scholarly journals Controlled administration of aerosolized SARS-CoV-2 to K18-hACE2 transgenic mice uncouples respiratory infection and anosmia from fatal neuroinvasion

2021 ◽  
Author(s):  
Valeria Fumagalli ◽  
Micol Rava ◽  
Davide Marotta ◽  
Pietro Di Lucia ◽  
Chiara Laura ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Experimental Approach ◽  
Small Animal ◽  
Therapeutic Interventions ◽  
Cns Infection ◽  
Lung Pathology ◽  
Transcriptional Signature ◽  
Aerosol Exposure ◽  
Aerosol Infection

The development of a tractable small animal model faithfully reproducing human COVID-19 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid SARS-CoV-2 suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model's usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction, but did not lead to fatal viral neuroinvasion. When compared to intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition and a transcriptional signature comparable to that observed in SARS-CoV-2-infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions.

scholarly journals Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

2021 ◽  
Author(s):  
Gema M Olivarria ◽  
Yuting Cheng ◽  
Collin Pachow ◽  
Lindsay A Hohsfield ◽  
Charlene Smith-Geater ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Viral Replication ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cns Infection ◽  
Lung Pathology ◽  
Viral Pathogen ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Human Ipsc

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ~50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease.

scholarly journals Survey-Based Analysis of Current Trends for Prescribing Gastrointestinal Protectants among Small-Animal General Practitioners in Portugal

2021 ◽  
Vol 8 (5) ◽  
pp. 70
Author(s):  
Rita Baptista ◽  
Ryane Englar ◽  
Berta São Braz ◽  
Rodolfo Oliveira Leal
Keyword(s):  
General Practitioners ◽  
Healthcare Providers ◽  
Small Animal ◽  
Cross Sectional Study ◽  
Online Forums ◽  
Educational Strategies ◽  
Cross Sectional ◽  
Current Trends ◽  
Therapeutic Value

In both human and veterinary healthcare, gastrointestinal protectants (GIPs) are considered a staple of clinical practice in that they are prescribed by general practitioners (GPs) and specialists alike. Concerning GIP use, overprescription of proton pump inhibitors (PPIs) has become a growing concern among human healthcare providers. This trend has also been documented within veterinary practice, prompting the American College of Veterinary Internal Medicine (ACVIM) to publish a consensus statement in 2018 concerning evidence-based indications for GIP use. This observational cross-sectional study evaluated self-reported prescribing protocols among Portuguese GPs to determine whether there is adherence to the consensus guidelines. Respondents were Portuguese GPs recruited by social media posts in veterinarian online forums. Data were collected from 124 respondents concerning their GIPs of choice and their rationales for prescribing them. Data were mined for prescription patterns and protocols. Among GIPs, PPIs were prescribed more often. Rationales for use included gastrointestinal ulceration and erosion (GUE), prophylactic management of nonerosive gastritis, pancreatitis, reflux esophagitis, and steroid-induced ulceration. Once-daily administration of PPIs was the most frequent dosing regime among respondents. Ninety-six percent of PPI prescribers advocated that the drug be administered either shortly before or at mealtime. Forty-nine percent of respondents supported long-term use of PPIs. Fifty-nine percent of respondents acknowledged discontinuing PPIs abruptly. This study supports that Portuguese GPs commonly prescribe GIPs in accordance with ACVIM recommendations to medically manage GUE. However, misuse of GIPs does occur, and they have been prescribed where their therapeutic value is debatable. Educational strategies should target GPs in an effort to reduce GIP misuse.

Long-term acrylamide exposure exacerbates brain and lung pathology in a mouse malaria model

2021 ◽  
pp. 112132
Author(s):  
Ha Ngo-Thanh ◽  
Trang Dam Thuy ◽  
Kazutomo Suzue ◽  
Wataru Kamitani ◽  
Hideaki Yokoo ◽  
...  
Keyword(s):  
Lung Pathology ◽  
Malaria Model

scholarly journals Bisecting GlcNAc structure is implicated in suppression of stroma-dependent haemopoiesis in transgenic mice expressing N-acetylglucosaminyltransferase III

1998 ◽  
Vol 331 (3) ◽  
pp. 733-742 ◽  
Author(s):  
Masafumi YOSHIMURA ◽  
Yoshito IHARA ◽  
Tetsuo NISHIURA ◽  
Yu OKAJIMA ◽  
Megumu OGAWA ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Stromal Cells ◽  
Bone Marrow Cells ◽  
Adherent Cell ◽  
Wild Type ◽  
Spleen Cells ◽  
Bisecting Glcnac ◽  
Marrow Cells

Several sugar structures have been reported to be necessary for haemopoiesis. We analysed the haematological phenotypes of transgenic mice expressing β-1,4 N-acetylglucosaminyltransferase III (GnT-III), which forms bisecting N-acetylglucosamine on asparagine-linked oligosaccharides. In the transgenic mice, the GnT-III activity was elevated in bone marrow, spleen and peripheral blood and in isolated mononuclear cells from these tissues, whereas no activity was found in these tissues of wild-type mice. Stromal cells after long-term cultures of transgenic-derived bone marrow and spleen cells also showed elevated GnT-III activity, compared with an undetectable activity in wild-type stromal cells. As judged by HPLC analysis, lectin blotting and lectin cytotoxicity assay, bisecting GlcNAc residues were increased on both blood cells and stromal cells from bone marrow and spleen in transgenic mice. The transgenic mice displayed spleen atrophy, hypocellular bone marrow and pancytopenia. Bone marrow cells and spleen cells from transgenic mice produced fewer haemopoietic colonies. After lethal irradiation followed by bone marrow transplantation, transgenic recipient mice showed pancytopenia compared with wild-type recipient mice. Bone marrow cells from transgenic donors gave haematological reconstitution at the same level as wild-type donor cells. In addition, non-adherent cell production was decreased in long-term bone marrow cell cultures of transgenic mice. Collectively these results indicate that the stroma-supported haemopoiesis is compromised in transgenic mice expressing GnT-III, providing the first demonstration that the N-glycans have some significant roles in stroma-dependent haemopoiesis.

Animal models of hypoxic-ischemic encephalopathy: optimal choices for the best outcomes

2017 ◽  
Vol 28 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Lan Huang ◽  
Fengyan Zhao ◽  
Yi Qu ◽  
Li Zhang ◽  
Yan Wang ◽  
...  
Keyword(s):  
Animal Models ◽  
Small Animal ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Large Animal ◽  
Large Animal Models ◽  
Neurological Research ◽  
Serious Disease ◽  
Ischemic Encephalopathy

AbstractHypoxic-ischemic encephalopathy (HIE), a serious disease leading to neonatal death, is becoming a key area of pediatric neurological research. Despite remarkable advances in the understanding of HIE, the explicit pathogenesis of HIE is unclear, and well-established treatments are absent. Animal models are usually considered as the first step in the exploration of the underlying disease and in evaluating promising therapeutic interventions. Various animal models of HIE have been developed with distinct characteristics, and it is important to choose an appropriate animal model according to the experimental objectives. Generally, small animal models may be more suitable for exploring the mechanisms of HIE, whereas large animal models are better for translational studies. This review focuses on the features of commonly used HIE animal models with respect to their modeling strategies, merits, and shortcomings, and associated neuropathological changes, providing a comprehensive reference for improving existing animal models and developing new animal models.

MINIMAL LUNG PATHOLOGY IN LONG-TERM PRIMATE SURVIVORS OF HEART-LUNG TRANSPLANTATIO

1987 ◽  
Vol 44 (6) ◽  
pp. 852-854 ◽  
Author(s):  
Ari Harjula ◽  
John C. Baldwin ◽  
Henry D. Tazelaar ◽  
Bruce A. Reitz ◽  
Norman E. Shumway
Keyword(s):  
Lung Pathology

scholarly journals Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

2016 ◽  
Vol 84 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
Charles S. Rosenberg ◽  
Weibo Zhang ◽  
Juan M. Bustamante ◽  
Rick L. Tarleton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Trypanosoma Cruzi ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Pathogen Control ◽  
Immunodominant Epitopes

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.

α-Oxoaldehyde metabolism and diabetic complications

2003 ◽  
Vol 31 (6) ◽  
pp. 1358-1363 ◽  
Author(s):  
P.J. Beisswenger ◽  
S.K. Howell ◽  
R.G. Nelson ◽  
M. Mauer ◽  
B.S. Szwergold
Keyword(s):  
Diabetic Complications ◽  
Complex Mixture ◽  
Therapeutic Interventions ◽  
Diabetic Patients ◽  
Human Populations ◽  
Control Mechanisms ◽  
Protective Mechanisms ◽  
Glycation End Products ◽  
End Products

The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate α-oxoaldehydes, have been identified. We have observed significant increases in production of the α-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of α-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.

scholarly journals Evaluation of Moxifloxacin-Containing Regimens in Pathologically Distinct Murine Tuberculosis Models

2015 ◽  
Vol 59 (7) ◽  
pp. 4026-4030 ◽  
Author(s):  
Si-Yang Li ◽  
Scott M. Irwin ◽  
Paul J. Converse ◽  
Khisi E. Mdluli ◽  
Anne J. Lenaerts ◽  
...  
Keyword(s):  
Mouse Strain ◽  
Predictive Accuracy ◽  
Term Treatment ◽  
Mouse Strains ◽  
Disappointing Result ◽  
Similar Treatment ◽  
Infection Models ◽  
Long Term Treatment ◽  
Aerosol Infection

ABSTRACTIn the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6-month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models used to support regimen development. In parallel with the REMox-TB trial, we compared the efficacy of the same three regimens against chronic TB infection in the commonly used BALB/c mouse strain and in C3HeB/FeJ mice, which have attracted recent interest as a nonclinical efficacy model because they develop caseous lung lesions which may better resemble human TB. In long-term treatment experiments at two institutions, using low-dose aerosol infection models with 6- to 8-week incubation periods in both mouse strains, control mice received rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), and test mice received the same regimen with moxifloxacin replacing isoniazid (RMZE) or ethambutol (RHZM). Outcome measures were lung CFU counts during treatment and relapse after various durations of treatment. At both institutions and in both mouse strains, RMZE and RHZM reduced by approximately 1 month and 0 to 1 month, respectively, the treatment duration needed to produce the same relapse rate as RHZE. These results demonstrating generally similar treatment-shortening effects of the moxifloxacin-containing regimens in each mouse strain, with effect sizes consistent with the REMox-TB trial results, reinforce the predictive value of murine models for TB regimen development.

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