Did you know that guinea pigs cough? I didn’t… but then I’ve never had a pet guinea pig… In fact I’ve discovered that all mammals cough, who knew?! Guinea pigs apparently have a cough pathway (from something stimulating a cough through neural networks and chemical signals to the actual cough) that is the same as humans so they are a great animal model for studying coughs in humans…??

Have the Nuts & Bolts Team finally lost the plot due to Covid-19 and what does this rambling about small furry animals have to do with microbiology I hear you ask? Let’s see where this one goes; we do like to challenge your loyalty to the subject of microbiology!
 
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?
 
Historical coughing?
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!!

Next the researchers took various modified MTB strains and compared extracts from these with their ability to cause a cough. This showed that MTB strains without the ability to produce SL-1 did not cause coughing.
 
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?
 
Reference
Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough. C Ruhl, B Pasko, H Khan, et al. Cell, 181; 293-305

One of life’s unsolved mysteries is “how did life on Earth begin?” Did it start here spontaneously as “God created us” or did Darwin get it right with his “evolution theory”? And are we alone in our universe? Let’s skip the God versus Darwin bit and jump straight to the question “did life arrive from outer space” and “can life survive in space?”
 
When times get “trying” here on planet Earth ECIC wishes she was on Pluto with her cats, her rules and no people! But she may not be alone!! The newest research suggests that bacteria can survive in the hostile environment of space; maybe the dream of living on Pluto with remote “homeworking” for a Consultant Microbiologist might be a reality (our hospital computer system is called Enterprise after all!)
 
No, No, No, stick with me!!! It’s true, those pesky microorganisms have been found to survive on the outside of the ISS (International Space Station). There’s even a named theory… the theory that living organisms can survive and transfer through space is known as “panspermia”. 

“I have a patient with facial cellulitis but they’re not responding to antibiotics, my Consultant has asked me to find out if there is a stronger antibiotic we can give” said the oncall doctor.
 
The Microbiologist rolled his eyes; why do people persist in thinking about antibiotics in terms of “stronger” when what they really mean is “broader spectrum”!
 
“Why don’t you start by telling me something about the patient?” said the Microbiologist through gritted teeth.
 
“Oh, okay” said the Doctor, thinking this was just going to waste more of his precious time.
 
“She has just returned from trekking in Bolivia where they stayed in mud huts. The patient thinks they might have been bitten on the face as there were quite a lot of big beetles around. She now has a swollen right eye and we’ve been giving IV Teicoplanin but it hasn’t made any difference so we want to give her something… stronger.”
 
His curiosity piqued, the Microbiologist let the latest “stronger” slip past.
 
“Are both upper and lower eyelids swollen? What did the insects look like exactly?”

​“Yes, both eyelids are swollen and I have no idea what the bugs looked like” said the Doctor, thinking this was taking entirely too long.
 
“Okay, this sounds like Romana’s sign. I think your patient might actually have Chagas disease. Have you done a blood film? You need to send us blood for PCR and in the meantime I’ll pop over and see if your patient can describe the bugs in more detail”.
 
“Huh, so there is no antibiotic choice then?” grunted the Doctor thinking he wasn’t going to get that stronger antibiotic after all… and got the impression the Microbiologist was going off on a tangent which he wasn’t going to know much about!
 
What is Chagas disease?
Chagas disease, also known as American trypanosomiasis, is caused by the parasite Trypanosoma cruzi. Most mammals can be infected by T. cruzi including humans, rodents, cats, dogs and cattle.
 
Infection is spread by an insect vector, usually the Triatomine bugs (also known as Kissing, Reduviid or Assassin bugs). While the bug is feeding it defecates and leaves it’s faeces to either penetrate the bite wound or, if on the face, it penetrates through the conjunctiva… yep it poos in your eye! Gross….
 
Chagas disease can also be spread via blood transfusion from an infected donor as well as congenital infection from an infected mother to her child (the risk of congenital infection from an infected mother is up to 10%). Many countries have systems in place to restrict blood donation from those who have either lived in or visited endemic countries. Less commonly infection can occur from transplanted organs or via ingestion of food or water contaminated with Reduviid bug faeces.
 
Apparently Chagas disease is responsible for the most illnesses and deaths of any parasite in the Western hemisphere, including more than malaria! Chagas disease occurs throughout the Americas from the Southern United States to the North of Argentina and Chile, with an estimated 6 million cases. The highest prevalence of Chagas disease is in Bolivia, Argentina, Paraguay, Ecuador, El Salvador, and Guatemala.
 
Traditionally Chagas disease was an infection of people in rural areas where the insect vector lived in cracks in the walls, or the thatched roofs, of adobe houses. However with increasing population movement both internally and globally Chagas disease acquired rurally can present at a later date in urban environments as well as in non-endemic countries. Control programs have eliminated the insect vector in countries like Brazil meaning that the proportion of congenital infections is now higher than naturally acquired infection.
 
How does Chagas disease present?
The incubation period for Chagas disease is usually 1-2 weeks but can be up to 4 months in transfusion transmission.
 
Most acute infections (within 8-12 weeks) with T. cruzi occur in children and are asymptomatic or very mild. Others experience mild fever, lymphadenopathy, malaise and hepatosplenomegaly (enlarged liver and spleen). A few patients get a swelling at the site of inoculation, known as a Chagoma; if this occurs after conjunctival inoculation causing swelling of the eye lids then it is known as Romana’s sign. Serious acute infection with myocarditis or meningoencephalitis occurs in less than 1% of patients.
 
However the most serious manifestations of Chagas disease, in 20-40% of patients, present up to 30 years later with either cardiac or less commonly gastrointestinal disease.
 
Cardiac Chagas disease usually presents with progressive heart failure, shortness of breath, fatigue, pulmonary and peripheral oedema (fluid accumulation) and chest pain. The heart becomes dilated and there is a risk of arrhythmias and emboli as a result of the heart not beating properly. The prognosis from cardiac disease is poor with over 30% dying from sudden cardiac death within 8 years from diagnosis. Others will die young from progressive heart failure; although there are scoring systems, e.g. the Rassi score, for trying to work out who will die and when, these are not that reliable.
 
Gastrointestinal Chagas disease is due to an autoimmune cross reaction triggered by antibody against the parasite which damages the nerves supplying the gut, especially the oesophagus and distal colon. Loss of innervation leads to progressive dilatation and eventually mega-oesophagus and mega-colon. Patients are unable to swallow safely and are at risk of aspiration and choking; they also become unable to absorb food properly, develop bowel obstruction and malnutrition.
 
How is Chagas disease diagnosed?
The easiest way to diagnose acute Chagas disease is to look at a film of blood and see the parasite in the red blood cells. The parasitaemia lasts about 90 days; in chronic infections the film will be negative as the parasites have been cleared from the bloodstream. Acute Chagas disease is now normally diagnosed using PCR on whole blood.
 
Chronic Chagas disease is difficult to diagnose and requires demonstration of IgG against T. cruzi. Because none of the tests are particularly good, and are prone to false positives, two different tests based on different antibody reactions should be used and the diagnosis made if BOTH are positive AND the patient has evidence of myocarditis or gastrointestinal disease.
 
Patients treated for Chagas disease should have follow up serology; the IgG should reduce with successful treatment. If the amount of IgG does not reduce then the patient may require retreating.
 
How is Chagas disease treated?
There are 2 parts to the treatment of Chagas disease; treatment of the parasitic infection and treatment of the chronic cardiac and gastrointestinal complications.
 
Antiparasitic drugs are used for both acute and chronic Chagas disease. There are two drugs; Benznidazole and Nifurtimox. Benznidazole tends to be first line treatment as it is better tolerated with fewer side effects. Treatment in acute infection reduces the duration and severity of symptoms (if present) and clears the parasitaemia resulting in cure in 60-85% (>90% for congenital infection if treated in the first year of life).
 
Treatment with antiparasitic drugs in the chronic form can reduce progression of cardiac and gastrointestinal disease by about 70-80%, especially if given before symptoms have progressed too far towards severe heart failure, mega-oesophagus or mega-colon.
 
Cardiac disease is treated in the same way as heart failure or arrhythmias for other causes with diuretics, beta-blockers and anticoagulants. Gastrointestinal disease is managed with dietary changes but ultimately patients may require extensive surgery with oesophagectomy and colectomy.
 
Prevention
The best way for travellers to prevent infection with T. cruzi is to avoid being exposed to the insect vector, sleeping under insecticide impregnated nets, not staying in rustic accommodation and avoiding street food that might be contaminated with insect faeces. Essentially travellers can avoid infection by normal simple common sense “safe traveller” behaviour.
 
For people living in endemic countries the same measures for prevention apply. Many South American countries have embarked on programs to improve rural housing by replacing adobe huts with brick and corrugated iron buildings… not as pretty maybe but considerably safer.
 
Congenital infections can be reduced by screening pregnant women by PCR as negative PCR correlates with very low or absent parasites in blood and therefore substantially reduced risk of in utero infection. There are no drugs that can be used safely in pregnancy to reduce the risk of transmission in PCR positive women. You have to wait for the child to be born before trying to treat the child and the mother.
 
So the Microbiologist spoke to the patient who described the Reduviid bugs in great detail (apparently they are 2cm long but quite pretty!). A film was looked at that day by the haematologists who saw parasites in the blood film. With the diagnosis confirmed the patient was started on Benznidazole and follow up blood tests fortunately showed a complete cure, although they had developed a phobia to big creepy bugs… but I guess that was to be expected really!

Back in November last year I wrote a blog about tick borne encephalitis (TBE) in the UK caused by viruses under the title “Deadly brain disease passed by ticks now in Britain”… not my title but rather the Telegraph newspaper. This was related to the discovery of deer ticks in Thetford Forest which showed evidence of infection with the TBE Flaviviruses. However this isn’t the only cause of TBE in the World, there are others such as the parasitic disease babesiosis… and you’ve guessed it…. we now have it here in the UK! Wonderful!?

More and more of us are being affected by imposed quarantine measures (sometimes at very short notice!). Holiday plans are all over the place (we are not going to the Drakensberg’s, our flight is cancelled, UK residents are banned and there is 14 days of quarantine even if we could get in! Boom, our holiday’s gone BUST!). There is mass quarantining on a global scale. But added to this is the fact that in the UK you must also quarantine yourself if you are exposed to a person with Covid-19. No ifs, no buts, do not pass “Go”, do not “collect £200”. But where does the term quarantine come from, what does it mean and are we “actually” using it correctly?

Okay, you don’t really need me to tell you that the Covid-19 pandemic has been a bit of a nightmare; medically, socially and psychologically. As of the 12th August there have been 20.4 million cases reported worldwide with 744,000 deaths. These are pretty scary numbers but large scale death and destruction from infectious diseases is nothing new.
 
Infectious diseases have been the leading cause of death for the human species, and over recent centuries there have been some horrendous pandemics that make Covid-19 so far look pretty small. In this blog I’m going to look at just 3 infectious diseases whose pandemics give Covid-19 some perspective…
 
Cue wavy lines and wobbly music as we go back in time to the 6th Century…
 
Plagues
The first of our “recent” plague pandemics is known as the Plague of Justinian (541-542), which affected the Eastern Roman Empire, especially Constantinople and the Mediterranean region. It is estimated to have killed 50 million people during the initial pandemic and in the 200 years after when it continued to circulate. This was up to a quarter of the World’s population at this time! Justinian I was Emperor of Rome when the pandemic started; apparently he caught the plague but survived.
 
The next plague pandemic was the Black Death (1347-1353) which killed an estimated 30-60% of the population of Europe, about 100-125 million people! There are thousands of ossuaries (bone collections) in Churches around Europe full of the remains of those killed by the Black Death. The Black Death resulted in a number of social, religious and political upheavals that shaped the future of Europe including movement of people in to cities, decline of the power of the Church and increased power of governments.

Editor Chief in Charge and I have spent the weekend trying to work out what we’re going to do if/when we can’t go on holiday later this year because of a certain unmentionable pesky virus. The basic answer is that we might not be going somewhere exotic! But why might not being able to go on holiday somewhere exotic be a good idea?!?
 
I know… pufferfish!
 
Pufferfish are tropical fish found especially in Asia. They are called pufferfish because they have a rather unusual defence strategy; they can fill their stomachs with water so that they balloon up into a ball shooting numerous spiky spines outwards. Any predator stupid enough to try and eat a pufferfish gets a mouth or stomach full of spines and probably chokes… nasty. Bloat, from the Disney film “Finding Nemo” was a pufferfish; he blows up like a beach ball every time something startles him… he’s my favourite character and he’s hilarious!

One of the most striking features of the Covid-19 pandemic from my perspective has been the massive volume of scientific papers released on the internet. There have been 10’s of thousands of papers which is both amazing and worrying. But why is it worrying, surely the faster we have more information the better? Well maybe not…
 
According to recent studies 2% of researchers admit that they have committed fraud in their work, but they thought that 14% of their colleagues had also committed fraud… fraud is basically lying…. Also in a study of 20,000 biomedical research papers 2% contained deliberately falsified images… this was reported on BBC Inside Science - Science Fraud & Bias, Immunity to COVID-19. [My wife told me about this radio broadcast she heard whilst cuddling our two new Cats Protection foster kittens (Toes and Splodge)!]

“I have a patient with a bright red nose” said the junior Doctor.
 
The Microbiologist double-checked his calendar to make sure it wasn’t March 15th and the junior performing a joke for Comic Relief’s “Red Nose Day”, a charity day here in the UK!
 
“What do you mean a bright red nose” the Microbiologist asked, adding “it’s not Comic Relief Day, you know?” heading off the “fooled you” prank.
 
“What!?”... The junior inhaled deeply, ignored the Microbiologist, and continued “It’s a kind of reddish purple and very painful. It looks a bit like cellulitis but it is in a very odd place, and the patient doesn’t have a fever. What antibiotics do you think we should give?”
 
Muttering, “this isn’t just a dial an antibiotic line”, the Microbiologist decided he would like to see this patient’s nose and find out what was going on himself before advising what treatment should be started…
 
He added “your patient needs a diagnosis before throwing random drugs at them to see if they get better”.
 
As the Microbiologist walked into the patient’s room to introduce himself he couldn’t help but see that the patient did indeed have a bright red nose. He chuckled to himself; the patient definitely didn’t need one of those plastic red noses.
 
After a brief embarrassed pause the Microbiologist finally introduced himself. The patient smiled and then unconsciously reached up and stroked his nose with his thumb and forefinger.
 
With sudden understanding the Microbiologist asked “do you have anything to do with animals, either work or at home?”
 
“I am a keen keeper of Koi carp and have just finished transferring them to their new pond… I designed it myself” the patient said proudly.
 
It was the Microbiologists turn to smile. “You have erysipeloid” he told the patient confidently.
 
“Eh, sip, what? No, I have Koi carp, they’re fish!” said the patient, confused.

I came across a story this week about a patient from Florida, USA, who had been diagnosed with a really unusual infection caused by a microorganism called Naegleria fowleri. It caught my attention because firstly it is very rare and so I was intrigued and secondly because during a lockdown it should be extremely difficult to catch it! So I had to investigate further…
 
What is Naegleria fowleri?
Naegleria fowleri is a free-living amoeba found in freshwater and soil throughout the World, preferring temperatures between 30-45 oC. It does not survive in seawater. The most common risk factor for acquiring N. fowleri is contact with water through sports such as swimming, water skiing and diving as well as messing around in mud or bathing in contaminated hot springs (it is “free-living” after all!). So this explains my curiosity as to how this patient had acquired their infection as it should be very difficult to “get exposed” to N. fowleri during a lockdown, because there wouldn’t be any water sports or other exposures going on at this time!