Interferons in SARS treatment – a doubled-edged sword

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19). It has caused a global pandemic that is posing a major threat to millions of people’s health. Part of the reason that causes this pandemic is the lack of pre-existent adaptive immunity among the population. Before successful development and deployment of effective vaccine, the first line of defence against SARS-CoV-2 in our body is our innate immunity. Once the cell detects atypical signatures related to viruses, such as double-stranded RNA, it secrets signalling proteins to alarm its surrounding cells, known as cytokines [1]. Secreted cytokines vary across cell types, and each has its own role in organizing the body’s defence against viruses. Some of the most important defences against viruses are the interferons (IFN), which recognise specific receptors in the surface of the cell as a key and a lock. The interaction of interferon with its receptor induces the expression of antiviral proteins in cytoplasm and nucleus of the cell to combat infection more effectively. Researchers has studied the functions of interferons for decades and developed recombinant proteins to be used in protein therapies, for example, to treat hepatitis C virus [2]. The current COVID-19 pandemic raises the important questions about the role of individual cytokines and, in particular interferons, in body’s response to SARS-CoV-2.

Schematic representation of the structure of interferons (illustration by David Goodsell)

As SARS-CoV-2 is a newly identified virus, researchers are still investigating the details about the importance of individual cytokines in COVID-19. However, we can infer their potential functions from its better studied relative SARS-CoV-1, the coronavirus that caused an outbreak in 2003. Cinatl and colleagues revealed that type I interferon (IFN-I), which includes IFN alpha and beta, can be used to effectively inhibit replication of SARS-CoV-1 in vitro [3]. In vivo studies using human ACE-2 transgenic macaques confirmed the anti-SARS effect of IFN-I. Haagmans and colleagues tested the effect of pegylated IFN-alpha injection on macaques infected with SARS-Cov-1 and they showed lower viral titres in both throat swab and lung homogenate, and better histopathology results [4]. The suppression of SARS-CoV-1 infection was even stronger when IFN was injected prior to the infection with the virus. Gao and colleagues conducted similar experiment in macaques using IFN-I nasal spray, which also showed protective effects [5]. The preliminary clinical studies on SARS-CoV-1 patients treated with IFN-I showed improvement in oxygen saturation and symptoms [6], but larger scale clinical trials were inconclusive due to the lack of patients as the outbreak quickly ceased by summer [7].  

Channappanavar et al., Cell Host Microb, 2016

Although IFN treatment sounds clinically promising for SARS-CoV-1 outbreak, we have also learnt that cytokines could be destructive when they go rampage. Typically, one week after SARS infection, patients that have arterial oxygen saturation (SO2) > 91% will recover within a week, while those that have SO2 < 91% enter a crisis phase that require access to ventilators, and have higher mortality rate. Cameron and colleagues discovered that patients that entered the crisis phase have naturally significantly higher levels of proinflammatory cytokines [8]. Channappanavar and colleagues studied further the IFN-induced tissular damage using human ACE-2 transgenic mouse model [9]. Surprisingly, mice lacking the receptor for IFN-I showed milder symptom (measured by body weight loss) and lower mortality rate when compared with wild-type mice after infected with lethal dose of SARS-CoV-1. Moreover, other studies have shown correlation between elevated levels of cytokines and severe symptoms in SARS-CoV-1 and MERS-CoV [10]. Can we thus conclude that interferons do more harm than good? Using transgenic mice model, Channappanavar and colleagues discovered that multiple cytokines, including IFN-I, showed a 24-hour delay in expression level after SARS-CoV-1 infection. Early intervention of IFN-I treatment cured SARS in infected mice and had substantially milder symptoms than mice lacking the IFN-I receptor. Therefore, it appears that IFN-I response at the right timing effectively contains the virus, but at the wrong time is responsible for severe symptoms in SARS-CoV-1 infection (see figure [9]). It remains unclear how our understanding of SARS-CoV-1 could help us combat SARS-CoV-2, but these discoveries could be beneficial in the development of effective treatment or even to understand the battle between our immune system and the virus and its consequences.

Writen by Honglin Chen, DPhil student

References

  • [1]  Kumar, H., Kawai, T. and Akira, S., 2011. Pathogen recognition by the innate immune system. International reviews of immunology, 30(1), pp.16-34.
  • [2]  Feld, J.J. and Hoofnagle, J.H., 2005. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature, 436(7053), pp.967-972.
  • [3]  Cinatl, J., Morgenstern, B., Bauer, G., Chandra, P., Rabenau, H. and Doerr, H.W., 2003. Treatment of SARS with human interferons. The Lancet, 362(9380), pp.293-294.
  • [4]  Haagmans, B.L., Kuiken, T., Martina, B.E., Fouchier, R.A., Rimmelzwaan, G.F., Van Amerongen, G., van Riel, D., De Jong, T., Itamura, S., Chan, K.H. and Tashiro, M., 2004. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nature medicine, 10(3), pp.290-293.  
  • [5]  Gao, H., Zhang, L.L., Wei, Q., Duan, Z.J., Tu, X.M., Yu, Z.A., Deng, W., Zhang, L.P., Bao, L.L., Zhang, B. and Tong, W., 2005. Preventive and therapeutic effects of recombinant IFN-alpha2b nasal spray on SARS-CoV infection in Macaca mulata. Zhonghua shi yan he lin chuang bing du xue za zhi= Zhonghua shiyan he linchuang bingduxue zazhi= Chinese journal of experimental and clinical virology, 19(3), pp.207-210.
  • [6]  Loutfy, M.R., Blatt, L.M., Siminovitch, K.A., Ward, S., Wolff, B., Lho, H., Pham, D.H., Deif, H., LaMere, E.A., Chang, M. and Kain, K.C., 2003. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. Jama, 290(24), pp.3222-3228.
  • [7]  Stockman, L.J., Bellamy, R. and Garner, P., 2006. SARS: systematic review of treatment effects. PLoS medicine, 3(9).
  • [8]  Cameron, M.J., Ran, L., Xu, L., Danesh, A., Bermejo-Martin, J.F., Cameron, C.M., Muller, M.P., Gold, W.L., Richardson, S.E., Poutanen, S.M. and Willey, B.M., 2007. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. Journal of virology, 81(16), pp.8692-8706.
  • [9]  Channappanavar, R., Fehr, A.R., Vijay, R., Mack, M., Zhao, J., Meyerholz, D.K. and Perlman, S., 2016. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell host & microbe, 19(2), pp.181-193.
  • [10]  Channappanavar, R. and Perlman, S., 2017, July. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. In Seminars in immunopathology (Vol. 39, No. 5, pp. 529-539). Springer Berlin Heidelberg.