SARS attacks!

If someone could claim the dubious title of the first major emerging pathology of the 21st century, it is without doubt the severe acute respiratory syndrome (SARS). On November 16th 2002, the first case of an atypical serious pneumonia lacking an identified infectious agent was reported in the Guangdong province of China and spread soon after from Hong Kong, Vietnam and Canada around the planet. What we retain from this episode that skirted the pandemia are its prominent media coverage (panic sells), a slight hitch in international communication as the Chinese authorities took some time to inform the World Health Organization (WHO) and the efficient cooperation leading to the fast identification and sequencing of the corpus delicti – a novel coronavirus termed SARS-CoV – by laboratories from the U.S.A, Canada, Hong Kong, Germany, France and China by the end of March 2003 [2]. In comparison, identification of Human Immunodeficiency Virus (HIV) took about two years. During the following decade, research focused on the usual suspects, that are proteins, in infection, virulence and antibody development. Yan Li et al. played the originality card by identifying GU-rich pieces of the SARS-CoV genome as the David defying the Goliath of the host immune system [1].

Coming across extracellular DNA and RNA swimming around when you are a cell is usually bad news, as they stem either from agonizing companions or from nasty intruders, all the more when you happen to be a member of the innate immune system equipped with some pattern recognition receptors (PRRs). Among them, Toll-like receptors TLR3 and TLR9 have been proven to recognize double-stranded RNA and unmethylated CpG-rich bacterial or viral DNA respectively a while ago [3], [4]. The fact that ssRNA also activates the immune system is more recent news though. Florian Heil and colleagues provided the first concrete evidence in 2004 by feeding the GU-rich single-strand RNA40 (ssRNA40) from HIV-1 to human and murine macrophages and dendritic cells [5]. The resulting bottom line is that murine TLR7 and human TLR8 recognize single-strand GU-rich RNA and trigger the secretion of inflammatory and regulatory cytokines. Moreover, immune cells are not the only cell population at risk, as TLR7 is expressed in a wide range of different types of neurons as well as in astrocytes and microglia. Lehmann et al. demonstrated that ssRNA40 causes neuronal cell death in mice through binding to TLR7 activating subsequently MyD88 and caspase-3 in a cell-autonomous manner exacerbated by microglial inflammatory ssRNA40/TLR7 dependent signaling, while TLR7−/− mice are entirely protected against ssRNA40 induced neuronal death [6].

Nevertheless, only a few concrete examples of viral ssRNA have been identified and experimentally validated as TLR7/8 agonists until now, among them ssRNA40 and the SARS-CoV culprits described by Li et al. Thus, an interesting question is how widespread the feature of owning GU-rich ssRNAs to drive immune cells crazy is. Obviously it is not restricted to a specific viral genus: HIV-1 is a lentivrus, SARS-CoV a coronavirus and a certain flavivirus, the Langat virus (LGTV), looks like another good candidate based on data in press provided by Baker et al. linking TLR7 to the regulation of the neuroinflammatory response to LGTV infection in the CNS [7]. However, the newcomer and outsider among its own genus SARS-CoV, whose overall level of similarity with other coronaviruses is reduced, might have put the finishing touches to this useful tool made of ssRNAs.

By the way, where doTLR7/8 encounter their viral ssRNA ligands? Given that both receptors are localized in the endosome, it is rather likely that ssRNA ends up there after receptor-mediated endocytosis of the virus or fusion of the viral particle and the infected cell. The strict compartmentalization is a must, as ssRNA with GU-motives is not an exclusive brand of the viral genome and several autoimmune diseases like systemic lupus erythematosus (SLE) or reumathoid arthritis correlate with CpG DNAs and RNA in extracellular compartments as well as the production of autoantibodies against endogenous RNA [5], [7]. Host-released extracellular RNA is also frequently detected in brains of neurodegenerative disorder patients like Alzheimer's disease, where it contributes in spreading damage of the central nervous system (CNS) through TLR signaling [6].

Preventing the immune system from going berserk with lethal side-effects at the sight of released nucleic acids turns out to be a tricky one due to the redundancy of the TLR family (10 members in humans). Lee and colleagues proposed recently a strategy relying on nucleic acid-binding cationic polymers as anti-inflammatory agents [8]. Indeed, hexadimethrine bromide (HDMBr) and 1,4-diaminobutane core-PAMAM-G3 (PAMAM-G3) are able to counter the immune stimulatory effect of all nucleic-acid TLR ligands in multiple inflammatory cell types in vitro and in vivo, acting as molecular scavengers both neutralizing the free nucleic acids and altering their intracellular distribution.

Therefore, among the potential therapeutical implications of the findings of Li and colleagues figure the occasion to use viral ssRNA as adjuvants for vaccination and immunotherapy [5] as well as the possibility to stop the escalating immune response by blocking the activation of TLR7/8 by ssRNA either from bacterial or viral attack or inappropriate autoimmune TLR activation [7].

After all, the second merit of SARS will be to have boosted the career of antiviral drug research against coronaviruses, as good as inexistent before 2003.

Also, better keep away from civets.