My Research: Respiratory Syncytial Virus

“So what do you do?” 

“Have you heard of Respiratory Syncytial Virus?”

“No, never”

“What about Influenza”

“Oh yeah of course”

“Well its kind of like that…”

(The beginning of every conversation about my research)

So far, my posts have been focused on various aspects of PhD life. However I realised that I haven’t written anything about what my PhD is focused on. The big research question that I’ve devoted a few years of my life to. Well hopefully in this post, I’ll be able to explain what I’m working on and in particular, why my work is important.

What is Respiratory Syncytial Virus (RSV) ?

RSV was discovered over 60 years ago during an outbreak in chimps that resembled the common cold. RSV is a respiratory pathogen, and its main targets for infection are airway epithelial cells (found in your lungs and nasal passages). Today we recognise RSV as the main cause of acute lower respiratory tract infections (ARTIs) in infants worldwide. In fact, recently RSV was reported to be the main cause of childhood pneumonia.

RSV Structure
An RSV virion attaching to and entering a host cell

Who gets infected by RSV?

Surprisingly, barely anyone is aware of RSV (apart from medics, researchers and the occasional mother). I find this quite ironic, considering everyone has been infected by it. That’s right, virtually everyone is infected with RSV by the age of 2, with the peak rate of infection occurring at approximately 2 months of age.  Unfortunately you can be re-infected throughout life, as your immune system does not remember RSV very well. The elderly are also particularly susceptible to RSV infection. You can expect RSV epidemics each winter, as it is a seasonal pathogen (see below).

RSV age and date
Reports of RSV infection are highest in children < 1 year old and most common during the winter season

What sort of disease does RSV cause?

So everyone has had an RSV infection, but do you remember yours? Your encounter with RSV was likely not particularly memorable. In fact, your parents might not even have noticed anything out of the ordinary. That’s because for most infants, RSV infection causes symptoms like the common cold. However, some infants will develop severe RSV disease. This usually manifests as bronchiolitis or pneumonia and will require hospitalization. In 2015, it was estimated that 59,600 children under the age of 5 died from RSV infections.  This is where we encounter the big problem…

bronchiolitis_anatomy_pi
An inflamed bronchiole wall leading to mucus build up and blockage of the airways is characteristic of bronchiolitis

What treatments are available?

Despite being discovered over 60 years ago, there is no vaccine or therapeutic for RSV. The only available prophylaxis (drugs that must be administered prior to infection) is Palivizumab, which is injected monthly throughout the RSV season. The problem is that Palivizumab is very expensive. As a result, it is restricted to infants considered “high-risk” of developing severe RSV disease.

IMG_20180409_144429
No vaccine, no therapeutic, all we have is Palivizumab, and it’s too expensive to give to all the children who need it

So, who are these “high-risk” individuals?

According to the literature, the high-risk groups for developing severe RSV disease are:

  • premature birth
  • congenital heart disease
  • bronchopulmonary dysplasia
  • immunodeficiency

Palivizumab was initially given to infants born premature (< 35 weeks gestation) but has been restricted further due to poor economic cost – benefit ratios. Today, Palivizumab is only administered to infants born < 29 weeks gestation who have an additional risk factor.

Interesting Developments

Interestingly, the majority of infants hospitalized with severe RSV disease are previously healthy (i.e. they don’t fall into the conventional “risk groups”). This means that we cannot predict which infants will develop severe RSV disease and require hospitalization. Furthermore, the majority of those that will develop severe disease won’t be eligible to receive Palivizumab. These findings have hinted at the existence of other predisposing factors which have yet to be identified. This is where my research is focused.

The WD-PNEC Model

In our lab, we collect nasal swabs from children undergoing elective surgery in the hospital. We are able to grow the cells from these swabs in such a way that they look and behave as they would in the patients nose. They are known as well-differentiated primary nasal epithelial cells (WD-PNECs). These WD-PNECs sprout cilia (tiny hairs) and produce mucus that we must clean every other day (gross right?). However, this is exactly what makes them so valuable. The fact that they look and behave so authentically makes them a fantastic model for studying that particular child’s immune response to RSV infection.

If you look closely, you’ll see tiny vibrations amidst the cells. This is the cilia “beating”.

If you look closely, you’ll spot the layer of mucus, gliding over the cells from top to bottom.

My Research

My research project came from a simple question,

“Do infants develop severe RSV disease due to a naturally weaker immune response to RSV infection?”

In order to answer this question, we grew our WD-PNECs from nasal swabs collected from children with histories of either severe or mild RSV disease. Both groups of WD-PNECs were then infected with RSV in the lab, and we measured the expression level of various immune response genes.

We successfully identified a panel of genes that were differentially expressed between the two groups. Two genes in particular were expressed much lower following RSV infection in the severe group compared to the mild group. This suggested that the diminished expression of these genes following RSV infection may explain susceptibility to severe RSV disease.

These two genes are the foundation of my project, and I’m currently working to determine precisely how they protect against RSV infection.

Composite
One of the prettier images I’ve captured during my research. These are RSV infected cells (green), their nuclei (blue), and a product of one of my genes of interest (red).

What impact will my work have?

If successful, my project will provide a better understanding of which infants are truly “high-risk” for developing severe RSV disease. This will allow more effective allocation of current / future drugs and provide a more comprehensive understanding of the immune response to RSV in humans.

I’ve thoroughly enjoyed my research so far and the idea of my research having a positive impact on the world is one of the things that keeps me motivated.

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