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1.
Front Immunol ; 12: 785355, 2021.
Article in English | MEDLINE | ID: covidwho-1594099

ABSTRACT

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.


Subject(s)
Aging/immunology , COVID-19/immunology , Immunity, Innate/immunology , Lung/immunology , Nociceptors/immunology , SARS-CoV-2/immunology , Transient Receptor Potential Channels/immunology , Aged , COVID-19/virology , Humans , Lung/innervation , Lung/virology , Nociceptors/metabolism , Nociceptors/virology , SARS-CoV-2/physiology , Sensory Receptor Cells/immunology , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/virology , Transient Receptor Potential Channels/metabolism
2.
Dev Cell ; 56(23): 3250-3263.e5, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1458566

ABSTRACT

Viral entry and egress are important determinants of virus infectivity and pathogenicity. ß-coronaviruses, including the COVID-19 virus SARS-CoV-2 and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. Here, we show that SARS-CoV-2 ORF3a, but not SARS-CoV ORF3a, promotes lysosomal exocytosis. SARS-CoV-2 ORF3a facilitates lysosomal targeting of the BORC-ARL8b complex, which mediates trafficking of lysosomes to the vicinity of the plasma membrane, and exocytosis-related SNARE proteins. The Ca2+ channel TRPML3 is required for SARS-CoV-2 ORF3a-mediated lysosomal exocytosis. Expression of SARS-CoV-2 ORF3a greatly elevates extracellular viral release in cells infected with the coronavirus MHV-A59, which itself lacks ORF3a. In SARS-CoV-2 ORF3a, Ser171 and Trp193 are critical for promoting lysosomal exocytosis and blocking autophagy. When these residues are introduced into SARS-CoV ORF3a, it acquires the ability to promote lysosomal exocytosis and inhibit autophagy. Our results reveal a mechanism by which SARS-CoV-2 interacts with host factors to promote its extracellular egress.


Subject(s)
ADP-Ribosylation Factors/metabolism , Autophagy , Exocytosis , Lysosomes/physiology , Transient Receptor Potential Channels/metabolism , Viroporin Proteins/metabolism , Virus Release , ADP-Ribosylation Factors/genetics , Animals , COVID-19/virology , HeLa Cells , Humans , Mice , SARS-CoV-2/isolation & purification , Transient Receptor Potential Channels/genetics , Viroporin Proteins/genetics
3.
Cells ; 10(7)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1323124

ABSTRACT

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.


Subject(s)
Pneumonia/metabolism , Protein Multimerization , Transient Receptor Potential Channels/metabolism , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Ion Channel Gating , Models, Biological , Pneumonia/pathology , Pneumonia/physiopathology
4.
Chem Biol Interact ; 345: 109567, 2021 Aug 25.
Article in English | MEDLINE | ID: covidwho-1275178

ABSTRACT

Coronavirus disease 2019 [COVID-19] is a global health threat caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV2] that requires two proteins for entry: angiotensin-converting enzyme 2 [ACE2] and -membrane protease serine 2 [TMPRSS2]. Many patients complain from pneumonia, cough, fever, and gastrointestinal (GI) problems. Notably, different TRP channels are expressed in various tissues infected by SARS-CoV-2. TRP channels are cation channels that show a common architecture with high permeability to calcium [Ca2+] in most sub-families. Literature review shed light on the possible role of TRP channels in COVID-19 disease. TRP channels may take part in inflammation, pain, fever, anosmia, ageusia, respiratory, cardiovascular, GI and neurological complications related to COVID-19. Also, TRP channels could be the targets for many active compounds that showed effectiveness against SARS-CoV-2. Desensitization or blocking TRP channels by antibodies, aptamers, small molecules or venoms can be an option for COVID-19 prevention and future treatment. This review provides insights into the involvement of TRP channels in different symptoms and mechanisms of SARS-CoV-2 , potential treatments targeting these channels and highlights missing gaps in literature.


Subject(s)
COVID-19/drug therapy , COVID-19/prevention & control , Molecular Targeted Therapy , Transient Receptor Potential Channels/metabolism , COVID-19/metabolism , Humans
5.
Int Rev Cell Mol Biol ; 363: 203-269, 2021.
Article in English | MEDLINE | ID: covidwho-1212320

ABSTRACT

An increase in intracellular Ca2+ concentration ([Ca2+]i) regulates a plethora of functions in the cardiovascular (CV) system, including contraction in cardiomyocytes and vascular smooth muscle cells (VSMCs), and angiogenesis in vascular endothelial cells and endothelial colony forming cells. The sarco/endoplasmic reticulum (SR/ER) represents the largest endogenous Ca2+ store, which releases Ca2+ through ryanodine receptors (RyRs) and/or inositol-1,4,5-trisphosphate receptors (InsP3Rs) upon extracellular stimulation. The acidic vesicles of the endolysosomal (EL) compartment represent an additional endogenous Ca2+ store, which is targeted by several second messengers, including nicotinic acid adenine dinucleotide phosphate (NAADP) and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], and may release intraluminal Ca2+ through multiple Ca2+ permeable channels, including two-pore channels 1 and 2 (TPC1-2) and Transient Receptor Potential Mucolipin 1 (TRPML1). Herein, we discuss the emerging, pathophysiological role of EL Ca2+ signaling in the CV system. We describe the role of cardiac TPCs in ß-adrenoceptor stimulation, arrhythmia, hypertrophy, and ischemia-reperfusion injury. We then illustrate the role of EL Ca2+ signaling in VSMCs, where TPCs promote vasoconstriction and contribute to pulmonary artery hypertension and atherosclerosis, whereas TRPML1 sustains vasodilation and is also involved in atherosclerosis. Subsequently, we describe the mechanisms whereby endothelial TPCs promote vasodilation, contribute to neurovascular coupling in the brain and stimulate angiogenesis and vasculogenesis. Finally, we discuss about the possibility to target TPCs, which are likely to mediate CV cell infection by the Severe Acute Respiratory Disease-Coronavirus-2, with Food and Drug Administration-approved drugs to alleviate the detrimental effects of Coronavirus Disease-19 on the CV system.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Calcium Signaling/physiology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/metabolism , Cardiovascular System/metabolism , Lysosomes/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/metabolism , Animals , Brain/blood supply , Brain/metabolism , COVID-19/metabolism , Calcium Channels/metabolism , Cardiovascular Diseases/drug therapy , Endoplasmic Reticulum/metabolism , Endothelial Cells/metabolism , Humans , Models, Cardiovascular , Myocytes, Cardiac/metabolism , NADP/analogs & derivatives , NADP/metabolism , Receptors, Adrenergic, beta/metabolism , Sarcoplasmic Reticulum/metabolism , Transient Receptor Potential Channels/metabolism
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