’s transfer to the primary respiratory entry site.
The Molecular Mechanism of Cellular Access
Once a viral particle lands on a mucosal surface, the process of cellular entry is governed by a precise molecular “key-and-lock” mechanism. The spike (S) protein, a large glycoprotein that decorates the surface of the SARS-CoV-2 virion, acts as the key for entry. This protein must bind to a specific receptor on the surface of the host cell, which acts as the lock. The host cell receptor utilized by SARS-CoV-2 is the Angiotensin-Converting Enzyme 2, or ACE2.
The interaction between the viral spike protein and the host cell’s ACE2 receptor is the determinant step in establishing an infection. The spike protein binds to the ACE2 receptor with high affinity, effectively docking the virus to the cell membrane. This binding is not sufficient for entry, as the spike protein must first be “primed” by a host cell protease. This priming step involves the host protease cutting the spike protein at specific cleavage sites, which activates the protein for the subsequent step of membrane fusion.
The most prominent host enzyme involved in this priming is Transmembrane Protease, Serine 2, or TMPRSS2, which is co-expressed with ACE2 on the surface of respiratory epithelial cells. TMPRSS2 cleaves the spike protein, exposing a fusion domain that enables the viral and cellular membranes to merge. This membrane fusion event allows the genetic material of the virus to be released directly into the host cell’s cytoplasm, completing the cellular access step. In cells lacking TMPRSS2, the virus can enter through a slower, less efficient pathway involving endocytosis, where the entire particle is engulfed by the cell.
Initial Infection and Localized Spread
Following successful cellular access, the virus immediately begins rapid replication within the first host cells, primarily the respiratory epithelial cells of the nasal cavity. This initial phase leads to a quick rise in the concentration of infectious viral progeny within the tissue. Studies on nasal turbinate tissue show a productive infection with a substantial increase in viral genetic material within the first 24 hours post-infection.
This localized replication phase causes immediate damage to the respiratory epithelium, specifically targeting and destroying ciliated cells. Ciliated cells are responsible for mucociliary clearance, the body’s mechanism for sweeping mucus and trapped pathogens out of the airways. The destruction of these cells impairs the body’s ability to clear the virus, leading to further viral persistence and shedding into the environment. This localized infection in the upper respiratory tract is often what causes the first, milder symptoms like nasal congestion and a runny nose.
The upper respiratory tract infection can then progress to a lower respiratory tract infection via a process of “self-transmission.” This occurs through two primary mechanisms: the aspiration of infected mucus and nasal secretions that drain down the throat and into the lungs, and the re-inhalation of aerosols generated from the infected mucosal membranes. This downward spread of the virus can eventually lead to more severe disease, with the infection establishing itself in the lower airways and lung tissue.