Emerging Coronaviruses: lessons from the past and future challenges

Abstract

The emergence of viruses causing diseases in humans is constant in History. Most emergent viruses have been transmitted from animal hosts to humans (zoonosis). Coronaviruses (CoVs) have frequently crossed the species barriers and two novel coronaviruses have caused important zoonosis in the twenty-first century. Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 in South East China and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 in Saudi Arabia. Both viruses cause acute respiratory distress syndrome and are associated with high mortality rates, around 10% and 35% respectively. However, mortality rates higher than 50% are observed in the aged and immunosuppressed populations. The identification of the genes involved in CoV virulence and in signaling pathways contributing to pathogenesis has been addressed using SARS- and MERS-CoVs in order to develop effective therapeutic and preventive strategies that can be readily applied to new emergent coronaviruses. Using a reverse genetics system, SARS-CoV envelope E gene (E) has been deleted leading to an attenuated phenotype (SARS-CoV-¿E). The expression of proinflammatory cytokines was reduced in the lungs of mice infected with a mouse adapted SARS-CoV-MA15-¿E compared to lungs infected with the wild type virus. In infections by SARS-CoV with and without E protein, NF-¿B was the only proinflammatory pathway differentially activated. Interestingly, the addition of an inhibitor of NF- ¿B led to a reduced inflammatory response after SARS-CoV infection and to an increase in mice survival. Therefore, these inhibitors could serve, in principle, as antivirals. A reduction in neutrophil migration to lung-infected areas was observed in mice infected with SARS-CoV-MA15- ¿E, probably contributing to the lower degree of inflammation detected and to SARS-CoV-¿E attenuation. SARS-CoV E protein is a viroporin with different functional domains: a transmembrane region with ion channel activity and a PDZ binding domain mapping at the most carboxy-terminus. Alteration of these domains attenuated the virus, and the mechanisms of attenuation have been studied. These attenuated mutants provided long-term protection both in young and elderly mice against the challenge with pathogenic SARS-CoVs. Deletion of E gene in MERS-CoV using a reverse genetics system, led to a replication-competent propagation-defective virus that is a safe vaccine candidate. These data indicated that SARS-CoV and MERS-CoV with E protein deleted or modified are promising vaccine candidates.