Now for a real leap in my train of thought. Why do patients with tuberculosis (TB) cough? Okay that might seem like an off the wall thought, I have just re-established my TB MDT meeting with the Respiratory Consultants so maybe I can blame them!? But like me, have you ever wondered why patients cough? No… got better things to be doing? Hmmmmm, maybe it’s just me then….
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (MTB), is probably the most common infection in the World (yep certainly more than pesky Covid-19!). It is estimated that 25% of the World’s population is infected with M. tuberculosis. That’s about 1.75 billion people. Added to that 1.5 million people die every year from TB (as of today World Covid-19 deaths are 946K). TB is in the Top 10 causes of death worldwide, and is the highest death caused by a single microorganism. Whereas globally we are struggling to control and “treat” Covid-19, TB is PREVENTABLE and CURABLE.
TB is spread from person-to-person via large droplets, much the same as Covid-19. The reproductive rate (R0) for TB depends on whether the person has latent TB (i.e. the infection is contained by the person’s immune system) or whether the patient is actually coughing out the bacterium. Oh yeah this blog was about coughing!! Latent TB has an R0 of about 0.25-0.5 whereas symptomatic (coughing) TB has an R0 of 4 (every person with “coughing” TB infects 4 other people).
So if infection is spread by people coughing, the bacterium MTB needs people to cough in order to spread the infection.
So we come back to my original question, why do guinea pigs cough?
Up until now we thought people with TB coughed because the infection caused inflammation and tissue damage in the lungs leading to the local production of cytokines and other inflammatory molecules. These molecules caused increased production of receptors involved in cough hypersensitivity which then responded to excess mucous and the patient coughed. It turns out this is wrong!
A landmark study from Texas, USA, has shown that MTB produces a glycolipid molecule called sulfolipid-1 (SL-1) which makes guinea pigs cough. It turns out that MTB produces a lot of SL-1 as it forms a major component of the bacterium’s cell wall, in fact it makes up 1% of the dry weight of MTB, cool fact!
SL-1 has been known about since 1959, and work done in the 1970s showed that SL-1 was a major virulence factor for MTB. But no one had worked out what SL-1 actually did… until now.
How did the researchers show SL-1 causes coughing?
The researchers from Texas studied MTB in guinea pigs because, as we now know, guinea pigs cough like humans. First of all the researchers showed that a nebulised extract containing only lipid molecules from TB was sufficient to cause a cough whereas an extract identical in every way except it didn’t contain the lipid molecules didn’t cause a cough (and before you ask I have no idea how you give a guinea pig a nebuliser). So ECIC looks into that and well nebulisers in Guinea pigs… is a thing, I swear ECIC needs to get out more!!
The next step was to show that SL-1 did interact and stimulate nociceptive neurons in vitro (i.e. outside of an animal host) and sure enough SL-1 did stimulate these nerves.
The researchers then went back to the guinea pigs and repeated the nebuliser experiment with a pure extract of SL-1 and sure enough SL-1 caused a cough.
The final step in the research was to take MTB strains that did not produce SL-1 and see what happened when they infected guinea pigs. It turns out that MTB that doesn’t produce SL-1 still causes the infection TB in exactly the same way as with wild type bacteria BUT in the modified infections the guinea pigs just don’t cough.
It turns out that SL-1 actually directly stimulates nociceptive (pain sensing) neurons in lungs which then triggers coughing.
So this is a lot of work to show that MTB actually induces coughing in infected guinea pigs, so who cares? Why would MTB “want” to make us cough?
If SL-1 actually causes the cough it can help the bacterium spread; it’s manipulating us to further its domination! (A little dramatic maybe but TRUE!!). Guinea pigs have shown that people with TB cough because the bacterium, MTB, tells them to cough! Cool huh?
Why would M. tuberculosis have evolved a way of making us cough?
Let’s go back to how MTB spreads from person-to-person. TB is spread via large droplets and the most efficient way for an infected person to produce large droplets is to form them by coughing. So coughing aids the spread of TB. It is therefore most certainly an evolutionary advantage to MTB for its host to cough, and what better way to make sure its host coughs then for the bacterium itself to be responsible for making its host cough.
This is exactly what MTB appears to do. It doesn’t rely on its host “reflex” to cough, it “tells” its host to cough by producing the molecule SL-1 which stimulates the host’s nervous system and causes a cough which expels bacteria out of the lungs ready to infect other people!
Gosh, Nature is so clever!!
So what does this mean for clinical medicine?
For me this is where it gets even more exciting. Can I use the word “exciting”!? If TB is spread by coughing, and we know the molecule SL-1 is responsible for the coughing, then could we produce another molecule that blocks SL-1 and stop the coughing? If we could abolish the coughing whilst treating the patients then we could prevent TB from spreading. This would bring the R0 down well below 1 and maybe one day TB would eventually burn out. We would essentially be saying “MTB you can cause the infection in this person, but you can’t spread to anyone else”. And if we can block droplet spread in this way, can it be applied to other respiratory infections… including pesky Covid-19?
Just think about it; a bacterium that has been the scourge of humans for thousands of years, causing billions of cases and millions of deaths, eventually dying out. What an amazing thing that would be?
Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough. C Ruhl, B Pasko, H Khan, et al. Cell, 181; 293-305