Coronas are not (just) beers.

Severe acute respiratory syndrome (SARS), as its name suggests, is a respiratory illness Coronaviridaewhich largely targets the upper respiratory tract, with its defining symptom being a fever with a temperature of 38°C (100.4°F) or higher. Other symptoms include flu-like symptoms such as chills, muscle aches, headaches, fatigue and sore throat. As the illness progresses, patients may then develop a dry cough and/or shortness of breath, followed by pneumonia, respiratory failure, and acute respiratory distress, potentially leading to death. The incubation period of the virus is about 2-13 days, with a mean of 5 days.

SARS is caused by the virus SARS-coronavirus (SARS-CoV). This virus was responsible for the SARS epidemic of November 2002 to July 2003. At the end of epidemic, there were a total of 8273 cases, and 775 deaths. The case fatality rate – that is, the number of deaths as a ratio of the number of cases – has been stated as being somewhere between 9.6%-11%, depending on the definition of case fatality rate used. Although the case fatality rate was somewhat high (the case fatality rate for the recent 2009 influenza pandemic was about 0.03%), the number of deaths was likely mitigated by the fact that many of the people infected by SARS-CoV had access to very good supportive/palliative healthcare, helping their immune systems to fight off the virus.

An electron micrograph of a SARS-CoV virion. Image by CDC/ C. D. Humphrey and T. G. Ksiazek.

An electron micrograph of a SARS-CoV virion. Note the distinctive “corona”, which gives the family Coronaviridae its name. Image by CDC/ C. D. Humphrey and T. G. Ksiazek.

SARS-CoV is a coronavirus, so named for the protein spikes that surround this spherical virus, which looks like a corona. Although SARS-CoV was initially suspected to have originated in masked palm civets – which were commonly sold in markets in China, where some of the first cases of SARS was reported – it was finally traced back via phylogenetics to the Chinese horseshoe bat. Both the human and civet cat SARS-CoV were found to have descended from bat coronaviruses.

Although there are no cures or vaccines currently available for SARS-CoV, there is a vaccine in development by MassBiologics, cooperating with researchers at NIH and the CDC. The 2002-2003 epidemic was successfully controlled by quarantining those infected, and suspected to be infected by the virus, and is a viable alternative solution in countries where such measures can be effectively implemented. The determination of the incubation period of the virus was a vital part of this counter-measure, as it enabled health officials to determine how long had to elapse before people who had come into contact with SARS patients could be declared free from SARS.

A similar coronavirus surfaced in Saudi Arabia in April 2012. Known as Middle East respiratory syndrome coronavirus (MERS-CoV), there have been 94 confirmed cases, 16 probable cases and 47 dead, with a case fatality rate of approximately 50%, as of August 2013. Like SARS, this is a viral respiratory illness; its symptoms include fever, cough and shortness of breath, which may be followed by kidney failure and respiratory distress, potentially leading to death. People who have weaker immune systems are more likely to die from Middle East respiratory syndrome (MERS). Thus far, all cases have been linked to the Middle Eastern area.

A negatively-stained electron micrograph of MERS-CoV,  revealing its ultrastructural morphology. Image by CDC/ Cynthia Goldsmith; Azaibi Tamin, Ph.D.

A negatively-stained electron micrograph of MERS-CoV, revealing its ultrastructural morphology. Image by CDC/ Cynthia Goldsmith; Azaibi Tamin, Ph.D.

MERS-CoV can be transmitted from person to person if there has been close contact without protective equipment e.g. gloves and masks, but in general, it appears that there has not been a sustained spread of MERS in people. There are three main epidemiological patterns to the transmission of MERS-CoV – 1) sporadic cases, probably after coming into contact with an animal carrying MERS-CoV. 2) Family clusters and 3) healthcare workers are similar, as they are both sets of people who would have come into close contact with an infected person while the person is contagious. The incubation period of MERS-CoV seems to be from 2-14 days; thus, isolation protocols similar to those as carried out in the SARS 2002-2003 epidemic can be applied to people who are suspected to be infected with MERS-CoV. There is also no known cure or vaccine for MERS-CoV. The only treatment available is supportive/palliative care, ensuring that the patient manages to live while their immune system fights off the virus.

Not much is known about MERS-CoV; it seems to be a genetic match to a coronavirus found in Egyptian tomb bats, but recently there has been a report that camels may be the actual animal reservoir for this strain of coronavirus. It also appears that a large amount of virus is actually needed to cause an infection, as only about 20% of our respiratory epithelial cells – that is to say, about 20% of our lungs and airways – are carrying the protein receptor DPP4, which allows MERS-CoV to enter, and hence infect, them.

On an slightly more unsettling note, it seems that there has been at least one case of asymptomatic MERS – that is to say, a person was infected, and then produced anti-MERS-CoV antibodies, without ever showing signs of MERS. If asymptomatic MERS can be confirmed, and people with asymptomatic MERS can transmit the virus to other people, this could potentially explain the sporadic cases of MERS that seem to pop up out of nowhere. Of course, this would also lower the case fatality rate of MERS-CoV. There are also further concerns about the potential for a serious epidemic as there will be an increase in the number of people going to Mecca in Saudi Arabia for the Muslim Haj. While a vaccine could potentially be developed, it might be that the MERS epidemic would burn itself out the same way the SARS epidemic did, thus rendering the development of the vaccine unnecessary and unprofitable.

 

References:

Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003

Tracking SARS back to its source

S. K. P. Lau, P. C. Y. Woo, K. S. M. Li, Y. Huang, H-W. Tsoi, B. H. L Wong, S. S. Y. Wong, S-Y. Leung, K-H. Chan and K-Y. Yuen. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats PNAS Vol. 102 No. 39 14040–14045, doi: 10.1073/pnas.0506735102

Special Online Edition: The SARS Epidemic

CDC | MERS

A. Rambaut MERS-Coronavirus Molecular Epidemiology and Genetic Analysis – Origin and Evolution

C. BEM Reusken, B. L. Haagmans, M. A. Müller, C. Gutierrez, G-J. Godeke, B. Meyer, D. Muth, V. S. Raj, L. Smits-De Vries, V. M. Corman, J-F. Drexler, S. L. Smits, Y. E. El Tahir, R. De Sousa, J. van Beek, N. Nowotny, K. van Maanen, E. Hidalgo-Hermoso, B-J. Bosch, P. Rottier, A. Osterhaus, C. Gortázar-Schmidt, C. Drosten, M. PG Koopmans Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study The Lancet Infectious Diseases, Volume 13, Issue 10, 859 – 866 doi:10.1016/S1473-3099(13)70164-6

R. Roos Saudis, WHO Report 8 Silent MERS Cases

D. Butler Receptor for new coronavirus found


Virology 100x: Round and round we go; where we stop, nobody knows

Viruses are so varied because each virus has evolved to specifically infect one particular host. There are so many different types of viruses that it’s difficult to describe them with a generality; what they have in common is merely as I wrote in an earlier post – that they’re obligate intracellular parasites comprising of nucleoprotein complexes with a protective protein coat (and possibly a lipid envelope). However, with classification, we are able to make generalisations within a particular subset of viruses – particularly with respect to how they infect and replicate, then bust out of our cells. If we are able to figure out how viruses replicate and infect our cells, we are then in a better position to prevent them from replicating in, or even better, from entering and infecting our cells in the first place.

Viruses are primarily classified according to their genetic material; that is to say, whether they have DNA or RNA. After splitting into these two groups, there are further subsets, such as whether the genetic material is single- or double-stranded; if the viral genome is whole or segmented – amongst others.

Baltimore classification

See text for explanation on Baltimore classification

This method of classification is called the Baltimore classification, after its developer David Baltimore. The genetic nature of a virus is important because it determines where and how the replication of the DNA or RNA takes place (either the nucleus or the cytoplasm), which in turn partially determines what steps the virus must take to get its genome there. Thus, it is possible for us to predict certain features of a virus’s replication cycle based purely on its genetic nature.

The stages in viral replication are so closely linked that it is difficult to separate them sometimes, and the number of stages range from seven to eight, or even nine, depending on who you are talking to. Nevertheless, they can be grouped into three main areas dealing with Entry into, Replication in, and Exit from host cells. Adsorption & Attachment, Entry, and Uncoating are stages in how the viruses enter cells; Transcription, Expression/Synthesis, and Replication are stages in viral replication; Assembly, Maturation, and Release are stages in how viruses exit cells.

As viruses don’t have any means of moving around, they depend on collisions with other things moving around in our bodies to push them along, causing random movement (also known as Brownian motion). Viruses are adsorbed onto the surface of the cells they are trying to infect, where they attach to the host cell by inserting their protein key into the host protein/sugar-chain lock, and thus gain entry into the cell.

The virus then enters the host cell via one of three methods. First, the translocation of the entire virus particle across the cell membrane; not much is known about this process, unfortunately. The second and third methods both involve endocytosis, which is the process by which our cells engulf particles such as nutrients (and in this case, viruses) from outside the cell. Endocytosis causes the formation of little pockets called vesicles, which go on to merge with larger pockets (containing fairly hostile environments) called lysosomes, which break down the particles that are brought into the cell for use throughout the cell. Triggered by the change in environment in lysosomes, viruses undergo uncoating, where the viral genome is exposed to the cellular environment. In the second method of entry, no further direct virus-host interactions are required, whereas in the third method, often employed by enveloped viruses, the viral lipid envelope and the cell membrane fuse to allow entry of the viral genome into the cell.

Upon entry, the virus then takes over the cell machinery and uses the cells’ enzymes to start transcribing and replicating its genome, and synthesizing the protein components of more viral particles. The precise order and manner of these stages is dependent on the nature of the viral genetic material¹.

Finally, the assembly of the newly-synthesized viral proteins and newly-replicated genetic material forms new viral particles, which is followed by protein cleavage where necessary for the maturation of the new viral progeny, and the release of the new viruses into the world again, usually by budding from the cell, or causing the cell to burst.

By deciphering how the various steps of any particular virus’s replication cycle happens, we are better able to prevent and/or treat a viral infection; for instance, the various drugs available in HIV therapy are based around the steps HIV takes to replicate itself. HIV is a class VI virus, meaning that it requires reverse transcriptase to replicate; one of the first HIV treatments was zidovudine (commonly known as AZT), which was aimed at inhibiting reverse transcriptase. Many other HIV drugs have continued to be developed in the same vein, and research has gone into finding drugs that can inhibit virus entry, maturation and exit as well.

 

 

 

1. Viruses are classed using the Baltimore Classification scheme according to how they replicate.

Class I and Class II have DNA for their genetic material. Class I viruses are able to express their genes upon entry as the genes are made of double-stranded DNA; replication of the genome and expression/synthesis of proteins are then carried on concurrently. Replication is almost exclusively nuclear in Class I viruses, with the exception of poxviruses, which are able to replicate their DNA in the cytoplasm. Class II viruses, with single-stranded DNA, typically have to undergo genome replication in the cell nucleus first before protein expression can be carried out.

Class III, IV and V have RNA for their genetic material. Class III viruses have segmented double-stranded RNA genomes, which are transcribed separately to produce mRNA and synthesize proteins in the cell cytoplasm. Class IV viruses’ (+)sense RNA are able to synthesize viral proteins immediately after infection in the cell cytoplasm, as they use their genomes like mRNAs; Class V viruses, on the other hand, have to make a (+)sense RNA from their (-)sense RNA genome first.

Class VI and VII viruses both use reverse transcription in their replication, although the point in the viral replication cycle at which reverse transcription is carried out is different for both classes. Class VI has diploid single-stranded (+)sense RNA, but this genetic material does not serve as mRNA immediately after infection. Instead, they use viral reverse transcriptase to create a DNA intermediate for replication and protein synthesis after infection. Class VII has double-stranded DNA, much like our own cells, which can be transcribed into mRNA, and the resulting mRNA read to make viral proteins. Reverse transcriptase comes in near the end of the replication cycle, to re-create the virus DNA from its mRNA.