SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterol-increased endosomal pH of alveolar macrophages

Cellular & molecular immunology

2022 Feb 01

Wang, Z;Lv, J;Yu, P;Qu, Y;Zhou, Y;Zhou, L;Zhu, Q;Li, S;Song, J;Deng, W;Gao, R;Liu, Y;Liu, J;Tong, WM;Qin, C;Huang, B;
PMID: 34983944 | DOI: 10.1038/s41423-021-00813-6

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

Molecular metabolism

2021 Nov 26

Costa, A;Ai, M;Nunn, N;Culotta, I;Hunter, J;Boudjadja, MB;Valencia-Torres, L;Aviello, G;Hodson, DJ;Snider, BM;Coskun, T;Emmerson, PJ;Luckman, SM;D'Agostino, G;
PMID: 34844019 | DOI: 10.1016/j.molmet.2021.101407

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated, however the neuronal substrates involved are poorly understood.We employed a combination of neuroanatomical, genetic and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain.We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs, as well as for induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance.In addition to disclosing a neuronal population that is necessary for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea - a major factor for withdrawal from treatment.

Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions

Translational psychiatry

2021 Sep 30

Han, Y;Yuan, K;Wang, Z;Liu, WJ;Lu, ZA;Liu, L;Shi, L;Yan, W;Yuan, JL;Li, JL;Shi, J;Liu, ZC;Wang, GH;Kosten, T;Bao, YP;Lu, L;
PMID: 34593760 | DOI: 10.1038/s41398-021-01629-8

The coronavirus disease 2019 (COVID-19) pandemic has caused large-scale economic and social losses and worldwide deaths. Although most COVID-19 patients have initially complained of respiratory insufficiency, the presence of neuropsychiatric manifestations is also reported frequently, ranging from headache, hyposmia/anosmia, and neuromuscular dysfunction to stroke, seizure, encephalopathy, altered mental status, and psychiatric disorders, both in the acute phase and in the long term. These neuropsychiatric complications have emerged as a potential indicator of worsened clinical outcomes and poor prognosis, thus contributing to mortality in COVID-19 patients. Their etiology remains largely unclear and probably involves multiple neuroinvasive pathways. Here, we summarize recent animal and human studies for neurotrophic properties of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and elucidate potential neuropathogenic mechanisms involved in the viral invasion of the central nervous system as a cause for brain damage and neurological impairments. We then discuss the potential therapeutic strategy for intervening and preventing neuropsychiatric complications associated with SARS-CoV-2 infection. Time-series monitoring of clinical-neurochemical-radiological progress of neuropsychiatric and neuroimmune complications need implementation in individuals exposed to SARS-CoV-2. The development of a screening, intervention, and therapeutic framework to prevent and reduce neuropsychiatric sequela is urgently needed and crucial for the short- and long-term recovery of COVID-19 patients.

LB740 SARS-CoV-2-associated ‘covid toes:’ multiplex immunofluorescent characterization of pathophysiology

Journal of Investigative Dermatology

2021 Sep 01

Moon, J;Costa da Silva, A;Tran, J;Kim, C;Sharma, R;Hinshaw, M;Shields, B;Brooks, E;Cowen, E;Singh, A;Drolet, B;Mays, J;Arkin, L;
| DOI: 10.1016/j.jid.2021.07.093

Coincident with the start of the COVID-19 pandemic, dermatologists worldwide have reported an uncharacteristic increase in pernio or chilblains (aka ‘COVID toes’). However, the lack of systemic illness, low PCR positivity and lack of consistent seroconversion have led some authors to postulate an epiphenomenon. SARS-CoV-2 spike protein has been identified in a limited number of skin biopsies in few publications, yet there remain conflicting reports regarding other SARS-CoV-2 associated proteins, the presence or absence of viral RNA, and a unifying pathophysiology. In cooperation with the COVID Human Genome Effort, our “COVID toes” biobank was established to identify both the genetic and immunologic basis and provide clinically relevant insights into targeted therapeutics. As of March 2021, we have enrolled 96 patients, creating a prospective biorepository with clinical data, saliva, serial blood collection, and skin biopsies. Here we aim to comprehensively investigate the conflicting findings, detail the inflammatory response, and identify the source of interferon signaling with multiplex immunofluorescence (IFA) and the RNAscope fluorescent assay to detect viral mRNA. Median patient age was 17 (range 2 e 72) and 44/96 (46%) were male. Preliminary IFA results demonstrate detection of SARS-CoV-2 components, robust MxA detection and plasmacytoid dendritic cell (pDC) colocalization, identifying PDCs as the likely primary source of IFN-I production and implicates an excessive localized IFN-I response in affected patients.

Long-term functional alterations following prenatal GLP-1R activation

Neurotoxicology and teratology

2021 Apr 20

Graham, DL;Madkour, HS;Noble, BL;Schatschneider, C;Stanwood, GD;
PMID: 33864929 | DOI: 10.1016/j.ntt.2021.106984

Evidence supporting the use of glucagon-like peptide-1 (GLP-1) analogues to pharmacologically treat disorders beyond type 2 diabetes and obesity is increasing. However, little is known about how activation of the GLP-1 receptor (GLP-1R) during pregnancy affects maternal and offspring outcomes. We treated female C57Bl/6 J mice prior to conception and throughout gestation with a long-lasting GLP-1R agonist, Exendin-4. While GLP-1R activation has significant effects on food and drug reward, depression, locomotor activity, and cognition in adults, we found few changes in these domains in exendin-4-exposed offspring. Repeated injections of Exendin-4 had minimal effects on the dams and may have enhanced maternal care. Offspring exposed to the drug weighed significantly more than their control counterparts during the preweaning period and demonstrated alterations in anxiety-like outcomes, which indicate a developmental role for GLP-1R modulation in the stress response that may be sex-specific.

SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters

Nature

2022 Jan 21

Halfmann, PJ;Iida, S;Iwatsuki-Horimoto, K;Maemura, T;Kiso, M;Scheaffer, SM;Darling, TL;Joshi, A;Loeber, S;Singh, G;Foster, SL;Ying, B;Case, JB;Chong, Z;Whitener, B;Moliva, J;Floyd, K;Ujie, M;Nakajima, N;Ito, M;Wright, R;Uraki, R;Warang, P;Gagne, M;Li, R;Sakai-Tagawa, Y;Liu, Y;Larson, D;Osorio, JE;Hernandez-Ortiz, JP;Henry, AR;Ciouderis, K;Florek, KR;Patel, M;Odle, A;Wong, LR;Bateman, AC;Wang, Z;Edara, VV;Chong, Z;Franks, J;Jeevan, T;Fabrizio, T;DeBeauchamp, J;Kercher, L;Seiler, P;Gonzalez-Reiche, AS;Sordillo, EM;Chang, LA;van Bakel, H;Simon, V;Consortium Mount Sinai Pathogen Surveillance (PSP) study group, ;Douek, DC;Sullivan, NJ;Thackray, LB;Ueki, H;Yamayoshi, S;Imai, M;Perlman, S;Webby, RJ;Seder, RA;Suthar, MS;García-Sastre, A;Schotsaert, M;Suzuki, T;Boon, ACM;Diamond, MS;Kawaoka, Y;
PMID: 35062015 | DOI: 10.1038/s41586-022-04441-6

The recent emergence of B.1.1.529, the Omicron variant1,2 has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling data suggesting that B.1.1.529 spike can bind more avidly to murine ACE23,4, we observed less infection in 129, C57BL/6, BALB/c, and K18-hACE2 transgenic mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

Bilateral Chilblain-like Lesions of the Toes Characterized by Microvascular Remodeling in Adolescents During the COVID-19 Pandemic

JAMA network open

2021 Jun 01

Discepolo, V;Catzola, A;Pierri, L;Mascolo, M;Della Casa, F;Vastarella, M;Smith, G;Travaglino, A;Punziano, A;Nappa, P;Staibano, S;Bruzzese, E;Fabbrocini, G;Guarino, A;Alessio, M;
PMID: 34110396 | DOI: 10.1001/jamanetworkopen.2021.11369

Chilblain-like lesions have been one of the most frequently described cutaneous manifestations during the COVID-19 pandemic. Their etiopathogenesis, including the role of SARS-CoV-2, remains elusive.To examine the association of chilblain-like lesions with SARS-CoV-2 infection.This prospective case series enrolled 17 adolescents who presented with chilblain-like lesions from April 1 to June 30, 2020, at a tertiary referral academic hospital in Italy.Macroscopic (clinical and dermoscopic) and microscopic (histopathologic) analysis contributed to a thorough understanding of the lesions. Nasopharyngeal swab, serologic testing, and in situ hybridization of the skin biopsy specimens were performed to test for SARS-CoV-2 infection. Laboratory tests explored signs of systemic inflammation or thrombophilia. Structural changes in peripheral microcirculation were investigated by capillaroscopy.Of the 17 adolescents (9 [52.9%] male; median [interquartile range] age, 13.2 [12.5-14.3] years) enrolled during the first wave of the COVID-19 pandemic, 16 (94.1%) had bilaterally localized distal erythematous or cyanotic lesions. A triad of red dots (16 [100%]), white rosettes (11 [68.8%]), and white streaks (10 [62.5%]) characterized the dermoscopic picture. Histologic analysis revealed a remodeling of the dermal blood vessels with a lobular arrangement, wall thickening, and a mild perivascular lymphocytic infiltrate. SARS-CoV-2 infection was excluded by molecular and serologic testing. In situ hybridization did not highlight the viral genome in the lesions.This study delineated the clinical, histologic, and laboratory features of chilblain-like lesions that emerged during the COVID-19 pandemic, and its findings do not support their association with SARS-CoV-2 infection. The lesions occurred in otherwise healthy adolescents, had a long but benign course to self-resolution, and were characterized by a microvascular remodeling with perivascular lymphocytic infiltrate but no other signs of vasculitis. These results suggest that chilblain-like lesions do not imply a concomitant SARS-CoV-2 infection. Ongoing studies will help clarify the etiopathogenic mechanisms.

Apc-mutant cells act as supercompetitors in intestinal tumour initiation

Nature

2021 Jun 01

van Neerven, SM;de Groot, NE;Nijman, LE;Scicluna, BP;van Driel, MS;Lecca, MC;Warmerdam, DO;Kakkar, V;Moreno, LF;Vieira Braga, FA;Sanches, DR;Ramesh, P;Ten Hoorn, S;Aelvoet, AS;van Boxel, MF;Koens, L;Krawczyk, PM;Koster, J;Dekker, E;Medema, JP;Winton, DJ;Bijlsma, MF;Morrissey, E;Léveillé, N;Vermeulen, L;
PMID: 34079128 | DOI: 10.1038/s41586-021-03558-4

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3β. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

Hamsters Expressing Human Angiotensin-Converting Enzyme 2 Develop Severe Disease following Exposure to SARS-CoV-2

mBio

2022 Jan 25

Golden, JW;Li, R;Cline, CR;Zeng, X;Mucker, EM;Fuentes-Lao, AJ;Spik, KW;Williams, JA;Twenhafel, N;Davis, N;Moore, JL;Stevens, S;Blue, E;Garrison, AR;Larson, DD;Stewart, R;Kunzler, M;Liu, Y;Wang, Z;Hooper, JW;
PMID: 35073750 | DOI: 10.1128/mbio.02906-21

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global health emergency. While most human disease is mild to moderate, some infections lead to a severe disease characterized by acute respiratory distress, hypoxia, anosmia, ageusia, and, in some instances, neurological involvement. Small-animal models reproducing severe disease, including neurological sequela, are needed to characterize the pathophysiological mechanism(s) of disease and to identify medical countermeasures. Transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the K18 promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge when high viral doses are used. Here, we report on SARS-CoV-2 infection of hamsters engineered to express the hACE2 receptor under the control of the K18 promoter. K18-hACE2 hamsters infected with a relatively low dose of 100 or 1,000 PFU of SARS-CoV-2 developed a severe and lethal disease, with most animals succumbing by day 5 postinfection. Hamsters developed severe lesions and inflammation within the upper and lower respiratory system, including infection of the nasal cavities causing marked destruction of the olfactory epithelium as well as severe bronchopneumonia that extended deep into the alveoli. Additionally, SARS-CoV-2 infection spread to the central nervous system (CNS), including the brain stem and spinal cord. Wild-type (WT) hamsters naturally support SARS-CoV-2 infection, with the primary lesions present in the respiratory tract and nasal cavity. Overall, infection in the K18-hACE2 hamsters is more extensive than that in WT hamsters, with more CNS involvement and a lethal outcome. These findings demonstrate the K18-hACE2 hamster model will be valuable for studying SARS-CoV-2. IMPORTANCE The rapid emergence of SARS-CoV-2 has created a global health emergency. While most human SARS-CoV-2 disease is mild, some people develop severe, life-threatening disease. Small-animal models mimicking the severe aspects of human disease are needed to more clearly understand the pathophysiological processes driving this progression. Here, we studied SARS-CoV-2 infection in hamsters engineered to express the human angiotensin-converting enzyme 2 viral receptor under the control of the K18 promoter. SARS-CoV-2 produces a severe and lethal infection in transgenic hamsters that mirrors the most severe aspects of COVID-19 in humans, including respiratory and neurological injury. In contrast to other animal systems, hamsters manifest disease with levels of input virus more consistent with natural human infection. This system will be useful for the study of SARS-CoV-2 disease and the development of drugs targeting this virus.

Postmortem Minimally Invasive Autopsy in Critically Ill Covid-19 Patients at the Bedside: A Proof-of-Concept Study at the Icu

SSRN

2023 Jun 02

Lahmer, T;Weirich, G;Porubsky, S;Rasch, S;Kammerstetter, F;Schustetter, C;Schüffler, P;Erber, J;Dibos, M;delbridge, c;kuhn, p;Jeske, S;steinhardt, m;Chaker, A;Heim, M;Heemann, U;Schmid, R;weichert, W;Stock, K;Slotta, J;
| DOI: 10.2139/ssrn.4464818

Methods: In this proof-of-concept study, we performed bedside ultrasound-guided minimally invasive autopsies (US-MIA) of patients that had died from critical COVID-19 in the intensive care unit (ICU) using a structured protocol to obtain almost autolytic-free tissue. Biopsies were assessed for quality (vitality and length) and for diagnosis. The efficiency of the procedure was monitored in five cases by recording the time of each step and safety issues by swabbing personal protective equipment and devices for viral contamination.

Diagnostic role of technitium-99m bone scan in severe COVID-19-associated myositis

Radiology case reports

2021 May 14

Hookey, G;Ahmad, Q;McCune, T;Kowalewska, J;Amaker, B;Inayat, N;
PMID: 34007372 | DOI: 10.1016/j.radcr.2021.05.019

Coronavirus disease 2019 (COVID-19), initially appreciated as a respiratory illness, is now known to affect many organs in the human body. Significant data has become available on muscle involvement, with creatinine kinase elevations present in a significant percentage of patients. For those with suspected COVID-19-associated myositis, the imaging modality of choice has been gadolinium-enhanced magnetic resonance imaging; however, the use of technitium-99m bone scan has not been previously reported. Here, we report two cases of COVID-19 patients with severe elevation in creatinine kinase who underwent technitium-99m bone scan. The resulting images showed diffuse symmetrical muscle involvement. Both patients developed acute renal injury due to rhabdomyolysis. To our knowledge, this is the first report of bone scan as a diagnostic imaging modality for COVID-19-associated myositis.

Lung transplantation for coronavirus disease 2019 associated severe acute respiratory distress syndrome

Current opinion in anaesthesiology

2022 Oct 28

Garza-Castillon, R;Bharat, A;
PMID: 36302203 | DOI: 10.1097/ACO.0000000000001203

The purpose of this review is to analyze the most recent and relevant literature involving lung transplantation for coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS), the pathological mechanisms of lung injury, selection criteria and outcomes.Pathological analysis of lungs after COVID-19 ARDS has shown architectural distortion similar to that observed in explanted lungs from patients undergoing lung transplantation for end-stage lung diseases such as emphysema. Short-term outcomes after lung transplantation for COVID-19 associated respiratory failure are comparable to those performed for other indications.Lung transplantation after COVID-19 ARDS is a potentially life-saving procedure for appropriately selected patients with no evidence of lung function recovery despite maximal treatment. Lung transplantation should be ideally performed in high-volume centers with expertise.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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