Middle East Respiratory Syndrome-Coronavirus Infection into Established hDPP4-Transgenic Mice Accelerates Lung Damage Via Activation of the Pro-Inflammatory Response and Pulmonary Fibrosis

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) infects the lower respiratory airway of humans, leading to severe acute respiratory failure. Unlike human dipeptidyl peptidase 4 (hDPP4), a receptor for MERS-CoV, mouse DPP4 (mDPP4) failed to support MERS-CoV infection. Consequently, diverse transgenic mouse models expressing hDPP4 have been developed using diverse methods, although some models show no mortality and/or only transient and mild-to-moderate clinical signs following MERS-CoV infection. Additionally, overexpressed hDPP4 is associated with neurological complications and breeding difficulties in some transgenic mice, resulting in impeding further studies. Here, we generated stable hDPP4-transgenic mice that were sufficiently susceptible to MERS-CoV infection. The transgenic mice showed weight loss, decreased pulmonary function, and increased mortality with minimal perturbation of overexpressed hDPP4 after MERS-CoV infection. In addition, we observed histopathological signs indicative of progressive pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory monocytes, and macrophage polarization as well as elevated expression of profibrotic molecules and acute inflammatory response in the lung of MERS-CoV-infected hDPP4-transgenic mice. Collectively, we suggest that this hDPP4-transgenic mouse is useful in understanding the pathogenesis of MERS-CoV infection and for antiviral research and vaccine development against the virus. 428 Kim et al. J. Microbiol. Biotechnol.

T Cells in Fibrosis and Fibrotic Diseases

“…COVID-19 is accompanied by fibrosis ( 145 , 146 ), and is particularly dangerous for patients with pulmonary fibrotic diseases including cystic fibrosis ( 147 ). Pulmonary fibrosis is also commonly developed in patients with other virus-induced respiratory diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV) ( 148 – 150 ) and Middle East respiratory syndrome (MERS) ( 151 ). A better understanding of cellular and molecular mechanisms will help treat fibrosis in patients with severe virus-induced diseases.…”

Distribution of ACE2, CD147, CD26, and other SARS‐CoV‐2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID‐19 risk factors

“…CD26 (encoded by DPP4 ) has emerged recently as a potential receptor for SARS‐CoV‐2, due to the fact that it is a main cellular entry for MERS‐CoV 43,44 . Recent structural studies predict that SARS‐CoV‐2 spike protein directly interact with CD26 on the host cells 21 .…”

Mesenchymal Stem Cell Derived Exosomes: a Nano Platform for Therapeutics and Drug Delivery in Combating COVID-19

“… Polarization of lung macrophages: As previously mentioned, during viral infection, cytokine storm is generated due to the impaired immune response leading to further lung damage. This is largely mediated by pro-inflammatory macrophages in the lungs [ 59 ]. The regulation of these pro-inflammatory macrophages (producing inflammatory cytokines such as IL-8, IL-6, IL-1β, and TNF-α) to anti-inflammatory macrophages (producing immunosuppressive cytokines like IL-10 and TGF-β) by exosomes may aid in the further reversal of the disease pathophysiology.…”