John Murphy, CEO The COVID-19 Long-haul Foundation
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is a pleiotropic pathogen with profound effects on epithelial tissues across multiple organ systems. While respiratory epithelium represents the primary portal of entry, accumulating evidence demonstrates direct and indirect viral effects on stratified squamous epithelium, dermal structures, extracellular matrix components, and epithelial–mesenchymal interfaces. These effects are mediated through viral tropism for ACE2-expressing cells, host protease availability, innate immune activation, endothelial–epithelial cross-talk, and persistent inflammatory signaling. In a subset of patients, epithelial injury persists beyond the acute phase, contributing to chronic dermatologic, mucocutaneous, and fibrotic manifestations characteristic of post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID). This review synthesizes current evidence on the etiology, genomics, epithelial physiology, tissue pathology, and clinical manifestations of SARS-CoV-2 infection involving epidermal, dermal, and matrix compartments, and critically evaluates therapeutic interventions and reported outcomes in long-haul populations.
Etiology and Viral Entry into Epithelial Tissues
SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus of the Betacoronavirus genus. Infection begins with viral attachment to the angiotensin-converting enzyme 2 (ACE2) receptor, followed by spike protein priming by host proteases including transmembrane serine protease 2 (TMPRSS2) and cathepsins. ACE2 expression is enriched in ciliated respiratory epithelial cells but is also present in keratinocytes, eccrine glands, oral mucosa, and endothelial-adjacent epithelial layers, providing a mechanistic basis for multisystem epithelial involvement.¹–³
Cutaneous epithelial infection is thought to occur through a combination of direct viral exposure, hematogenous dissemination, and immune-mediated injury. Viral RNA and protein have been detected in skin biopsies from patients with COVID-19–associated dermatologic findings, including chilblain-like lesions and vasculopathic eruptions.⁴,⁵
Genomics and Host–Epithelial Interactions
The ~30-kb SARS-CoV-2 genome encodes nonstructural proteins that interfere with host interferon signaling, epithelial barrier integrity, and cellular stress responses. Nonstructural proteins such as NSP1 and NSP6 suppress host mRNA translation and autophagy, respectively, impairing epithelial cell recovery following infection.⁶
Host genetic variability further modulates epithelial susceptibility. Polymorphisms affecting interferon signaling, keratinocyte immune responsiveness, and extracellular matrix remodeling have been implicated in variable cutaneous and mucosal outcomes.⁷ Epigenetic alterations induced by viral infection, including chromatin remodeling in epithelial progenitor cells, may contribute to persistent tissue dysfunction observed in long COVID.⁸
Physiology of Epithelial Infection and Barrier Disruption
Epithelial tissues serve as both physical barriers and immunologically active interfaces. SARS-CoV-2 disrupts tight junction proteins such as claudins and occludins, leading to increased permeability and dysregulated inflammatory signaling. In respiratory and cutaneous epithelium alike, viral infection triggers NF-κB–mediated cytokine release, recruitment of innate immune cells, and oxidative stress.⁹,¹⁰
In the skin, keratinocyte activation results in aberrant differentiation, altered cornification, and impaired wound healing. Damage to adnexal structures—including hair follicles and sweat glands—has been reported, correlating clinically with alopecia and dysautonomic sweating abnormalities in post-acute disease.¹¹
Pathology of Dermis, Epidermis, and Extracellular Matrix
Histopathologic studies of COVID-19–associated skin lesions demonstrate epidermal necrosis, vacuolar interface dermatitis, microthrombi in dermal vessels, and perivascular lymphocytic infiltrates.¹² Endothelial dysfunction plays a critical role, with complement activation and microvascular injury propagating epithelial ischemia and matrix degradation.¹³
Extracellular matrix (ECM) remodeling is a prominent feature of both acute and chronic disease. Increased matrix metalloproteinase activity, fibroblast activation, and collagen disorganization have been observed in affected tissues.¹⁴ These processes mirror fibrotic changes seen in pulmonary tissue and suggest shared pathogenic mechanisms across epithelial compartments.
Clinical Manifestations of Epithelial Involvement
Cutaneous manifestations of COVID-19 span a broad clinical spectrum, including maculopapular eruptions, urticaria, livedo reticularis, vesicular lesions, and chilblain-like acral lesions.¹⁵ Mucocutaneous involvement may include oral ulcers, glossitis, and conjunctival epithelial inflammation.
In long COVID, patients frequently report persistent dermatologic symptoms such as chronic pruritus, dysesthesia, hair loss, delayed wound healing, and episodic inflammatory rashes. These manifestations often coexist with systemic symptoms, supporting a model of ongoing epithelial–immune dysregulation.¹⁶
Post-Acute Sequelae and Long-Haul Epithelial Dysfunction
PASC affects an estimated 10–30% of individuals following SARS-CoV-2 infection.¹⁷ Persistent epithelial abnormalities may result from viral persistence in tissue reservoirs, autoantibody formation, or maladaptive tissue repair. Skin biopsies from long-haul patients have demonstrated chronic inflammatory infiltrates and altered keratinocyte gene expression months after acute infection.¹⁸
Therapeutic Interventions and Reported Outcomes
Acute Phase Management
During acute infection, management of epithelial manifestations is largely supportive. Topical corticosteroids, antihistamines, and emollients are commonly used for cutaneous symptoms, while systemic corticosteroids are reserved for severe inflammatory disease.¹⁹ Antiviral therapy may reduce epithelial viral burden when administered early.²⁰
Long COVID Treatment Regimens
There is no standardized treatment for epithelial manifestations of long COVID. Multimodal approaches have been employed, including:
- Topical and systemic anti-inflammatory agents
- Antihistamines and mast-cell stabilizers
- Low-dose corticosteroids in select cases
- Physical and dermatologic rehabilitation
Reported response rates vary widely, with partial improvement observed in approximately 40–60% of patients in observational cohorts.²¹ Controlled trial data remain limited.
Conclusion
SARS-CoV-2 exerts complex and enduring effects on epithelial tissues, extending well beyond the respiratory tract. Disruption of epithelial integrity, immune dysregulation, endothelial injury, and matrix remodeling together account for the diverse cutaneous and mucosal manifestations observed in both acute and post-acute COVID-19. Improved mechanistic understanding and rigorously designed clinical trials are urgently needed to guide treatment of long-haul epithelial disease.
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