Yet another reason to hate mosquitoes

Living in the UK I am often sucked into writing my blogs based only on news stories occurring here. This time I have decided to change that formula and focus on a story that has hit the headlines the other side of the pond in the United States. The headlines are surrounding the increasing spread of West Nile virus. As of 14^th August there had been 696 cases and 26 deaths. Come the start of September these numbers had increased to 1993 cases and 87 deaths, then as of the 9^th September (only a week later) the numbers had reached 2636 cases and 118 deaths. This outbreak is the largest in the US since 2003 in terms of the number infected, and also has the highest proportion of the most serious form of infection since the virus was first discovered in the US in 1999. West Nile virus is not necessarily something many people know about beyond the headlines, so as usual, this has spurred me into writing a blog giving some detail on the virus itself.

Culex mosquito

The first thing to point out with this virus is that it is classed as an arbovirus. This is the fancy word for a virus that is transmitted by an arthropod vector, much like malaria for example (though that is not caused by a virus). West Nile virus (WNV) is transmitted by a species of mosquito known as Culex, while malaria is carried by a different species known as Anopheles. WNV is the most widely distributed of all the arboviruses, seen in every continent, except Antarctica. It is important to know that the virus is spread by mosquitoes as this plays a major role in the epidemiology of the virus, as will hopefully become apparent in this blog.

Along with mosquitoes (and obviously humans) the virus is found in birds, and it is in fact these animals that are the natural reservoir for the virus, not humans. Evidence for this comes from the fact that the virus replicates best when in a species with a high body temperature. Most birds have a natural body temperature of around 41^OC, which is ideal for the replication of WNV. Humans on the other hand have a temperature around 37^OC, which has been shown to limit the replicative ability of the virus, indicating humans are merely an incidental host. The virus is best adapted to replicate in birds, but can use humans if needs be.

Usually Culex mosquitoes feed on birds that are carrying the virus and spread it amongst the bird population. However, in very hot and dry weather this changes. Under these climactic conditions it becomes harder for plants to survive. Plant death has an impact on the population levels of the insects that feed on them. Since many birds feed on insects, if there are less insects the population number of birds will also suffer. If there are less birds to feed on the mosquitoes will move on to a less favoured, but more accessible meal; humans. So when hot and dry weather is seen for prolonged periods of time there is an increase in the level of mosquitoes feeding on humans, raising the chance for spread of WNV in the human population. This is exactly what is happening in America right now, some of the worst affected areas (such as Texas, where roughly 40% of cases have occurred) are currently in drought which very high temperatures (even for summer).

West Nile virus particles

 WNV in humans is often an asymptomatic infection (partly down to the fact that we are only an incidental host), with roughly 80% of people who get the virus not developing any symptoms. Close to 20% of people infected will develop non-neuroinvasive disease that is characterised by fever, aches, vomiting etc. While West Nile fever is nasty for a few weeks, people with this form of infection will usually recover and be completely healthy. However, around 1 in 150 people infected by the virus will develop the most severe, neuroinvasive, form of the disease, which is characterised by virus entering the brain. This form of WNV infection is responsible for most fatalities.

The current outbreak in America has so far been characterised by a much higher percentage of patients showing neuroinvasive infection, though it is not clear why. These patients develop encephalitis (swelling of the brain) and can develop other complications such as meningitis. The fact that the virus causes swelling of the brain adds an interesting characteristic to the infection. Young children have a suppler skull than adults. If a child develops encephalitis from neuroinvasive WNV infection there is much more give in the skull meaning they are less likely to suffer severe complications. People over the age of 55 are at this highest risk of severe complications from neuroinvasive WNV due to their skull being firm (the brain has no room in which to swell).

Currently there is no vaccine and no specific antiviral drugs against WNV. Weirdly the main form of treatment that is given for WNV infection is steroids. This is weird in the sense that steroids suppress a patient’s immune system. While suppressing the immune system is clearly not good in terms of fighting off a viral infection, inflammation is also controlled by the immune system. Therefore, if the system is suppressed there will be less inflammation, meaning the swelling of the brain seen in neuroinvasive infection will not occur (or will at least be suppressed). Over time the patients on steroid treatment will be able to remove the virus due to the fact that it does not replicate particularly well in humans (as I mentioned previously). However, it is likely that this recovery will be a drawn out process due to the compromised immune system (the patients will suffer the fever, aches, vomiting etc for longer). This is clearly not a particularly good strategy to deal with the virus, and clearly more work needs to be done in the field. Hopefully the current outbreak in the US will help keep funding up in the WNV area and allow for the development of an effective vaccine, or at least specific antiviral drugs.

The current outbreak of WNV in the USA has the second highest number of cases seen since the virus was first introduced to the country in 1999. The outbreak is also the most severe in terms of a high percentage of patients developing neuroinvasive infection. There has recently been a huge jump in the number of confirmed cases; back in mid-August there were 693 cases, come the start of September there were 1993 cases and a week later there were 2636 cases. These figures imply that the virus is spreading rapidly, however this is slightly misleading, as there is a delay between patients being tested and the results being received. Another contributing factor to the slightly misleading figures is that more and more people are being tested due to the current hype around the outbreak. In a normal year it is likely that many people will develop non-neuroinvasive WNV but will pass it off as just a bout of flu (fever, aches, vomiting etc), so will not be tested (and therefore recorded). Since WNV is in the headlines, more people are being tested, meaning the numbers are slightly distorted. I’m not denying that this outbreak is serious; I’m just pointing out a small fact about these kinds of statistics that is often overlooked. Fortunately, in some respects, the virus is completely reliant on the mosquitoes, therefore when summer ends and the mosquito numbers drop the epidemic will end. There is an end point to this epidemic, hopefully sooner rather than later.

Watch this spot

On 24^th August statistics were released showing that the number of measles cases in the UK have almost doubled in the first half of 2012, as compared to the first half of 2011. Figures from the Health Protection Agency show that in the first six months of the year the number of cases have risen from 497 to 964. This large increase can be partly attributed to two significant outbreaks in Merseyside and Sussex. Interestingly, even though there have been outbreaks and an overall rise in the number of cases, the uptake of the MMR vaccine (protecting against measles, mumps and rubella) is at a very high level, with 93% of patients receiving the first dose and 87% receiving the second dose. Due to this story making the headlines and the fact that there is a lot of interesting stuff about the measles virus I thought I would write a blog on it all.

Measles vaccination

First and foremost I’d like to make one thing clear, there is no proven link between MMR and the development of autism. This is an old story but it’s hard to talk about measles without talking about the MMR debacle. Back in 1998 a study, conducted by Andrew Wakefield, was published in The Lancet medical journal demonstrating a link between receiving the MMR vaccine and developing autism in children. This study ignited a debate over the safety of the vaccine and saw the uptake rates fall to the lowest level since the introduction of the triple vaccine back in 1988. However, controversy reigned over the study and numerous other studies were conducted using millions of children. All of these ensuing studies failed to find any evidence of a link between MMR and autism. Over time it came to light that Wakefield had conducted the research with multiple undeclared conflicts of interest including funding from a law firm preparing a legal case against the MMR vaccine (it was reported that he personally received more than £400,000 from the firm). The Lancet paper was eventually retracted and Wakefield found guilty of serious professional misconduct, ending with him being stuck off the Medical Register in the UK. Suffice it to say, there is no clear evidence that the MMR vaccine has a link to the development of autism and the vaccine has been proven to be safe and effective at preventing infection from all three diseases.

Now that the controversy is out of the way, we can move on to the even more interesting biological aspects of the virus. The first thing I would like to look at is what the virus gets up to when it causes disease. The measles virus is spread by the aerosol route, much like influenza. A patient may sneeze or cough droplets carrying the virus particles which then move on (through the air or via surfaces) to infect a new individual. Due to the route of transmission the virus will first enter into an individual’s respiratory tract and make its way to the lungs. In the lungs the virus is able to infect resident immune cells; these are cells that are naturally housed in the lungs ready to pounce on any invading organism. The virus uses the SLAM (also known as CD150) receptors to enter the cells. Once these cells are infected they will leave the lungs and head to the lymph nodes. At this point the virus will replicate and start to infect more cells causing swelling of the nodes. Eventually the virus will leave the lymph nodes to infect epithelial cells around the body (these are cells that make up all the surfaces of the body: the skin, the lining of the gut, the lining of the lungs and so on). When the virus makes it to skin cells it will enter and cause the famous rash seen in measles patients. This whole process, from lungs, to lymph nodes, to skin, takes around 10-14 days (the incubation period of the virus).

Classical measles rash

All that is left for the virus to do now is to transmit to a new host, meaning it needs to get back to the lungs. For a long time it was unclear how this was achieved. The SLAM receptor used when the virus enters had been known about for a long time, but there are no SLAM receptors that would allow the virus to get back to the lungs, the entrance was known, but the exit was hidden. It wasn’t until late last year when the exit door was found to be a protein known as Nectin 4. This protein is only found on one side of the cell, known as the basolateral side (the side which is in contact with the blood system). It would be impossible for the virus to use Nectin 4 upon entry through the lungs, but once already in the blood system it has easy access to Nectin 4, allowing the virus to enter the lung cells and spread in a cough or a sneeze. Nectin 4 is also the protein that allows the virus to get into skin cells, so is responsible for the classical rash. It might just be me who thinks this, but the fact that this virus has evolved to use two completely different receptors, on two completely different cell types, for the processes of entry and exit, is very cool!

The next aspect of the virus I’d like to look at is the paradoxical immuno-suppression that is seen following infection. A patient who contracts measles tends to mount a very good immune response against the virus and will, over time kill it (the normal situation with most infections). However, for a couple of weeks to a month after the virus has been removed (and the disease cleared) the patient has a weakened immune system. The measles virus in itself is not a particularly dangerous virus; the real danger comes from the weakened immune system that follows infection and makes the patient particularly susceptible to secondary infections. Most deaths associated with measles are caused by pneumonia or diarrhoea, both of which are secondary infections. The reasons behind this immuno-suppression are not fully understood. It has been seen that even after the virus has been cleared from the body parts of the viral genome can still be detected in the blood for weeks after infection and we also know that measles targets immune cells through the SLAM receptor (as I mentioned above). It is possible that both of these factors may contribute to the measles-associated immuno-suppression that can cause complications to the viral disease (the genome could distract the immune system so it is only focused on measles and nothing else, and targeting immune cells may kill them).

Electron microscope image of measles virus

The final aspect of the measles virus I’d like to share with you is its infectivity. Measles is one of the most infective diseases that we know of. Infectivity is measured by a value known as R₀. This value is the number of people who will be infected from an individual carrying the disease, through the course of the infection. So an R₀ of 3 means a patient with a disease will, on average, infect 3 other people. To give some context to this, HIV has an R₀ of 2-5, seasonal influenza has an R₀ of 2-3 while smallpox and polio both have a R₀ value of 5-7.  Even with a low R₀ HIV has managed to infect nearly 34 million people and until its eradication, smallpox was an incredibly feared disease; even seemingly small values can wreak havoc. Measles has a R_o of a whopping 14-18! So for every person who carries the measles virus, they could (were it not for the vaccine) infect between 14 and 18 people. A scary fact when compared to the other viruses.

Two apt demonstrations of the infectivity of measles virus have been seen in Indiana (USA). The first of these was in 2005 when an outbreak was traced to an unvaccinated girl who had recently travelled to Romania. She came back harbouring the virus, but yet to display any symptoms (most likely while the virus was replicating in her lymph nodes). She then proceeded to go to a church gathering as the first symptoms (cough, sneezing etc) appeared. At this gathering there were 500 people, of these 50 were unvaccinated against measles and of these unvaccinated people 16 were infected by the one girl carrying the virus (R₀ between 14 and 18 remember). Another outbreak occurred in Indiana in February this year following Super Bowl XLVI. Roughly 17 people were diagnosed with measles following the game. Although the person responsible has not been identified as with the 2005 outbreak, it is again likely that all 17 cases stemmed from one infected individual.

I think measles is a fascinating virus. Unlike many other viruses it is highly evolved to target two different receptors and therefore two completely different cell types. On its way in, the virus uses SLAM receptors found on immune cells, then to escape and pass on to new people it uses the Nectin 4 receptor of epithelial cells. The virus is generally well controlled by our immune system, but once cleared it leaves the nasty parting gift of prolonged immuno-suppression, making a patient highly susceptible to secondary infections, which are responsible for many of the complications seen with measles infections. Measles is also one of the most infectious viruses we know about. Fortunately we have a very effective vaccine in the form of the trivalent MMR jab. Due to how highly infectious measles is it is essential to have very high coverage of the vaccine. The World Health Organisation has set a target of 95% coverage, a target which, here in the UK, we are very close to achieving, with 93% coverage for the first jab. However, even falling slightly short, and having a lower uptake for the second jab (only 87%) gives the virus enough opportunity to spread and cause outbreaks as have been seen during the first half of 2012. Measles is a preventable disease, and is very likely to be the next target for eradication, if we ever manage to get rid of polio. The key is to keep on vaccinating!