Statins May Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection.

LETTER

The recent paper by Totura and colleagues (1) revealed that Toll-like receptor 3 (TLR3) signaling contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Despite the importance of SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) as public health threats, there are currently no drugs available to treat these coronaviruses, with current evidence suggesting that the antiviral drugs ribavirin and interferon (IFN) are only slightly efficacious in ameliorating SARS-CoV or MERS-CoV infections (2). Now human-to-human infections of MERS-CoV are more frequently reported, with a total case fatality rate of 37.7% (2). Therefore, a feasible but effective treatment is needed urgently, especially treatment with FDA-approved drugs, including some over-the-counter (OTC) drugs.

Like avian influenza viruses (AIVs), MERS-CoVs set off a cytokine storm (3), which is likely to lead to the subsequent acute respiratory distress syndrome (ARDS). Therefore, some immunomodulatory therapies were suggested for respiratory virus infections, such as celecoxib, mesalamine, cyclosporine, and the TLR4 antagonist eritoran (4). TLRs play a critical role in the recognition of pathogens and induction of the innate immune response to many viruses. The TLR3 agonist poly(I⋅C) and the TLR4 agonist lipopolysaccharide (LPS) are protective against SARS-CoV infection in mice (1). TLR4−/− mice are resistant to acute lung injury via AIV infections (5). However, TLR4−/− mice have significantly more disease resulting from SARS-CoV infection than wild-type mice (1). The protective signaling via TLR4 pathways may be a unique feature in the pathogenesis of coronaviruses compared to other respiratory pathogens, such as influenza viruses (1).

Despite the opposite functions of TLR4s in AIV and SARS-CoV infections, MYD88 (myeloid differentiation primary response 88; downstream of TLRs) plays an important role in the survival of respiratory virus infections (Fig. 1). The MYD88 gene was observed to be highly induced by SARS-CoV infection (1). Interestingly, either excessive expression of MYD88 (1) or a deficiency in MYD88 expression (6) resulted in high mortality rates after MERS-CoV infections, implying that a balanced immune response is crucial for survival of respiratory virus infections.

FIG 1 

Roles of statins in TLR-MYD88 and NF-κB pathways during MERS-CoV infections. IRFs, interferon regulatory factors; MAL, MYD88 adaptor-like; MYD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa B; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adapter-inducing beta interferon.

Downstream of TLR-MYD88 pathways, activation of NF-κB is a hallmark of coronavirus infections, and inhibition of NF-κB reduced lung infection and significantly increased mouse survival after SARS-CoV infection (7).

Among TLR-MYD88 antagonists, statins are the most common FDA-approved drugs (atorvastatin will be sold as an OTC drug). Statins do not affect the MYD88 level significantly under normal conditions but maintain (stabilized) MYD88 at the normal level during hypoxia or after hydrogen peroxide treatments (8, 9). Furthermore, atorvastatin at 10 µM significantly attenuated NF-κB activation within 24 h, whereas at lower doses of 0.1 and 1 µM, the treatment time had to be prolonged for up to 48 h for a significant inhibition to occur (10). Thus, an early and high dose of a statin (such as a single dose of 40 mg atorvastatin per day, equaling a 0.1 µM plasma concentration) might be an idea for treatment of MERS-CoV infections. Given that 3- to 10-times-higher levels of inflammatory cytokines and chemokines were observed after MERS-CoV infection than after no infection (3), statins may not be very effective for late-stage patients. Timely administration of statins may be crucial to surviving MERS-CoV infection.