scholarly journals Generation of a Transgenic Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease

2015 ◽  
Vol 89 (7) ◽  
pp. 3659-3670 ◽  
Author(s):  
Anurodh Shankar Agrawal ◽  
Tania Garron ◽  
Xinrong Tao ◽  
Bi-Hung Peng ◽  
Maki Wakamiya ◽  
...  
Keyword(s):  
Middle East ◽  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Nonhuman Primates ◽  
Lung Infection ◽  
Transgenic Mouse Model ◽  
Middle East Respiratory Syndrome ◽  
Mouse Lung ◽  
Infection Model

ABSTRACTThe emergence of Middle East respiratory syndrome-coronavirus (MERS-CoV) in the Middle East since 2012 has caused more than 900 human infections with ∼40% mortality to date. Animal models are needed for studying pathogenesis and for development of preventive and therapeutic agents against MERS-CoV infection. Nonhuman primates (rhesus macaques and marmosets) are expensive models of limited availability. Although a mouse lung infection model has been described using adenovirus vectors expressing human CD26/dipeptidyl peptidase 4 (DPP4), it is believed that a transgenic mouse model is needed for MERS-CoV research. We have developed this transgenic mouse model as indicated in this study. We show that transgenic mice globally expressing hCD26/DPP4 were fully permissive to MERS-CoV infection, resulting in relentless weight loss and death within days postinfection. High infectious virus titers were recovered primarily from the lungs and brains of mice at 2 and 4 days postinfection, respectively, whereas viral RNAs were also detected in the heart, spleen, and intestine, indicating a disseminating viral infection. Infected Tg+mice developed a progressive pneumonia, characterized by extensive inflammatory infiltration. In contrast, an inconsistent mild perivascular cuffing was the only pathological change associated with the infected brains. Moreover, infected Tg+mice were able to activate genes encoding for many antiviral and inflammatory mediators within the lungs and brains, coinciding with the high levels of viral replication. This new and unique transgenic mouse model will be useful for furthering knowledge of MERS pathogenesis and for the development of vaccine and treatments against MERS-CoV infection.IMPORTANCESmall and economical animal models are required for the controlled and extensive studies needed for elucidating pathogenesis and development of vaccines and antivirals against MERS. Mice are the most desirable small-animal species for this purpose because of availability and the existence of a thorough knowledge base, particularly of genetics and immunology. The standard small animals, mice, hamsters, and ferrets, all lack the functional MERS-CoV receptor and are not susceptible to infection. So, initial studies were done with nonhuman primates, expensive models of limited availability. A mouse lung infection model was described where a mouse adenovirus was used to transfect lung cells for receptor expression. Nevertheless, all generally agree that a transgenic mouse model expressing the DPP4 receptor is needed for MERS-CoV research. We have developed this transgenic mouse model as indicated in this study. This new and unique transgenic mouse model will be useful for furthering MERS research.

scholarly journals Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease

2015 ◽  
Vol 90 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Xinrong Tao ◽  
Tania Garron ◽  
Anurodh Shankar Agrawal ◽  
Abdullah Algaissi ◽  
Bi-Hung Peng ◽  
...  
Keyword(s):  
Middle East ◽  
Animal Models ◽  
Mouse Model ◽  
Tissue Distribution ◽  
Transgenic Mouse ◽  
Lethal Dose ◽  
Transgenic Mouse Model ◽  
Middle East Respiratory Syndrome ◽  
Infection Model ◽  
High Dose

ABSTRACT Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID 50 ) and lethal dose (LD 50 ) of virus were estimated to be <1 and 10 TCID 50 of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID 50 /LD 50 determinations, and all were fully immune to challenge with 100 LD 50 of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD 50 of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10 5 LD 50 of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research. IMPORTANCE Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing hCD26/DPP4 viral receptor uniformly succumbed to death within 6 days, making it difficult to evaluate host responses to infection and disease. We further characterized this model by determining both the ID 50 and the LD 50 of MERS-CoV in order to establish both an infection model and a lethal model for MERS and followed this by investigating the antibody responses and immunity of the mice that survived MERS-CoV infection. Using the estimated LD 50 and ID 50 data, we dissected the kinetics of viral tissue distribution and pathology in mice challenged with 10 LD 50 of virus and utilized the model for preclinical evaluation of a vaccine and drug for treatment of MERS-CoV infection. This further-characterized transgenic mouse model will be useful for advancing MERS research.

scholarly journals Animal Models of Melanoma: An HGF/SF Transgenic Mouse Model May Facilitate Experimental Access to UV Initiating Events

2003 ◽  
Vol 16 (1) ◽  
pp. 16-25 ◽  
Author(s):  
Frances P. Noonan ◽  
James Dudek ◽  
Glenn Merlino ◽  
Edward C. De Fabo
Keyword(s):  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model

scholarly journals An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice

2021 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Yaozong Chen ◽  
Irfan Ullah ◽  
Jérémie Prévost ◽  
William D. Tolbert ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Transgenic Mouse Model ◽  
Effector Function ◽  
Effector Functions

SummaryEmerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.

scholarly journals PET Neuroimaging Studies of [18F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

2015 ◽  
Vol 6 (4) ◽  
pp. 535-541 ◽  
Author(s):  
Steven H. Liang ◽  
Jason P. Holland ◽  
Nickeisha A. Stephenson ◽  
Alina Kassenbrock ◽  
Benjamin H. Rotstein ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Nonhuman Primates ◽  
Transgenic Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Double Transgenic Mouse

A Novel Transgenic Mouse Model of Multiple Myeloma Reliably Predicts Drug Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 241-241 ◽  
Author(s):  
Michael Sebag ◽  
Keith Stewart ◽  
Stephen Palmer ◽  
Richard Kremer ◽  
Peter Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Drug Response ◽  
Plasma Cells ◽  
Transgenic Mouse Model ◽  
Post Treatment ◽  
Wild Type ◽  
Time Point

Abstract The search for novel and clinically effective anti-myeloma therapies has been hampered by a paucity of good pre-clinical animal models. Most established animal models of multiple myeloma (MM) fail in one or more crucial features to resemble human MM, frequently exhibiting extramedullary tumors or lacking a competent immune system. In addition, competing models are either too expensive or time consuming to generate and maintain. Finally, no model has been shown to reliably predict both drug response and drug inactivity. We have previously described a C57Bl6/J transgenic mouse model in which the expression of the human c-myc oncogene is activated in post-germinal B cells by somatic hypermutation. These mice (Vk*myc) spontaneously develop monoclonal gammopathies and plasma cell expansion beginning at 20 weeks of age. However, in contrast to other models, their plasma cells cannot be found in secondary lymphoid tissues. Now, we report that this model closely reproduces the clinical behavior of human MM. Serum protein electrophoresis (SPEP) as well as ELISA for serum IgG demonstrate that the incidence and quantity of monoclonal paraproteinemia are greatly elevated in the Vk*myc mice as compared to age matched wild type C57Bl6/J controls (50 weeks mean IgG 1.92g/dL Vk*myc vs 0.2g/dL controls; peak IgG levels up to 7.5g/dL). As these mice age, their paraproteins continue rising and remain far higher than that of controls at every time point. Mice with significant paraproteinemia demonstrate marrow with up to 50% plasma cells with evidence of a low proliferative index, similar to what is observed in human MM and unlike what is seen in other models of MM. Anemia is observed, with a mean hemoglobin of 8.9g/dL in the Vk*myc mice vs 13.4g/dL in the wild type. Vk*myc mice analyzed show marked bone thinning with a 20% reduction in total bone volume and in the number of trabeculae per unit area as shown by microCT. In addition a 15% reduction in bone mineral density was demonstrated in affected mice. We next demonstrated the efficacy of 3 drugs, used commonly in clinical practice to treat myeloma (melphalan, dexamethasone and bortezomib). These were given as single courses of daily IP injections for 5 days, for the first two drugs, and bi-weekly IP for 4 weeks for the third. As early as two weeks post treatment, a statistically significant reduction in serum paraprotein levels was observed in the treated mice versus vehicle treated controls. The reductions were maximal at 21d post treatment in the melphalan (−77.2%±39 p<0.02) and dexamethasone (−67.4%±29 p<0.02) groups and at 28d in the bortezomib group (−68.9%±9 p<.001). No reduction was seen in the vehicle treated controls at any time point. As with human myeloma, the effect of one course of treatment was transient in nature. In contrast, treatment of VK*myc mice with 3 drugs that have not shown clinical activity against myeloma as single agents (hydroxyurea, vincristine and fludarabine) did not reduce serum monoclonal proteins. We conclude that our Vk*myc model closely reproduces the clinical characteristics of human MM. We have also shown that this model responds to drugs known to be clinically active, while showing no response to drugs that have little or no effect against human MM. To our knowledge, this is the first time that this level of fidelity to human MM has been demonstrated in a pre-clinical animal model. Our model therefore represents a unique and powerful tool for pre-clinical anti-myeloma drug development.

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