Why does COVID-19 disproportionately affect older people

JCI Insight

Central European Journal of Immunology

COVID-19 is a highly contagious respiratory disease caused by the novel coronavirus SARS-CoV-2. Since October 2020 the second wave of the pandemic has been observed around the world, as pathogen specific herd immunity has not been built yet. Moreover, the current, more contagious pathogen carrying the D614G mutation has become the globally dominant form of SARS-CoV-2. In this article we present the current state of knowledge on the impact of ACE2 and the reninangiotensin system (RAS) and the innate immune system on different outcomes of COVID-19. Especially, we point out the dual role of the immune system and ACE2 in pathogenesis of the disease. Namely, at the initial stage of the infection anti-viral activity of innate immunity is responsible for inhibition of SARS-CoV-2 replication. On the other hand, a dysregulated immune response may cause the detrimental hyperinflammation ("cytokine storm") responsible for the severe course of the disease. Concomitantly, we analyse the roles of ACE2 in both facilitation of infection and abrogation of its effects, as the major cellular entry receptor for SARS-CoV-2 and an important enzyme responsible for tissue protection, respectively. Finally, we discuss the dominant impact of aging on the fatal outcome of COVID-19.

Biomedicines

Background. Clinical and experimental evidence point to a dysregulated immune response caused by SARS-CoV-2 as the primary mechanism of lung disease in COVID-19. However, the pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. This study aims to explore the inflammatory responses of alveolar epithelial cells to either the spike S1 protein or to a mixture of cytokines secreted by S1-activated macrophages. Methods and Results. The exposure of alveolar A549 cells to supernatants from spike-activated macrophages caused a further release of inflammatory mediators, with IL-8 reaching massive concentrations. The investigation of the molecular pathways indicated that NF-kB is involved in the transcription of IP-10 and RANTES, while STATs drive the expression of all the cytokines/chemokines tested, with the exception of IL-8 which is regulated by AP-1. Cytokines/chemokines produced by spike-activated macrophages are ...

Nepal Journal of Medical Sciences

2020

ABSTRACTThe clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptor ACE2 within the airway epithelial cell compartment. ACE2 is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction ...

CHEST Journal, 2003

services can be found online on the World Wide Web at: The online version of this article, along with updated information and ISSN:0012-3692 ) http://chestjournal.chestpubs.org/site/misc/reprints.xhtml Abbreviations: IFN ϭ interferon; IL ϭ interleukin; LPS ϭ lipopolysaccharide; mRNA ϭ messenger RNA; TNF ϭ tumor necrosis factor *From the Departments of Pulmonology (Drs. Lutter, Roger, Bresser, and Jansen), Experimental Immunology (Mr. van Wissen), and Experimental Internal Medicine (Mr. van der

Frontiers in Pharmacology, 2020

With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

2020

Currently, animal-to-human transmission of SARS-CoV-2 (COVID-19) has not yet been confirmed, whereas the main mode of transmission is human-to-human. Droplets are the main route of human-to-human transmission, whereas aerosols could be another route in addition to stool-based transmission. Currently, no evidence is available to indicate intrauterine vertical transmission of SARS-CoV-2 (COVID-19) in pregnant women. In the host, the life cycle of coronavirus consists of 5 steps: 1) attachment, 2) penetration, 3) biosynthesis, 4) maturation, and 5) release. Once viruses bind to host receptors (attachment), they enter host cells, particularly type II pneumocytes via endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the host's nucleus for replication and making viral proteins (biosynthesis). New viral particles are produced (maturation) and released. Spike protein of coronaviruses which determines the diversity of coronaviruses and host tropism is composed of a transmembrane trimetric glycoprotein protruding from the viral surface. Structural and functional studies demonstrated that the spike protein the of coronaviruses can bind to angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV. ACE2 expression is high in lung (high expression on lung epithelial cells), heart, ileum, and kidney. The lungs of severe COVID-19 patients demonstrate infiltration of a large number of inflammatory cells. Due to high ACE2 expression on the apical side of lung epithelial cells in the alveolar space, SARS-CoV-2 (COVID-19) can enter and destroy lung epithelial cells. Significant ACE2 expression on innate lymphoid cells (ILC)2, ILC3, and endothelial cells is also demonstrated. Pulmonary endothelial cells represent one third of the lung cells. Endothelial function includes promotion of anti-aggregation, fibrinolysis, and vasodilatation. Due to a significant role playing in thrombotic regulation, hypercoagulable profiles that are demonstrated in severe COVID-19 patients likely suggest significant endothelial injury. Pulmonary thrombosis and embolism accompanying elevation of d-dimer and fibrinogen levels have been demonstrated in severe COVID-19. In conclusion, further studies on understanding the roles of ILC1, ILC2, ILC3, including the difference in response to SARS-CoV-2 (COVID-19) infection between children and adults are urgently needed to develop efficient targeted therapies.

EC Pulmonology and Respiratory Medicine, 2020

Currently, animal-to-human transmission of SARS-CoV-2 (COVID-19) has not yet been confirmed, whereas the main mode of transmission is human-to-human. Droplets are the main route of human-to-human transmission, whereas aerosols could be another route in addition to stool-based transmission. Currently, no evidence is available to indicate intrauterine vertical transmission of SARS-CoV-2 (COVID-19) in pregnant women. In the host, the life cycle of coronavirus consists of 5 steps: 1) attachment, 2) penetration, 3) biosynthesis, 4) maturation and 5) release. Once viruses bind to host receptors (attachment), they enter host cells, particularly type II pneumocytes via endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the host's nucleus for replication and making viral proteins (biosynthesis). New viral particles are produced (maturation) and released. Spike protein of coronaviruses which determines the diversity of coronaviruses and host tropism is composed of a transmembrane trimetric glycoprotein protruding from the viral surface. Structural and functional studies demonstrated that the spike protein the of coronaviruses can bind to angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV. ACE2 expression is high in lung (high expression on lung epithelial cells), heart, ileum, and kidney. The lungs of severe COVID-19 patients demonstrate infiltration of a large number of inflammatory cells. Due to high ACE2 expression on the apical side of lung epithelial cells in the alveolar space, SARS-CoV-2 (COVID-19) can enter and destroy lung epithelial cells. Significant ACE2 expression on innate lymphoid cells (ILC)2, ILC3 and endothelial cells is also demonstrated. Pulmonary endothelial cells represent one third of the lung cells. Endothelial function includes promotion of anti-aggregation, fibrinolysis, and vasodilatation. Due to a significant role playing in thrombotic regulation, hypercoagulable profiles that are demonstrated in severe COVID-19 patients likely suggest significant endothelial injury. Pulmonary thrombosis and embolism accompanying elevation of d-dimer and fibrinogen levels have been demonstrated in severe COVID-19. In conclusion, further studies on understanding the roles of ILC1, ILC2, ILC3, including the difference in response to SARS-CoV-2 (COVID-19) infection between children and adults are urgently needed to develop efficient targeted therapies.

Advances in immunology, 2009

To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse model of lung disease that develops after respiratory viral infection. The disease that develops in this model is similar to asthma and chronic obstructive pulmonary disease (COPD) in humans and is manifested after the inciting virus has been cleared to trace levels. The model thereby mimics the relationship of paramyxoviral infection to the development of childhood asthma in humans. When the acute lung disease appears in this model (at 3 weeks after viral inoculation), it depends on an immune axis that is initiated by expression and activation of the high-affinity IgE receptor (FcvarepsilonRI) on conventional lung dendritic cells (cDCs) to recruit interleukin (IL)-13-producing CD4(+) T cells to the lower airways. However, when the chronic lung disease develops fully (at 7 weeks after inoculation), it is driven instead by an innate immune axis that relies on invariant natural killer T (i...