Effect of interferon alpha and cyclosporine treatment separately and in combination on Middle East Respiratory Syndrome Coronavirus (MERS-CoV) replication in a human in-vitro and ex-vivo culture model

Antiviral Research
Volume 155, July 2018, Pages 89-96

H. S. Li, Denise I. T. Kuok, M. C. Cheung, Mandy M. T. Ng, K. C.nNg, Kenrie P.Y.Hui, J. S.mMalik Peiris, Michael C. W. Chan John M. Nicholls

Abstract

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has emerged as a coronavirus infection of humans in the past 5 years. Though confined to certain geographical regions of the world, infection has been associated with a case fatality rate of 35%, and this mortality may be higher in ventilated patients. As there are few readily available animal models that accurately mimic human disease, it has been a challenge to ethically determine what optimum treatment strategies can be used for this disease. We used in-vitro and human ex-vivo explant cultures to investigate the effect of two immunomodulatory agents, interferon alpha and cyclosporine, singly and in combination, on MERS-CoV replication. In both culture systems the combined treatment was more effective than either agent used alone in reducing MERS-CoV replication. PCR SuperArray analysis showed that the reduction of virus replication was associated with a greater induction of interferon stimulated genes. As these therapeutic agents are already licensed for clinical use, it may be relevant to investigate their use for therapy of human MERS-CoV infection.

Keywords

Middle East Respiratory Syndrome Coronavirus (MERS-CoV)Type I interferon, Cyclosporine, Ex vivo explants

Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease

Virology
Volume 517, April 2018, Pages 98-107

Madeline G. Douglas, Jacob F. Kocher, Trevor Scobey, Ralph S. Baric, Adam S. Cockrell

Abstract

We recently established a mouse model (288–330+/+) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 × 106 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS-CoV (maM35c4) capable of achieving severe respiratory disease at doses between 103 and 105 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10–1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease.

Keywords

Coronavirus, MERS-CoV, Middle East respiratory syndrome, Respiratory disease, Acute respiratory distress syndrome, Spike protein

Structural insights of a self-assembling 9-residue peptide from the C-terminal tail of the SARS corona virus E-protein in DPC and SDS micelles: A combined high and low resolution spectroscopic study

Biochimica et Biophysica Acta (BBA) - Biomembranes
Volume 1860, Issue 2, February 2018, Pages 335-346

Anirban Ghosh, Dipita Bhattacharyya, Anirban Bhunia

Abstract

In recent years, several studies based on the interaction of self-assembling short peptides derived from viroporins with model membranes, have improved our understanding of the molecular mechanism of corona virus (CoV) infection under physiological conditions. In this study, we have characterized the mechanism of membrane interaction of a short, 9-residue peptide TK9 (T55VYVYSRVK63) that had been derived from the carboxyl terminal of the Severe Acute Respiratory Syndrome (SARS) corona virus (SARS CoV) envelope (E) protein. The peptide has been studied for its physical changes in the presence of both zwitterionic DPC and negatively charged SDS model membrane micelles, respectively, with the help of a battery of biophysical techniques including two-dimensional solution state NMR spectroscopy. Interestingly, in both micellar environments, TK9 adopted an alpha helical conformation; however, the helical propensities were much higher in the case of DPC compared to those of SDS micelle, suggesting that TK9 has more specificity towards eukaryotic cell membrane than the bacterial cell membrane. The orientation of the peptide TK9 also varies in the different micellar environments. The peptide's affinity was further manifested by its pronounced membrane disruption ability towards the mammalian compared to the bacterial membrane mimic. Collectively, the in-depth structural information on the interaction of TK9 with different membrane environments explains the host specificity and membrane orientation owing to subsequent membrane disruption implicated in the viral pathogenesis.

Keywords

NMR, SARS CoV, Micelle, NOESY, Paramagnetic relaxation

Current treatment options and the role of peptides as potential therapeutic components for Middle East Respiratory Syndrome (MERS): A review

Journal of Infection and Public Health
Volume 11, Issue 1, January–February 2018, Pages 9-17

Sabeena Mustafa, Hanan Balkhy, Musa N. Gabere

Abstract

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a highly pathogenic respiratory virus with mechanisms that may be driven by innate immune responses. Despite the effort of scientific studies related to this virus, Middle East Respiratory Syndrome (MERS) is still a public health concern. MERS-CoV infection has a high mortality rate, and to date, no therapeutic or vaccine has been discovered, that is effective in treating or preventing the disease. In this review, we summarize our understanding of the molecular and biological events of compounds acting as MERS-CoV inhibitors, the outcomes of existing therapeutic options and the various drugs undergoing clinical trials. Currently, several therapeutic options have been employed, such as convalescent plasma (CP), intravenous immunoglobulin (IVIG), monoclonal antibodies and repurposing of existing clinically approved drugs. However, these therapeutic options have drawbacks, thus the need for an alternative approach. The requirement for effective therapeutic treatment has brought the necessity for additional MERS treatments. We suggest that antimicrobial peptides (AMPs) may be used as alternative therapeutic agents against MERS-CoV infection. In addition, we propose the feasibility of developing effective agents by repurposing the existing and clinically approved anti-coronavirus and anti-viral peptide drugs.

Keywords

MERS-CoV, Ribavirin, Interferon, Peptide therapeutics, Convalescent plasma, Intravenous immunoglobin, Antimicrobial peptides

MERS-CoV infection: Mind the public knowledge gap

Journal of Infection and Public Health
Volume 11, Issue 1, January–February 2018, Pages 89-93

Amen Bawazir, Eman Al-Mazroo, Hoda Jradi, Anwar Ahmed, and Motasim Badria

Abstract

In August 2015, the Corona outbreak caused by Middle East respiratory syndrome coronavirus (MERS-CoV) was the 9th episode since June 2012 in Saudi Arabia. Little is known about the public awareness toward the nature or prevention of the disease. The aim of this work was to assess the knowledge of the adult population in Riyadh toward the MERS-CoV.

In this cross-sectional survey, a self-administrated questionnaire was distributed to randomly selected participants visiting malls in Riyadh. The questionnaire contained measurable epidemiological and clinical MERS-CoV knowledge level variables and relevant source of information.

The study included 676 participants. Mean age was 32.5 (±SD 8.6) years and 353 (47.8%) were males. Almost all participants heard about the corona disease and causative agent. The study showed a fair overall knowledge (66.0%), less knowledge on epidemiological features of the disease (58.3%), and good knowledge (90.7%) on the clinical manifestation of the MERS-CoV. Internet was the major (89.0%) source of disease information, and other sources including health care providers, SMS, television, magazines and books were low rated (all <25%). In a multivariate logistic regression analysis age ≤30 years (Odds Ratio (OR) = 1.647, 95%CI 1.048–2.584, P = 0.030), male gender (OR = 1.536, 95%CI 1.105–2.134, P = 0.01), and no tertiary education (OR = 1.957, 95%CI 1.264–3.030, P = 0.003) were independent significant predictors of poor epidemiological knowledge.

This study concludes that there was inadequate epidemiological knowledge received by the public and the reliance mostly on the clinical manifestations to recognizing the MERS-CoV disease. Comprehensive public health education programs is important to increase awareness of simple epidemiological determinants of the disease is warranted.

Keywords

Corona virus, Attitude, Riyadh, Saudi Arabia, MERS-CoV