Elevated Human Dipeptidyl Peptidase 4 Expression Reduces the Susceptibility of hDPP4 Transgenic Mice to Middle East Respiratory Syndrome Coronavirus Infection and Disease

Algaissi, Abdullah; Agrawal, Anurodh Shankar; Han, Song; Peng, Bi Hung; Luo, Chuming; Li, Fang; Chan, Teh Sheng; Couch, Robert B.; Tseng, Chien Te K.

doi:10.1093/infdis/jiy574

Cited by 24 publications

(22 citation statements)

References 18 publications

(31 reference statements)

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“…The differential expression of host factors that limits the infection should also be taken into account. DPP4 in soluble form has been demonstrated to protect against MERS-CoV infection in vitro and in a mouse model [23,114]; however, its presence in the lungs and role in MERS-CoV pathogenesis remain to be investigated. The host immune response also has the capacity to inhibit MERS-CoV infection.…”

Section: Host Factors In Mers-cov Pathogenesismentioning

confidence: 99%

Host Determinants of MERS-CoV Transmission and Pathogenesis

Widagdo¹,

Ayudhya²,

Hundie³

et al. 2019

Viruses

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Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen that causes respiratory infection in humans, ranging from asymptomatic to severe pneumonia. In dromedary camels, the virus only causes a mild infection but it spreads efficiently between animals. Differences in the behavior of the virus observed between individuals, as well as between humans and dromedary camels, highlight the role of host factors in MERS-CoV pathogenesis and transmission. One of these host factors, the MERS-CoV receptor dipeptidyl peptidase-4 (DPP4), may be a critical determinant because it is variably expressed in MERS-CoV-susceptible species as well as in humans. This could partially explain inter- and intraspecies differences in the tropism, pathogenesis, and transmissibility of MERS-CoV. In this review, we explore the role of DPP4 and other host factors in MERS-CoV transmission and pathogenesis—such as sialic acids, host proteases, and interferons. Further characterization of these host determinants may potentially offer novel insights to develop intervention strategies to tackle ongoing outbreaks.

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Section: Host Factors In Mers-cov Pathogenesismentioning

confidence: 99%

Host Determinants of MERS-CoV Transmission and Pathogenesis

Widagdo¹,

Ayudhya²,

Hundie³

et al. 2019

Viruses

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“…Previous studies showed that transgenic mice expressing the human DPP4 (hDPP4) receptor could be infected intranasally with MERS-CoV and developed acute pneumonia. [13][14][15] Therefore, hDPP4 transgenic mice were selected for exposure to MERS-CoV-containing aerosols using an animal nose-only exposure device.…”

Section: Introductionmentioning

confidence: 99%

The characteristics of hDPP4 transgenic mice subjected to aerosol MERS coronavirus infection via an animal nose‐only exposure device

Hao

et al. 2019

Anim Models and Exp Med

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractBackground: Middle East respiratory syndrome coronavirus (MERS-CoV), which is not fully understood in regard to certain transmission routes and pathogenesis and lacks specific therapeutics and vaccines, poses a global threat to public health. Methods:To simulate the clinical aerosol transmission route, hDPP4 transgenic mice were infected with MERS-CoV by an animal nose-only exposure device and compared with instillation-inoculated mice. The challenged mice were observed for 14 consecutive days and necropsied on days 3, 5, 7, and 9 to analyze viral load, histopathology, viral antigen distribution, and cytokines in tissues. Results: MERS-CoV aerosol-infected mice with an incubation period of 5-7 daysshowed weight loss on days 7-11, obvious lung lesions on day 7, high viral loads in the lungs on days 3-9 and in the brain on days 7-9, and 60% survival. MERS-CoV instillation-inoculated mice exhibited clinical signs on day 1, obvious lung lesions on days 3-5, continuous weight loss, 0% survival by day 5, and high viral loads in the lungs and brain on days 3-5. Viral antigen and high levels of proinflammatory cytokines and chemokines were detected in the aerosol and instillation groups. Disease, lung lesion, and viral replication progressions were slower in the MERS-CoV aerosol-infected mice than in the MERS-CoV instillation-inoculated mice.Conclusion: hDPP4 transgenic mice were successfully infected with MERS-CoV aerosols via an animal nose-only exposure device, and aerosol-and instillation-infected mice simulated the clinical symptoms of moderate diffuse interstitial pneumonia.However, the transgenic mice exposed to aerosol MERS-CoV developed disease and lung pathology progressions that more closely resembled those observed in humans. K E Y W O R D Sanimal nose-only exposure device, hDPP4 transgenic mice, intranasal instillation, MERS-CoV aerosol infection

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“…Dipeptidyl peptidase IV contact amino acids at the hDPP4/RBD interface are highly conserved among MERS-CoV-susceptible mammalian species (human, camel, and Specific events since the emergence of MERS-CoV in 2012 are emphasized above the timeline. References to mammalian models evaluated for MERS-CoV pathogenesis comprise hamster [19], ferret [20], rabbit [21][22][23][24], camel [25][26][27], nonhuman primates [28][29][30][31][32][33][34][35], and mouse [36][37][38][39][40][41][42][43][44][45][46][47][48] bat) ( Fig. 2) [51].…”

Section: Introductionmentioning

confidence: 99%

Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome

Leist

Cockrell

2019

Methods in Molecular Biology

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Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel therapeutic countermeasures have driven the development of animal models that can reproducibly replicate the pathology associated with MERS-CoV in human infections. The inability of MERS-CoV to replicate in the respiratory tracts of mice, hamsters, and ferrets stymied initial attempts to generate small animal models. Identification of human dipeptidyl peptidase IV (hDPP4) as the receptor for MERS-CoV infection opened the door for genetic engineering of mice. Precise molecular engineering of mouse DPP4 (mDPP4) with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology maintained inherent expression profiles, and limited MERS-CoV susceptibility to tissues that naturally express mDPP4, notably the lower respiratory tract wherein MERS-CoV elicits severe pulmonary pathology. Here, we describe the generation of the 288-330 +/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330), and the use of adaptive evolution to generate novel MERS-CoV isolates that cause fatal respiratory disease. The 288-330 +/+ mice are currently being used to evaluate novel drug, antibody, and vaccine therapeutic countermeasures for MERS-CoV. The chapter starts with a historical perspective on the emergence of MERS-CoV and animal models evaluated for MERS-CoV pathogenesis, and then outlines the development of the 288-330 +/+ mouse model, assays for assessing a MERS-CoV pulmonary infection in a mouse model, and describes some of the challenges associated with using genetically engineered mice.

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Elevated Human Dipeptidyl Peptidase 4 Expression Reduces the Susceptibility of hDPP4 Transgenic Mice to Middle East Respiratory Syndrome Coronavirus Infection and Disease

Cited by 24 publications

References 18 publications

Host Determinants of MERS-CoV Transmission and Pathogenesis

Host Determinants of MERS-CoV Transmission and Pathogenesis

The characteristics of hDPP4 transgenic mice subjected to aerosol MERS coronavirus infection via an animal nose‐only exposure device

Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome

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