{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:59:54Z","timestamp":1789153194038,"version":"build-2803163510"},"reference-count":83,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Pregnancy represents a distinct immunological and physiological state that modifies maternal susceptibility to SARS-CoV-2 and influences the clinical and biological course of COVID-19. Accumulating evidence indicates that the interaction between viral entry determinants, gestation-specific immune modulation, placental endocrine\u2013angiogenic pathways, and systemic inflammatory responses underlies the characteristic manifestations of SARS-CoV-2 infection during pregnancy. This review consolidates current understanding of SARS-CoV-2 viral structure, receptor biology, and the gestational regulation of key entry cofactors, including ACE2, TMPRSS2, NRP1, CTSL and FURIN, within reproductive and placental tissues. The review further integrates documented mechanisms of cytokine-mediated immune dysregulation, endothelial injury, thrombo-inflammation, and steroidogenic alteration observed in affected pregnancies, and examines their contribution to placental malperfusion, preeclampsia-like presentations, fetal growth abnormalities and preterm birth. Published molecular and computational studies characterising trophoblast antiviral defenses, receptor expression patterns, and structural determinants of Spike\u2013ACE2 affinity are synthesised to contextualise the biological basis of placental susceptibility and the rarity of confirmed transplacental transmission. Current evidence on maternal clinical outcomes, fetal and neonatal consequences, vaccination efficacy, therapeutic considerations and contemporary management guidelines is also critically reviewed. By integrating molecular, immunological, pathological and clinical insights, this article provides a comprehensive framework for understanding the interaction between SARS-CoV-2 infection and pregnancy-specific physiology, with implications for risk assessment, preventive strategies and maternal\u2013fetal care.<\/jats:p>","DOI":"10.3390\/v18040426","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:08:34Z","timestamp":1775030914000},"page":"426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Placental Vulnerability to SARS-CoV-2: Viral Entry Pathways and Immune Activation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7237-874X","authenticated-orcid":false,"given":"Madhumitha","family":"Natarajan","sequence":"first","affiliation":[{"name":"Division of Molecular Biology, School of Life Sciences, Jagadguru Shri Shivaratreeshwara (JSS) Academy of Higher Education and Research, Mysore 570015, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindu","family":"Jayashankar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Sri Jayachamarajendra College of Engineering, Mysore 570006, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu","family":"Nataraj","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, School of Life Sciences, Jagadguru Shri Shivaratreeshwara (JSS) Academy of Higher Education and Research, Mysore 570015, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Shen, Q., Dong, S., Shah, N.K., Li, S., Chen, G., Mehta, N.S., Gray, K.J., Lye, S.J., Edlow, A.G., and Shook, L.L. 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