Which receptor is located in the lungs

Increased levels of ACE2 in the lungs, as well as reduced levels in the vascular system, in T2D or obese patients and the possible mechanisms associated with the severity of COVID have recently been reviewed Kruglikov et al. ACE2 expression in the pancreas has also been under scrutiny, but results differ significantly between studies. Alternatively, the fact that diabetic patients are at high-risk of severe COVID disease could be related to their overall elevated metabolic inflammation which may predispose to the cytokine storm syndrome associated with multi-organ failure Bornstein et al.

Upon infection by SARS-CoV-2, the inflammatory state in T2D patients could be further exacerbated possibly leading to the cytokine storm and multi-organ failure Bornstein et al. Considering that the severity of COVID is highly associated with an age over 70 years except for obesity assessing the role of age on ACE2 expression in patients with comorbidities in extensive retrospective epidemiological studies would provide a broader picture of risk factors and accurately inform on the potential consequences of modulating ACE2.

Importantly, data collected from COVID patients at the beginning of the pandemics were mostly cross-sectional and limited to the description of known underlying chronic diseases without stratification according to therapeutic treatment.

Therefore, the question arose whether the observed association of comorbidities with COVID severities might result from the treatments rather than the condition itself. Limited data supports that anti-diabetic treatments, Pioglitazone or Liraglutide, also increase ACE2 mRNA and protein IB, ab in liver and adipose tissue and in the lung and the heart, respectively Pal and Bhadada, ; Zhang et al. The impact of corticosteroids or bronchodilators in COPD has to the best of our knowledge not yet been assessed.

Overall, the impact of treatments on ACE2 remains to be fully explored in humans. While evidence supports ACE2 increase in at least some comorbidities or in response to their associated treatments, it is not possible to conclude on the causality between ACE2 expression levels and the severity of COVID Pal and Bhadada, ; Vaduganathan et al.

Another meta-analysis of 9 studies including COVID patients with hypertension showed that while there was no association between treatment with RAS inhibitor and the severity of the disease, patients under RAS treatment were less likely to die OR 0.

A possible alternative explanation that was recently discussed for comorbidities is that disfunction or absence of ACE2 may result in increased levels of AngII and hyperactivation of B1R which leads to inflammation, fibrosis, oxidative stress, vasoconstriction and angioedema Chung et al.

In addition, while infection progresses, virus entry leads to the intake of ACE2, thereby resulting in a decreased amount of ACE2 at the membrane. It is possible that in patients presenting comorbidities associated with a dysregulation of the RAS system, AngII modulation by SARS-CoV-2 reaches a critical level that ultimately induces an inflammatory state causing fatal issues.

Further studies are required to determine if the use of neuropilins as co-receptors may partly explain that low levels of ACE2 in the respiratory epithelium are sufficient to allow efficient entry of SARS-CoV Heparan sulfate HS , a negatively charged polysaccharide often found attached to proteins proteoglycans on the cell surface and extracellular matrix Simon Davis and Parish, , has been proposed to act as co-receptor of SARS-CoV Differences in the structure and composition of HS between tissues is thought to define the tropism of some viruses Cagno et al.

A similar mechanism is suggested for murine coronavirus strain JHM infection that is sensitive to neuraminidase treatment and is enhanced upon expression of the entry receptor mouse carcinoembryonic antigen-related cell adhesion molecule mCEACAM Qing et al. As of today, this remains speculative and mostly based on in-silico predictions and modeling. Although these studies propose distinct regions of interaction of S with sialic acids, they point to a model in which SARS-CoV-2 could bind to ganglioside regions exposed at the cell membrane potentially favoring the subsequent interaction of the RBD with ACE2 Figure 1.

This is even more true for the potential role of sialic acids that remains speculative. Further studies, ideally in vivo in animal models or in patients will be necessary to delineate the specific role of each of these elements in the control of SARS-CoV-2 infection and whether they constitute potential therapeutic targets to effectively inhibit the spread of the virus in the respiratory system.

Whether the specific distribution of one or more of these factors in specific cell types could define SARS-CoV-2 tropism is a topic of interest. Despite convincing evidence that ACE2 is a high affinity receptor for SARS-CoV-2, the limited levels of expression throughout the respiratory system allow speculation on the uniqueness of this entry route.

CD protein is also highly detectable by IHC anti-CD detects only one band at the expected molecular weight by IB in the airway epithelium of lung tissue sections Aguiar et al. This same antibody has been tested in 17 COVID patients, 4 of which with moderate, 6 with severe and 7 with critical symptoms Bian et al. In conclusion, preliminary observations notably through patient treatment argue in favor of additional mechanistic studies to determine whether CD is involved in virus entry and defines novel tropism.

While GRP78 mainly resides in the ER, plasma membrane localization is also observed upon response to cellular stress Ibrahim et al. However, this study relies on the structure of S that differs from previously published structure obtained by cryo-EM in the number of disulfide bonds Wrapp et al. Indeed, while in the early phase of the pandemic, SARS-CoV-2 was believed to behave like other respiratory viruses leading to ARDS, it is now very clear that it is a very unusual pathogen that provokes manifestations outside the respiratory apparatus leading to fatal outcomes in vulnerable people.

Although research on receptors and proteases has highly benefited from accumulated knowledge on other human coronaviruses, notably the closely related SARS-CoV, much remains to be learned in the context of SARS-CoV-2 infection. Although this is a plausible model, it is disputed by the observation that ACE2 is at most poorly expressed in the respiratory epithelium. Whether co-receptors, such as NRP1, HS or sialic acids, exposed at the surface of target cells could be part of the answer to define a two-step attachment mechanism should be further addressed.

Research on alternative routes of entry is also worth pursuing. CD has emerged as a potential alternative entry receptor, but the fact that it is ubiquitously expressed raises questions about associated mechanisms that would be needed to explain the restricted tropism of SARS-CoV With COVID emerging as a disease with vascular consequences rather than just a respiratory syndrome, the identity of entry receptors is an even more important topic.

Intriguing preliminary data suggesting infection of endothelial cells is consistent with the role of ACE2. However, more solid data, notably relying on post-mortem analyses or from relevant animal models, are urgently needed to validate this observation and determine whether it is anecdotic or more widespread among COVID patients.

Such data will have an immense impact on our understanding of COVID pathogenesis and would undoubtedly guide future development of therapies. Finally, with the information currently available, it is very difficult to conclude on the role of the modulation of the entry receptors in patients with comorbidities associated with severe symptoms and fatal outcome of COVID The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

This article is distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use and redistribution provided that the original author and source are credited. Article citation count generated by polling the highest count across the following sources: PubMed Central , Crossref , Scopus. B-cell receptor BCR -mediated antigen internalization and presentation are essential for humoral memory immune responses.

Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown.

Here, we show that BCR-mediated recognition of antigen tethered to beads, to planar lipid-bilayers or expressed on cell surfaces causes localized plasma membrane PM permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers PM repair responses involving lysosomal exocytosis, and B-cells permeabilized by surface-associated antigen internalize more antigen than cells that remain intact.

Higher affinity antigens cause more B-cell permeabilization and lysosomal exocytosis and are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, providing the extracellular hydrolases that facilitate antigen internalization and presentation. Multiple mitogenic pathways capable of promoting mammalian cardiomyocyte CM proliferation have been identified as potential candidates for functional heart repair following myocardial infarction.

However, it is unclear whether the effects of these mitogens are species-specific and how they directly compare in the same cardiac setting. In 2D-cultured CMs from both species, and in highly mature 3D-engineered cardiac tissues generated from NRVMs, a constitutively active mutant form of the human gene Erbb2 cahErbb2 was the most potent tested mitogen.

Persistent expression of cahErbb2 induced CM proliferation, sarcomere loss, and remodeling of tissue structure and function, which were attenuated by small molecule inhibitors of Erk signaling. Cited 64 Views 18, Annotations Open annotations.

The current annotation count on this page is being calculated. Takamori, S. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons.

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Martin, C. Schmiedebergs Arch. Download references. The authors declare that they have no conflicts of interest with the contents of this article. We thank Dr. Donald Joseph and Dr. Kechun Yang for aid in electrophysiology, and Dr. Coyle for generously providing serine racemase knockout tissue lysates. Cynthia J. Panettieri Jr. You can also search for this author in PubMed Google Scholar.

Correspondence to David R. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Reprints and Permissions. Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells. Sci Rep 11, Download citation. Received : 07 August Accepted : 29 March Published : 15 April The cells in the airways are secretory, not neuronal, cells, and they may carry more than one receptor, so they are broadly tuned.

Instead of sending nerve impulses to the brain, they flood local nerves and muscles with serotonin and neuropeptides. The different mechanisms explain why cognition plays a much stronger role in taste and smell than in coughing in response to an irritant. It is possible, for example, to develop a taste for beer.

But nobody learns not to cough; the response is rapid and largely automatic. The scientists suspect these pulmonary neuroscretory cells contribute to the hypersensitivity of patients with COPD to airborne irritants. COPD is a group of diseases, including emphysema, that is characterized by coughing, wheezing, shortness of breath and chest tightness.

When the scientists looked at the airway tissues from patients with COPD, they discovered that they had more of these neurosecretory cells than airway tissues from healthy donors. But there is a problem.

They would be welcome. There has been a steep rise in these diseases in the past few decades, treatment options have been limited, and there are no cures. Building bacteria to keep us well. Edmond, Reis to serve as co-interim deans of Brown School. Are supply chain disruptions here to stay? Why is the North American fall so red, compared with Europe?