Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

doi:10.1128/JVI.01818-18

. 2019 Mar 5;93(6):e01818-18.

doi: 10.1128/JVI.01818-18. Print 2019 Mar 15.

Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

Naoko Iwata-Yoshikawa^#¹, Tadashi Okamura^#^{1

2

3}, Yukiko Shimizu², Osamu Kotani⁴, Hironori Sato⁴, Hanako Sekimukai^{1

5}, Shuetsu Fukushi⁶, Tadaki Suzuki¹, Yuko Sato¹, Makoto Takeda⁷, Masato Tashiro⁸, Hideki Hasegawa¹, Noriyo Nagata⁹

Affiliations

¹ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
² Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
³ Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
⁴ Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
⁵ Department of Tissue Physiology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
⁶ Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
⁷ Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.
⁸ Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
⁹ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.

^# Contributed equally.

PMID: 30626685
PMCID: PMC6401458
DOI: 10.1128/JVI.01818-18

Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

Naoko Iwata-Yoshikawa et al. J Virol. 2019.

. 2019 Mar 5;93(6):e01818-18.

doi: 10.1128/JVI.01818-18. Print 2019 Mar 15.

Authors

Affiliations

¹ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
² Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
³ Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
⁴ Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
⁵ Department of Tissue Physiology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
⁶ Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
⁷ Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.
⁸ Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
⁹ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.

^# Contributed equally.

PMID: 30626685
PMCID: PMC6401458
DOI: 10.1128/JVI.01818-18

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) infection can manifest as a mild illness, acute respiratory distress, organ failure, or death. Several animal models have been established to study disease pathogenesis and to develop vaccines and therapeutic agents. Here, we developed transgenic (Tg) mice on a C57BL/6 background; these mice expressed human CD26/dipeptidyl peptidase 4 (hDPP4), a functional receptor for MERS-CoV, under the control of an endogenous hDPP4 promoter. We then characterized this mouse model of MERS-CoV. The expression profile of hDPP4 in these mice was almost equivalent to that in human tissues, including kidney and lung; however, hDPP4 was overexpressed in murine CD3-positive cells within peripheral blood and lymphoid tissues. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with only transient loss of body weight. However, the immunopathology in young and adult Tg mice was different. On day 5 or 7 postinoculation, lungs of adult Tg mice contained higher levels of proinflammatory cytokines and chemokines associated with migration of macrophages. These results suggest that the immunopathology of MERS-CoV infection in the Tg mouse is age dependent. The mouse model described here will increase our understanding of disease pathogenesis and host mediators that protect against MERS-CoV infection.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) infections are endemic in the Middle East and a threat to public health worldwide. Rodents are not susceptible to the virus because they do not express functional receptors; therefore, we generated a new animal model of MERS-CoV infection based on transgenic mice expressing human DPP4 (hDPP4). The pattern of hDPP4 expression in this model was similar to that in human tissues (except lymphoid tissue). In addition, MERS-CoV was limited to the respiratory tract. Here, we focused on host factors involved in immunopathology in MERS-CoV infection and clarified differences in antiviral immune responses between young and adult transgenic mice. This new small-animal model could contribute to more in-depth study of the pathology of MERS-CoV infection and aid development of suitable treatments.

Keywords: DPP4; MERS-CoV; animal models; immunopathology; transgenic mouse.

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Figures

**FIG 1**
Generation of transgenic mice expressing human dipeptidyl peptidase 4 (hDPP4). (A) Schematic diagram showing a bacterial artificial chromosome (BAC) clone (clone RP11-345J9) containing the hDPP4 gene used to produce the transgenic mice. The open and filled circles denote the centromere (Cen) and telomere (Tel) of human chromosome 2, respectively. The gray arrows indicate the genes located downstream of the hDPP4 gene (white arrow). The cloned region in the BAC construct is denoted by a black line. GCG, glucagon gene; FAP, fibroblast activation protein; IFIH1, interferon induced with helicase C domain 1. (B) Expression of hDPP4 on peripheral blood CD3-positive T lymphocytes from the transgenic (Tg) mice. Tg1 and Tg2, hDPP4^+/− transgenic mouse lines 1 and 2; non-Tg, hDPP4^−/− mouse. (C) Genomic DNA was extracted from Tg2 mice, and human DPP4 exons 1 to 26 were subjected to PCR using specific primers. Lane M, marker; lane 1, exon 1; lane 2, exon 2; lane 3, exon 3; lane 4, exon 4; lane 5, exon 5; lane 6, exons 6 and 7; lane 7, exon 8; lane 8, exon 9; lane 9, exon 10; lane 10, exon 11; lane 11, exon 12; lane 12, exons 13 and 14; lane 13, exons 15 and 16; lane 14, exons 17 and 18; lane 15, exon 19; lane 16, exon 20; lane 17, exon 21; lane 18, exon 22; lane 19, exon 23; lane 20, exon 24; lane 21, exon 25; lanes 22 and 23, exon 26.

**FIG 2**
Expression of human dipeptidyl peptidase 4 (hDPP4) in tissues from humans and mice. Tg2, hDPP4^+/− transgenic mouse line 2; non-Tg, hDPP4^−/− mouse. (A) Western blot analysis of homogenized human and mouse tissues with an anti-hDPP4 polyclonal antibody or an anti-β-actin polyclonal antibody (internal control). Arrows indicate the positions of hDPP4 (110 kDa). (B) Immunohistochemical analysis of hDPP4 expression in human, Tg2, and non-Tg mouse tissues stained with an anti-hDPP4 polyclonal antibody. Sections were counterstained with hematoxylin. Scale bars, 50 μm (large images of liver, kidney, small intestine, pancreas, spleen, and lymph node), 20 μm (large images of lung and brain), and 25 μm (insets).

**FIG 3**
Innate immune responses in Tg2, non-Tg, and C57BL/6 mice. C57BL/6, non-Tg, and Tg2 mice received an intranasal inoculation of poly(I·C) or saline and were sacrificed 24 h later (n = 4/group). Expression of proinflammatory cytokines and chemokines in saline- and poly(I·C)-inoculated animals. P values were calculated using one-way ANOVA, followed by Tukey’s posttest (ns, not significant; *, P < 0.05). Error bars indicate the standard deviations.

**FIG 4**
Permissiveness of transgenic mice to infection by MERS-CoV. (A) The body weight of 10-week-old mice was monitored daily after intranasal inoculation of MERS-CoV at a dose of 10⁵ TCID₅₀ (n = 8 for hDPP4-transgenic mouse line 2 [Tg2]; n = 10 for C57BL/6 mice). Error bars represent the standard deviation (**, P < 0.01; ***, P < 0.001, by two-way ANOVA). (B) Seroconversion of Tg2 mice inoculated with MERS-CoV. Titer of MERS-CoV-specific neutralizing (NT) antibodies in mouse serum on days 7, 14, and 35 postinoculation with MERS-CoV (Tg2, n = 3 to 5; C57BL/6, n = 4 to 6). The dotted line denotes the detection limit of the assay. Error bars represent the standard deviations. (C) Viral load in the respiratory tract of mice inoculated with MERS-CoV. NW, nasal wash fluid; maxilla, maxilla including nostril; LW, lung wash fluid. Mice were euthanized at the indicated times post-viral inoculation (n = 3 to 4 per time point). Viral titer is expressed as the means ± standard deviations. The dotted line denotes the detection limit of the assay. **, P < 0.01; ***, P < 0.001 (two-way ANOVA). (D) Quantitative real-time RT-PCR analysis of MERS-CoV viral RNA in splenocytes isolated from Tg2 and C57BL/6 mice. RNA was extracted from splenocytes infected with MERS-CoV at a multiplicity of infection of 1. RNA levels were normalized against β-actin (endogenous control).

**FIG 5**
Histopathological changes in the lungs of human dipeptidyl peptidase 4 (hDPP4)-transgenic mice inoculated with MERS-CoV. Representative images of lungs from hDPP4^+/− transgenic mouse line 2 on days 1, 3, 5, 7, 14, and 35 postinoculation. Mild but progressive interstitial infiltration was seen within 7 days postinoculation (dpi) (left column, A, D, G, J, M, and P). IHC staining of sequential sections revealed abundant MERS-CoV antigen-positive cells in affected areas (middle column, B, E, H, K, N, and Q). Severe inflammation, with many mononuclear cells in the alveolar spaces and regenerated type II pneumocytes in the alveolar wall, was observed within 7 days p.i. (right column, C, F, I, L, O, and R). Scale bars: 100 μm (left and middle columns), 50 μm (right column), and 20 μm (insets of middle column). HE, hematoxylin and eosin staining; IHC, immunohistochemistry using an anti-MERS-CoV nucleocapsid protein polyclonal antibody; Ag, antigen.

**FIG 6**
Double-immunofluorescence images taken at 1 day p.i. showing human dipeptidyl peptidase 4 (hDPP4) (green) and MERS-CoV antigen (red) in the lungs of Tg2 mice infected with MERS-CoV. Viral antigen-positive cells in the lungs were hDPP4-positive bronchiolar epithelial cells (upper panels) and alveolar epithelial cells (lower panels). Original magnification, ×600.

**FIG 7**
Histopathological changes in the brain of human dipeptidyl peptidase 4 (hDPP4)-transgenic mice inoculated with MERS-CoV. (A, D, and G) Sagittal sections of the head, including the nasal cavity, olfactory bulb, and brain, of a Tg2 mouse infected with MERS-CoV (images taken at 3, 7, and 35 days p.i. [dpi]). Right panels show the brain cortex from samples from panels A, D, and G, respectively, with hematoxylin and eosin staining (B, E, and F) and immunohistochemical analysis of MERS-CoV antigen (C, F, I). Neither lesions nor MERS-CoV antigen-positive cells were detected in the brain. Scale bars, 1 mm (A, D, and G) and 20 μm (B, C, E, F, H, and I).

**FIG 8**
Susceptibility of adult human dipeptidyl peptidase 4 (hDPP4)-transgenic mice to MERS-CoV infection. Tg2, hDPP4^+/− transgenic mouse line 2; non-Tg, hDPP4^−/− mouse. (A) The body weight of 25-week-old mice was monitored daily after intranasal inoculation with MERS-CoV (n = 6 Tg2 mice and n = 7 non-Tg mice). *, P < 0.05; ***, P < 0.001 (two-way ANOVA). (B) Seroconversion of Tg2 mice inoculated with MERS-CoV. Titer of MERS-CoV-specific neutralizing (NT) antibodies in mouse serum on days 7, 14, and 35 postinoculation with MERS-CoV (Tg2, n = 4 to 6; non-Tg, n = 4). The dotted line denotes the detection limit of the assay. Error bars represent the standard deviation. (C) Viral titer in nasal wash fluid (NW), maxilla (including nostril), lung wash fluid (LW), and lungs of 25-week-old Tg2 and non-Tg mice at 3 days postinoculation (p.i.) (n = 4 mice per group). Viral titer is expressed as the mean ± standard deviation. The dotted line denotes the detection limit of the assay. **, P < 0.01; ***, P < 0.001 (two-way ANOVA).

**FIG 9**
Histopathological changes in the lungs of human dipeptidyl peptidase 4 (hDPP4)-transgenic mice inoculated with MERS-CoV. Representative histopathological images of the lungs from 25-week-old Tg2 mice at 1, 3, 5, 7, 14, and 35 days post-MERS-CoV infection. Images in the left (A, D, G, J, M, and P) and right (C, F, I, L, O, and R) columns show time-dependent recruitment of inflammatory cells to the lung. Marked inflammatory cell infiltration was noted at 7 days postinoculation (dpi) in panels J and L. Images in the middle column (B, E, H, K, N, and Q) show immunohistochemical staining for MERS-CoV antigen (Ag). Scale bars: 100 μm (left and middle columns), 50 μm (right column), and 20 μm (insets of middle column). HE, hematoxylin and eosin staining; IHC, immunohistochemistry using an anti-MERS-CoV nucleocapsid protein polyclonal antibody.

**FIG 10**
Identification of cells infiltrating the lung of Tg2 mice infected with MERS-CoV. Representative images of lungs from 10-week-old (young) and 25-week-old (adult) hDPP4^+/− transgenic mice (line 2) on day 7 postinoculation (p.i.). Infiltrating cells were positive for Iba-1 (green) or CD3 (brown). Bar, 20 μm.: Hematoxylin and eosin staining (HE) was used for the images in the upper panels, and anti-Iba-1 polyclonal antibody and anti-CD3 monoclonal antibody were used for IHC in the lower panels.

**FIG 11**
Cytokine and chemokine levels and expression of type I interferon (IFN) genes in the lungs of Tg2 mice infected with MERS-CoV. Cytokine and chemokine levels in lung samples from 10-week-old (A) and 25-week-old (B) mice are shown. Tg2 mice were inoculated with MERS-CoV or cell culture medium containing 2% FBS. Lungs were collected at the indicated times post-viral inoculation (n = 3 to 4 mice per time point). Data represent the means ± standard deviations. A dotted line denotes the detection limit of the assay. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (two-way ANOVA). (C) Quantitative real-time RT-PCR analysis of type I IFN gene expression in lung homogenates from Tg2 mice inoculated with MERS-CoV or cell culture medium containing 2% FBS. RNA levels were normalized against those of β-actin (endogenous control). Data represent the means ± standard deviations. A dotted line denotes the detection limit of the assay. *, P < 0.05; ***, P < 0.001 (two-way ANOVA).

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References

1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814–1820. doi:10.1056/NEJMoa1211721. - DOI - PubMed
1. Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254. doi:10.1038/nature12005. - DOI - PMC - PubMed
1. de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ. 2013. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 110:16598–16603. doi:10.1073/pnas.1310744110. - DOI - PMC - PubMed
1. Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, LaCasse R, Liu T, Zhu J, McLellan JS, Scott DP, Katze MG, Feldmann H, Munster VJ. 2014. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 10:e1004250. doi:10.1371/journal.ppat.1004250. - DOI - PMC - PubMed
1. Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT. 2015. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 89:3659–3670. doi:10.1128/JVI.03427-14. - DOI - PMC - PubMed

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[1] Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814–1820. doi:10.1056/NEJMoa1211721. - DOI - PubMed

[2] Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814–1820. doi:10.1056/NEJMoa1211721. - DOI - PubMed

[3] Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254. doi:10.1038/nature12005. - DOI - PMC - PubMed

[4] Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254. doi:10.1038/nature12005. - DOI - PMC - PubMed

[5] de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ. 2013. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 110:16598–16603. doi:10.1073/pnas.1310744110. - DOI - PMC - PubMed

[6] de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ. 2013. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 110:16598–16603. doi:10.1073/pnas.1310744110. - DOI - PMC - PubMed

[7] Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, LaCasse R, Liu T, Zhu J, McLellan JS, Scott DP, Katze MG, Feldmann H, Munster VJ. 2014. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 10:e1004250. doi:10.1371/journal.ppat.1004250. - DOI - PMC - PubMed

[8] Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, LaCasse R, Liu T, Zhu J, McLellan JS, Scott DP, Katze MG, Feldmann H, Munster VJ. 2014. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 10:e1004250. doi:10.1371/journal.ppat.1004250. - DOI - PMC - PubMed

[9] Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT. 2015. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 89:3659–3670. doi:10.1128/JVI.03427-14. - DOI - PMC - PubMed

[10] Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT. 2015. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 89:3659–3670. doi:10.1128/JVI.03427-14. - DOI - PMC - PubMed

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Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

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Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

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