Covid-19: a closer look
In the past weeks our lives have been deeply affected by the Covid-19 (coronavirus disease 2019) pandemic, which entered our life and profoundly changed our interaction with family and friends, our habits, our work.
Covid-19. What is it?
Covid-19 is an acute respiratory distress disease caused by a virus named SARS-CoV2, member of the virus family of coronaviruses. Coronaviruses are known to infect birds and mammals. There are four types of coronaviruses: alpha and beta which are known to infect mammals, while gamma and delta usually infect birds.
Coronaviruses have been circulating in humans and animals for long time and are also known causing agents of the common cold.
Beta coronavirus family includes i. SARS-CoV, which caused the SARS epidemic in 2002 making over 8.000 cases, over 700 deaths, and ended in 2004; ii. MERS-CoV, which caused the MERS epidemic in 2012 and made over 2500 cases, over 800 deaths and is still periodically occurring; iii. the recently identified SARS-CoV2, responsible for the current Covid-19 pandemic.
Beta coronaviruses derive from viruses circulating in bats, which jumped to humans through a process called “zoonotic transfer”. SARS-CoV and MERS-CoV zoonotic transfer occurred through intermediate hosts, meaning that the virus initially circulating in bats acquired the ability to infect other animals, civit cats and dromedary for SARS-CoV and MERS-CoV respectively, and then human beings. It is currently unknown whether SARS-CoV2 zoonotic transfer occurred directly from bats or through an intermediate host.
So far, over 500 Coronaviruses have been identified in bats, in China.
Differently from SARS epidemic, controlling disease transmission during the Covid-19 pandemic has been very difficult. One of the main reasons is that while in SARS there was no disease transmission until 24-36h after appearance of symptoms and lack of asymptomatic cases, making tracing of contacts highly effective, asymptomatic/mild cases are abundant in Covid-19, hence preventing an efficient control of disease transmission.
As of today (May 6th 2020), the number of cases confirmed in the world are 3.588.773 (Source: Situation Report, World Health Organization).
Molecular aspects of SARS-CoV2.
Coronavirus infection proceeds through four main phases: 1) virus entry into human cells; 2) expression and replication of viral genes; 3) induction of biological changes in the infected cells; 4) reaction of the immune system.
1) Virus entry into human cells. Coronaviruses’ genome is made of one large molecule of RNA. RNA and proteins associated (nucleocapsid proteins) are protected by a lipid envelope. Several proteins are present on the lipid envelope; among these, the spike proteins, which confer their typical crown-like appearance, and matrix proteins, which connect virus lipid envelope to nucleocapsid proteins. Matrix proteins have a key role during virus formation.
Spike proteins are made of an upper part which is called “receptor binding domain” (RBD), and a lower “fusion domain” mediating virus fusion with the host membrane during infection. When spike proteins interact with the ACE2 (Angiotensin-converting enzyme 2) receptor expressed on several different types of human cells (both SARS-CoV and SARS-CoV2 use the same receptor to infect human cells), the protein TMPRSS2 cuts the RBD domain from the fusion domain and activates the fusion domain. The virus is now able to fuse with the host membrane and release the RNA molecule into the human cell. The human cell is infected.
2) Expression and replication of viral genes. The RNA molecule which represents the genome of beta coronaviruses is translated into a “polyprotein”, namely a single protein which is then cut into 27 smaller viral proteins.
Once infected the human cells, coronaviruses have to replicate to propagate infection. Replication of the virus RNA molecule occurs by means of a protein called RNA-dependent-RNA-polymerase. Replication is an event prone to errors; Exonucelases (ExoN) and Nsp10 proteins partially correct these errors, through a process called “proofreading”. However, SARS-CoV mutants have the ability to adapt and prevent lethal mutations that may occur over multiple passages.
3) Induction of biological changes in the infected cells. After infection, the virus induces the formation of interconnected membrane structures (vesicles) where critical processes for virus diffusion occur. Among the proteins associated with these vesicles, there are:
-Nsp1 protein, which is a “pathogenicity factor” that supports virus infection by restricting gene expression of host cells, by downregulating key proteins enabling the virus to evade the immune system.
-assembly proteins
-accessory proteins, which are not key for virus replication in vitro, but are critical for their interaction with the host. SARS-CoV and SARS-CoV2 have similar accessory genes.
After replication of the viral genome and expression of the required proteins, viral particles are assembled in organelles of the host cells dedicated to protein synthesis, modification and trafficking: the Endoplasmic Reticulum and the Golgi.
4) Reaction of the immune system. A key response of the immune system to coronavirus infections is the activation of a signalling called “interferon response”.
While it is currently unknown for SARS-CoV2, SARS-CoV and MERS-CoV induce very little interferon response due to the existence, within their genome, of molecules called “antagonists”, which delay interferon response. The delayed interferon response causes an initial high virus replication. Moreover, when finally interferon response is activated, it is no more able to contrast virus replication but elicits the recruitment of inflammatory cells (monocytes/macrophages). The immune response leads to cytotoxicity: pneumonia, acute lung injury and acute respiratory distress syndrome occur.
Importantly, a current major challenge in Covid-19 research is to define whether antibodies from recovered patients are long-lasting and able to protect from reinfection. In SARS recovered patients, neutralizing antibodies are short-lived.
Reference: Webinar by Britt Glaunsinger, Howard Hughes Medical Institute, University of California Berkeley.