Viral mechanisms, tropism, and clinical relevance regarding the ophthalmic manifestations of SARS-CoV-2 infection

To explore the mechanisms underlying ocular infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we conducted a comprehensive review of current literature, focusing on viral entry pathways, receptor expression in ocular tissues, and associated clinical manifestations. This review encompasses studies published within the last five years with a focus on original research and systematic reviews that provide molecular, histological, or clinical evidence. The findings show that SARS-CoV-2 can infect ocular tissues through multiple receptors beyond angiotensin-converting enzyme 2 (ACE2), including transmembrane serine protease 2 (TMPRSS2), CD147, alanyl aminopeptidase N (ANPEP), dipeptidyl peptidase 4 (DPP4), angiotensin II receptor type 2 (AGTR2), and polymeric immunoglobulin receptor (PIGR), which are expressed in retinal, conjunctival, corneal, limbal, and photoreceptor cells. The virus may also reach ocular structures <i>via</i> neurovascular invasion. Clinically, patients with coronavirus disease 2019 (COVID-19) may present with a broad spectrum of ophthalmic manifestations, including conjunctivitis, hyperreflective lesions in the inner retinal layers, flame-shaped hemorrhages, cotton-wool spots, retinal pallor, hard exudates, and various forms of maculopathy, such as paracentral acute middle maculopathy and acute macular neuroretinopathy (AMN). These signs reflect both direct viral damage and secondary effects of systemic inflammation and microvascular injury. Understanding the molecular and clinical spectrum of ocular involvement is essential for early diagnosis, appropriate ophthalmologic care, and the prevention of long-term visual sequelae in patients affected by COVID-19.