MERS, an interferon/innate immune deficiency state, continues to surge

June 2, 2014

The Middle East respiratory syndrome (MERS) is an infectious viral disease with about 30% mortality caused by viral pneumonia and associated lung damage. The etiologic agent of MERS, MERS-CoV, is a member of the coronavirus family. Coronaviruses are responsible for a variety of pathologic effects in a broad spectrum of vertebrates including the virus currently responsible for epidemic piglet deaths in hog farms in the United States. The pathogenicity of MERS is due, in part, to the innate immune deficiency state that results from inhibition of a first responder to viral infection, interferon (IFN).

The Middle East respiratory syndrome (MERS) is an infectious viral disease with about 30% mortality caused by viral pneumonia and associated lung damage. The etiologic agent of MERS, MERS-CoV, is a member of the coronavirus family. Coronaviruses are responsible for a variety of pathologic effects in a broad spectrum of vertebrates including the virus currently responsible for epidemic piglet deaths in hog farms in the United States.1 The pathogenicity of MERS is due, in part, to the innate immune deficiency state that results from inhibition of a first responder to viral infection, interferon (IFN).2

Within the coronavirus family are 6 human viruses. Four are responsible for upper-respiratory infections associated with the common cold. The other 2, however, have high mortality rates in humans and are genetically closely related. The first human highly pathogenic virus to be recognized over a decade ago, SARS-CoV, was responsible for severe acute respiratory syndrome (SARS), which caused serious economic havoc in China and to a lesser extent in Canada with approximately 8,000 cases and about a 10% mortality rate. No new SARS cases have been recognized for the last 10 years. In 2012 a second coronavirus (MERS-CoV) emerged in Saudi Arabia with a similar pathogenesis to SARS. Both SARS-CoV and MERS-CoV are transmitted by close contact with healthcare workers at greatest risk of infection by MERS-CoV. The close contact that occurs with the annual Ramadan pilgrimage to Saudi Arabia raised concerns for an increased infection rate in 2013 that did not materialize. (Ramadan begins June 29th in 2014.) More recently, however, there has been a dramatic non-Ramadan associated increase in new cases of MERS. The 217 new cases reported for the month of April 2014 were more than the total number of 207 cases reported during the prior 2 years. As of May 16, 2014, 614 laboratory-confirmed cases have been reported globally associated with 181 deaths.3 Most recently 2 cases of MERS were diagnosed from travelers to the US from Saudi Arabia.

 

There are no approved antiviral agents or vaccines for MERS-CoV or SARS-CoV. Specific vaccines and viral inhibitors require years of discovery, animal safety studies, and clinical trials to determine human safety and efficacy to obtain regulatory approvals. In the event of a global emergency of a developing pandemic, drugs approved for use in other indications or drugs in the phase 3 regulatory approval process would have priority extended for possible use based on their established clinical safety record coupled with other evidence of efficacy. Highly pathogenic viruses have evolved mechanisms to inactivate the first responders to microbial infection.5 MERS-CoV and SARS-CoV appear to have evolved an infectious advantage over the 4 mildly pathogenic human coronaviral species by inhibition of innate immune responses.6  Recent studies on MERS-CoV reported that multiple components of the MERS virus (M, ORF 4a/b, ORF 5) inhibit the de novo production of a key component of innate immunity, IFN.2 Cells normally respond to an invading pathogenic virus by viral nucleic acids binding to 1 or more of the 10 human cellular proteins known as toll-like receptors (TLRs) that activate the cell nucleus by signaling to transiently produce antiviral response elements.7 One class of these antiviral response elements are the IFNs that serve to provide immunity to viral infection for uninfected cells.8 By this mechanism the body limits viral infection while a more permanent defense is achieved by the adoptive immune system. Abundant scientific evidence indicates that type I IFN (IFN-α, IFN-β) can help overcome the MERS-CoV or SARS-CoV induced inhibition of innate immunity.9-12 Both data from cells in culture as well as monkey studies indicate that IFN protects cells and animals from infection with MERS-CoV and/or SARS-CoV. When commercially available antivirals were compared for dose response efficacy against SARS-CoV in vitro, most failed to inhibit observable cell damage (cytopathic effect). Several IFNs including IFN-α-n1 (Wellferon), IFN-β-1b (Betaferon), and IFN-α-n3 (Alferon) and ribavirin inhibited cytopathic effect.9 IFN-α-n3 has a significantly higher specific activity against HIV than commercial recombinant IFNs and was equivalent to IFN-β-1b with both IFNs clearly superior to IFN-α-n1 or ribavirin.9,13 A TLR3 agonist,  rintatolimod (Ampligen), in phase 3 clinical trials has been demonstrated to be active in vivo against SARS-CoV. Using a mouse-adapted lethal mouse model, rintatolimod provided 100% in vivo protection.14

MERS and SARS appear to be the product of coronaviral-induced defects in innate immune responses. Exogenous replacement and/or induction of innate immunity with drugs demonstrated to be safe for humans with efficacy either in vitro or in vivo with doses achievable in humans deserves evaluation under clinical trial conditions. Treatment late in the course of human, highly lethal coronaviral infections (MERS/SARS) is unlikely to alter disease course.15 In order to provide statistical power, protocols need to be established for systematic evaluation rather than the random walk therapeutic options currently employed.

 

References

1. Masters PS, Perlman S. Coronoviridae. In: Knipe DM, Howley PM, eds. Fields Virology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2013;29:825–858.

2. Yang Y, Zhang L, Geng H, et al. The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell. 2013;4:951–961.

3. World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – update. http://www.who.int/csr/don/2014_05_16_mers/en/.
Accessed May 24, 2014.

4. Kaplan K. Newest U.S. MERS patient was infected by Indiana victim, CDC says. Los Angeles Times.http://www.latimes.com/science/sciencenow/la-sci-sn-mers-illinois-patient-cdc-20140517-story.html. Accessed May 24, 2014.

5. García-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in détente. Science. 2006;312:879–882.

6. Zielecki F, Weber M, Eickmann M, et al. Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus. J Virol. 2013;87:5300–5304.

7. Mitchell WM, Nicodemus CF, Carter WA, et al. Discordant biological and toxicological species responses to TLR3 activation. Am J Pathol. 2014;184:1062–1072.

8. Mitchell WM. Active sites of the animal viruses: potential sites of specific chemotherapeutic attack. In: Carter WC, ed. Selective Inhibitors of Viral Function. Cleveland, OH: CRC Press, 1973;51–80.

9. Tan EL, Ooi EE, Lin CY, et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004;10:581–586.

10. Kuri T, Zhang X, Habjan M, et al. Interferon priming enables cells to partially overturn the SARS coronavirus-induced block in innate immune activation. J Gen Virol. 2009;90:2686–2894.

11. Falzarano D, de Wit E, Martellaro C, et al. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep. 2013;3:1686.

12. Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013;19:1313–1317.

13. Fan SX, Skillman DR, Liao MJ, et al. Increased efficacy of human natural interferon alpha (IFN-alpha n3) versus human recombinant IFN-alpha 2 for inhibition of HIV-1 replication in primary human monocytes. AIDS Res Hum Retroviruses. 1993;9:1115–1122.

14. Day CW, Baric R, Cai SX, et al. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology. 2009;395:210–222.

15. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014;20:42–46.

 

Professor Mitchell is professor of pathology, microbiology, and immunology at Vanderbilt University. He is an independent member of the Hemispherx Biopharma, Inc., Board of Directors and has an equity interest in the company. Dr Strayer is medical director of Hemispherx Biopharma, Inc., and Dr Carter is CEO of Hemispherx Biopharma, Inc.