Conjugation of Human β-Defensin 2 to Spike Protein Receptor-Binding Domain Induces Antigen-Specific Protective Immunity against Middle East Respiratory Syndrome Coronavirus Infection in Human Dipeptidyl Peptidase 4 Transgenic Mice

Ju Kim,Yong-Suk Jang,Yongsu Jeong,Ye Lin Yang

doi:10.3390/vaccines8040635

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory symptoms. Due to the lack of medical countermeasures, effective and safe vaccines against MERS-CoV infection are urgently required. Although different types of candidate vaccines have been developed, their immunogenicity is limited, and the dose and administration route need optimization to achieve optimal protection. We here investigated the potential use of human β-defensin 2 (HBD 2) as an adjuvant to enhance the protection provided by MERS-CoV vaccination. We found that immunization of human dipeptidyl peptidase 4 (hDPP4)-transgenic (hDPP4-Tg) mice with spike protein receptor-binding domain (S RBD) conjugated with HBD 2 (S RBD-HBD 2) induced potent antigen (Ag)-specific adaptive immune responses and protected against MERS-CoV infection. In addition, immunization with S RBD-HBD 2 alleviated progressive pulmonary fibrosis in the lungs of MERS-CoV-infected hDPP4-Tg mice and suppressed endoplasmic reticulum stress signaling activation upon viral infection. Compared to intramuscular administration, intranasal administration of S RBD-HBD 2 induced more potent mucosal IgA responses and was more effective for protecting against intranasal MERS-CoV infection. In conclusion, our findings suggest that HBD 2 potentiates Ag-specific immune responses against viral Ag and can be used as an adjuvant enhancing the immunogenicity of subunit vaccine candidates against MERS-CoV.

Highlights

Since 2000, numerous potentially lethal zoonotic human diseases have emerged due to novel coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, MiddleEast respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS coronavirus 2 (SARS-CoV-2)in 2019
Using the human dipeptidyl peptidase 4 (hDPP4)-Tg mouse model, we show that MERS-CoV infection activates endoplasmic reticulum (ER) stress pathway components, including protein kinase RNA-like ER kinase (PERK), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and activating transcription factor 6 (ATF6)
Chop (p < 0.01) in lung tissues four dpi; their mRNA levels were reduced at six dpi. These results suggest that MERS-CoV infection in hDPP4-Tg mice leads to lung damage by triggering ER

Summary

Introduction

Since 2000, numerous potentially lethal zoonotic human diseases have emerged due to novel coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle. Owing to their pandemic potential, impact on global health, and lack of effective medical countermeasures, these coronaviruses have been included in the World Health Organization (WHO). Research and Development Blueprint list of priority diseases. The MERS-CoV outbreak in Korea in 2015 has caused significant morbidity and mortality, posing severe threats to public health and the economy [1]. Saudi Arabia still has the highest reported MERS-CoV mortality rate with approximately 80% [2]. Despite extensive research efforts to develop effective prophylactic. Most MERS-CoV vaccines under investigation involve inactivated virus, live attenuated virus, viral vector-based vaccines, recombinant virus subunits, and DNA vaccines [3].

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