Immunological and physiopathological approach of COVID-19 in pregnancy

Abstract

Coronavirus disease-2019 (COVID-19) related to Coronavirus-2 (SARS-CoV-2) is a worldwide health concern. Despite the majority of patients will evolve asymptomatic or mild-moderate upper respiratory tract infections, 20% will develop severe disease. Based on current pathogenetic knowledge, a severe COVID-19 form is mainly a hyperinflammatory, immune-mediated disorder, triggered by a viral infection. Due to their particular immunological features, pregnant women are supposed to be particularly susceptible to complicate by intracellular infections as well as immunological disturbances. As an example, immune-thrombosis has been identified as a common immune-mediated and pathogenic phenomenon both in COVID-19, in obstetric diseases and in COVID-19 pregnant women. According to extensive published clinical data, is rationale to expect an interference with the normal development of pregnancy in selected SARS-CoV-2-infected cases, mainly during third trimester.This manuscript provides insights of research to elucidate the potential harmful responses to SARS-CoV-2 and /or other coronavirus infections, as well as bidirectional interactions between COVID-19 and pregnancy to improve their respective management.

Keywords: COVID-19; Hyperinflammation; Immune-mediated; Obstetric disorder; Placental disease; Pregnancy outcome; SARS-CoV-2; Viral infection.

Fig. 1

Five stage model to explain clinical and immunological spectrum of COVID-19 disease

Fig. 2

SARS-CoV 2 infection in pregnancy: hypothetical pathogenic pathways in endothelial cells. The figure represents all molecular pathogenic pathways tha may happen when SARS-CoV-2 infects endothelial cells in context of pregnancy, including the fetal-maternal interface endothelial cells. The mechanism of SARS-CoV-2 human cell entry is possible as the Spike protein (S protein) on the envelope binds to the cell membrane glycoprotein angiotensin converting enzyme (ACE) homolog 2 (ACE2), which is involved in the renin–angiotensin–aldosterone system (RAS). The S protein is cleaved into S1 and S2, which enhance ACE2 and TMPRSS2, respectively. The binding induces competitive inhibition, causing ACE2 downregulation and shedding, reducing Ang- 1–7 synthesis while shifting to an increase of ACE1 activity, increasing Ang II and turning to vasoconstriction, inflammation and vascular permeability. After entering the cells, the viral RNA genome is released into the cytoplasm and is translated into polyproteins and structural proteins, after which the viral genome begins to replicate.The mature virion enters the endosome and interacts with toll-like receptors (TLR) from the immune cells to stimulate downstream inflammatory and clot pathways. The viral nuclear integration could induce protein expression in the infected cells that would contribute to enhance the inflammatory response and cell damage both directly and indirectly, increasing pro-coagulant tissue factor and inflammatory cell adhesion and attraction proteins (E-selectine, ICAM,VCAM), as well as reducing HO/CO or NOs that would contribute to vasocontriction, tissular hypoxia and underperfusion. The primarly inflammatory responses are driven by the innate immune system activation consisting in a massive invasion of neutrophils, monocytes and macrophages that release different proinflammatory cytokines and other proteins and molecules responsible to induce cell apoptosis and pyroptosis, leading to a different grade of tissue and organ damage. Simultaneoulsy, adaptive immune system comes on the scene through antigen-dependent lymphocyte activation by antigen presenting cells (APC) bearing viral antigenic peptides on human leukocyte antigens (HLA) molecules. APC-viral antigen complexes are recognized by virus-specific B and T cells (mainly CD8+) secreting, at different times, Th1 profile cytokines, which, reinforce previous inflammation, as well as Th2 adaptive humoral response by typical viral- induced pattern of neutralizing antibodies (Nab) IgM and IgG. In some cases, the appearance of Nab not only cannot limit viral replication, but trigger an hyperimmune response, owing to antibody dependent enhancement inflammatory pathways (ADE) that perpetuate responses from macrophages and Th1-lymphocyte, releasing a cytokine storm composed by IFN-α, IFN-γ, IL-1β, IL-2,IL-6, IL-12, IL-8, TNF-α etc. and more pro-inflammatory proteins like monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 alpha (MIP-1α), or MMP(tissue matrix metalloprotease). Additionally, these secondary inflammatory responses include antibody-dependent cell-mediated cytotoxicity, Ag-Ab immuncomplexes-mediated inflammatory pathways, including transient aPL-, and complement pathway hyperactivation that contributes to increasing tissue damage and hypoxia by releasing antiagiogenic factors (sFLT-1, sENG) and inducing platelet aggregation and clot cascade hiperactivation leading to thrombotic events