What are fungi?

Fungi are one of the great groups of organisms (and pathogens) that we encounter. They are eukaryotes distinct from both plants and animals (although they are more closely related to the latter). The fungi are a massively diverse group of well over a million species. The 'standard' type of fungus was brilliantly introduced in Richard Dawkins' The Ancestor's Tale thus:

Mushrooms and toadstools give the wrong impression - these conspicuous plant-like structures are the spore-producing tips of the iceberg. Most of the business part of the organism that made the mushroom is under the ground: a spreading network of threads called hyphae. The collection of hyphae belonging to one individual fungus is called the mycelium. The total length of mycelium of an individual fungus may be measured in kilometres, and may spread through a substantial area of soil.

A single mushroom is like a flower growing on a tree. But the 'tree', instead of being a tall, vertical structure, is spread out like the strings of a giant tennis racket underground, in the surface layers of the soil.

Of course, there is a huge amount of variation in such a bulky cohort. Some groups of fungi (like the yeasts), eshew the mycelium body plan, prefering to make a living as single cells that divide to form a clumpy mass. Some fungi can even flip between these two manifestations, and are called dimorphic fungi.

What the hyphae (or yeast cells) are doing is digesting whatever it is they are burrowing through: dead leaves and other decaying matter (in the case of soil fungi), curdled milk (in the case of cheese-making fungi), grapes (in the case of wine-making yeasts), or the grape-treader's toes (if he happens to suffer from athlete's foot).

(He really is a brilliant explainer, isn't he?) Of course, fungi can be identified in a more formal manner by various criteria, such as having a cell wall of both chitin and glucans, but that's not all that important for us here.

Fungi have proved very useful to human beings over the ages, being variously used to leaven bread, to ferment foodstuffs (thereby memorably generating beer and wine), and to fill our bellies (e.g. mushrooms).

Medically, the minority of fungi that are actually pathogenic are conventionally divided up into two groups:

• Superficial mycoses - in which the fungi grows at the bdy surface in skin, hair and nails.
• Deep mycoses - in which the fungi attack our internal organs.

As a rule of thumb, the superficial mycoses like athlete's foot and candidal vaginitis are common and far from life-threatening, whereas the deep mycoses, although frequently lethal, are opportunistic infections that require a significant degree of host immunosuppression in order to lodge within us.

When our bodies do come into contact with fungi, they usually throw the innate immune system's phagocytes at them. Neutrophils seem to be particarly important. If the fungus is small enough, it is simply phagocyosed and dealt with in the usual way, but it may still be attacked by extracellular factors produced by the phagocytes if this is not an option. The adaptive immune system also has a role, of course, most notably the T lymphocytes.

What types of vaccines are there?

Vaccines all share the characteristic of priming the adaptive immune system to fight a microorganism by exposing it to a 'dummy' beforehand. We all know that the adaptive immune system has 'memory', and that it is therefore able to react better towards an invader the second time around. Vaccines exploit this.

Vaccines can be divided up as follows:

• Killed (disabled) - this class of vaccines use whole organisms that have been killed beforehand (obviously!). The yearly 'flu vaccine is an example of a 'killed' vaccine. (Nitpick: the concept of 'killing' a virus assumes the virus was once alive, but not all microbiologists would agree with this.)
• Attenuated - this group also uses whole organisms, but this time they let the poor things live. However, they are then modified so that they are unable to cause disease in us. The topical MMR (measles, mumps, rubella) vaccine is one of these.
• Toxoid - if the organism elaborates a toxin that does most of the damage, it is possible to simply prime to body to fight the toxin itself, rather than the organism. This is what the familiar tetanus vaccine does.
• Subunit - why use a whole organism when you can just use the antigenic bits? The hepatitis vaccine, or the HPV vaccine, for instance, use only the relevant parts.

Hope that helps!

Another use for apoptosis

When learning of programmed cell death - apoptosis - many students often rightly question its use. At this point the lecturer will usually trot out a few well-worn examples (like chiseling away tissue from our embryonic hands to make five individual fingers), but it isn't often considered that cell loss is might sometimes be mechanism to prevent infection. (Amongst other theories, this has been postulated as the reason for the gut epithelium's high turnover rate, and even for menstruation.) Here's some research of a less speculative nature that you might find interesting.

Legionella pneumophila is the aerobic Gram-negative bacterium that causes Legionnaire's disease. It does most of its damage as an intracellular parasite within our macrophages. A recent study has shone light on why it is that our dendritic cells aren't as easily affected as our macrophages are.

Dendritic cells are, like macrophages, phagocytes and antigen-presenting cells. They are present in such diverse tissues as the skin, lung, nose and gastrointestinal tract, and they play a major role in the elimination of pathogens.

In many ways, dendritic cells are closely related to macrophages. So why are they resistant to infection by L. pneumophila, while macrophages aren't? The answer appears to be that our dendritic cells are rigged in a particular manner, so that if they become infected by L. pneumophila, they 'autodestruct' - i.e. undergo apoptosis. Needless to say, this "scorched earth" policy severely limits the ability of this pathogen to mount a successful attack on us.

The authors conclude:

"DCs [dendritic cells] are very proficient at migrating from peripheral tissues to the host lymphatic system following exposure to maturation stimuli, such as encounters with microbes. Because of this property, it has been suggested that DCs can function as a “Trojan Horse” capable of systemic dissemination of pathogens internalized at peripheral sites of infection. Here we show that rapid cell death is one mechanism DCs use to avoid being subverted by an intracellular pathogen. In addition to preventing pathogen replication and dissemination, apoptotic DCs harboring intracellular pathogens would become substrates for phagocytosis by neighboring DCs and macrophages, and most mechanisms used by intracellular pathogens to subvert host cellular function would be ineffective as long as the pathogen were residing in an apoptotic cell. Thus, apoptotic bodies containing pathogens would be degraded in lysosomes, resulting in the release of pathogen-derived molecules that could stimulate innate immune receptors and trigger adaptive responses by being presented on the cell surface in association with host MHC proteins. Based on these data, we hypothesize that rapid pathogen-induced apoptosis by DCs is an important innate immune response to intracellular pathogens."

Good news from France

For some time now, France has arguably been at the forefront of efforts to curb inappropriate antibiotic usage, thereby reducing the evolution of antibiotic resistance amongst bacteria.  In 2002 they launched their flagship program, called "Les antibiotiques c'est pas automatique" ("Antibiotics aren't automatic").  This used a multimodal approach to try to tackle the problem, including educational campaigns for health care workers and the public alike (emphasising the differences between viral and bacterial respiratory illnesses) and the promotion of rapid tests for streptococcal infections.  [Steptococci are the commonest bacterial cause of pharyngitis, but the commonest causes overall are viral, by a long shot.]

The results, as reported in this study, are impressive.  In just seven years (2000 - 2007) the rate of winter antibiotic prescriptions decreased by about 25% overall, with the largest drop (around 33%) being seen in children.  This is a hugely significant decrease, and one would surmise that it will have a positive impact (from our point of view, if not the bacteria's) on efforts to delay or prevent the development of antibiotic resistance.

Now let's see this program (which has now been all but proven to work) be expanded across the world.  Without delay.

New York Times summary of Swine Flu

For even more information on the potential "swine flu" threat, take a quick look at this really good, short summary clip from the New York Times.

Influenza - the basics

Seeing that the recent "swine flu" outbreak is catching the headlines, I thought I'd try to provide a little context - something inevitably missing from most of the terse news reports.

'Influenza' is the name of the disease caused by one of the influenza viruses.  Typical features are a fever, back and muscle aches, sore throat, headaches and a non-productive cough.  Usual strains of influenza cause an illness that lasts for about a week or two, and mortality is typically quite low - around 0.1%.  The usual cause of death is a superadded bacterial pneumonia (a bacterium, often Staph. aureus, takes advantage of the damaged lungs to cause infection there) but direct damage to the lungs by the virus is also fatal on occasion.  Mortality is highest at the extremes of age (the very old or young) and in pregnant women.

The virus is spread when a person inhales an infected respiratory droplet.  Usually, therefore, it is spread by coughs and sneezes, but the virus can also survive for short periods in the outside world, especially if encased by mucus or other secretions.  Thus, if you cough some infected droplets on to my table, I might manage to inhale them soon thereafter (probably by getting them on to my hands first, and then bringing my hands to my mouth to sneeze, eat, etc.) and still get infected. 

There are several major variants of influenza, and this is sometimes a cause of confusion. 

Influenza viruses are first divided into influenzas A, B and C, based on which version of a common antigen (the ribonucleoprotein, RNP) they have.  

• Influenza A viruses cause epidemics and pandemics, and its natural hosts are wild aquatic birds.  However, these viruses can occasionally infect other species, including (sadly) ourselves.  Out of the three groups, influenza A viruses cause the most severe infections in humans.
• Influenza B viruses can cause epidemics (not pandemics), and is almost entirely restricted to humans.
• Influenza C viruses cause only small epidemics, and infect only humans and pigs; the disease is usually mild and mostly affects children. It is less common than the other two types.

Now let's back up a little to explain the terminology.  If large numbers of cases of a particular disease are found in a certain area, epidemiologists classify the pattern as endemic, epidemic or pandemic.  An endemic disease is one that is widely distributed within a particular area, but at a relatively common rate.  In other words, if malaria is endemic to Malawi, the incidence of malaria this year is roughly equal to that of last year, and can be expected to be roughly the same as next year's incidence too.

In the case of an epidemic, however, what you see is a 'spike' in the number of cases, such that significantly more people are contracting the disease in a particular area than would be expected from past years.  A pandemic is an extension of an epidemic, where the epidemic is unexpectantly seen across a very large area, such as a continent.

Why does A have the potential to cause a pandemic, whereas the others don't?  To answer that, we have to dig a little deeper.  Influenza A is further subdivided into numerous strains, based on the major variants of two glycoproteins on its surface: hemaglutinin ("H", which helps in binding the virus to the host cell and then inserting its genome) and neuraminidase ("N", which releases newly formed virions from the cell surface).  So far, we've discovered 16 types of H and 9 types of N, meaning that there are 144 combinations in theory.  The particular strain of influenza A is written as a combination of the H and N number, such as H3N2.  

Influenza A is mainly a disease of aquatic birds, and this is reflected by the fact that over 70 strains of influenza A are known to infect them.  By contrast, only a handful of strains (precisely 10, although most aren't significant) have the capacity to infect humans.  Why is "the 'flu" such a problem then - why can't we all quickly develop immunity to the major types, and never be troubled by them again?

As always with microbes, they simply evolve too quickly.  Although only 10 strains can infect humans, each of these strains evolves - sometimes a little, sometimes a lot - each year, so that they present a sort of moving target for our immune systems.  The strain of H3N2 infecting people "this" year isn't exactly the same strain (despite what its name says) as the strain of H3N2 that infected people "that" year.

There are two main mechanisms for change.  Antigenic drift is rather poorly named, but reflects the common process whereby small changes arise spontaneously and some end up being favourable to the virus.  The changes are usually favourable because they are sufficiently different from last year's strain to reinfect even those of us who developed immunity.  This new type therefore has an evolutionary advantage on the old one, and soon comes to dominate.  This process affects influenzas A, B, and C.

Influenza A can also change by means of a second method.  Antigenic shift is a rapid and dramatic change in its genome whereby two other influenza A strains can combine and form a sort of hybrid.  This new strain is likely to be so different from either of its predecessors that it can take the market (i.e. us) by storm, since our immune systems are caught totally unprepared. This is the reason that influenza A can cause large epidemics (and pandemics) and also why it often produces the worst symptoms, whereas the infections with B and C types are more small scale and/or milder.

One of the things that makes antigenic shift possilbe is that influenza A's genome is divided into 8 segments (see the red coils in the diagram above).  If two different strains infect the same animal at the same time, mixing can occur, creating the chance to form a new strain containing some genomic segments from each of the original strains.  For instance, and H3N2 and and H1N1 co-infection might create H3N1 as progeny.  Alternatively an H1N1 strain that only affects one animal (e.g. a bird) might exchange material with an H1N1 strain that affects a different animal (e.g. a pig).  In either case, this therefore a much more drastic change than the small scale tinkering that antigenic drift represents.  If this new hybrid strain happens to have the capacity to infect humans, the trouble begins.  The above diagram (from Wikipedia) summarises things nicely.

These new hybrids, formed by antigenic shift, only occur in influenza A because influenza A infects such a wide variety of animals.  Pigs, as it turns out, are often the main culprits, although by no means the only ones.  They are susceptible to avian influenza types, swine (pig) influenza types and human influenza types, and therefore are an accident waiting to happen as far as antigenic shift is concerned.  If a human influenza type picked up a few new antigens from one of the other types, the new virus would likely (a) still be able to infect humans, and (b) represent a significant antigenic change so that very few people would be immune to it.  It would therefore be a new strain of influenza to which we would be susceptible.  This is what happens from time to time in farm workers who work in close proximity to pigs.

This is not enough to cause an epidemic or a pandemic, however, since so few of us are in close contact with pigs these days.  Farm workers may suffer, but there's precious little chance of you or I getting sick from it.  However, if the virus is able to be transmitted from human to human (either from the outset, or more probably from further antigenic drift), then we have the possibility of a pandemic.

In the case of "bird flu" (or "avian flu"), we have the former situation: a rather new influenza A virus (H5N1) that kills birds by the flockful and that can, on occasion, infect humans too.  So far, we have no evidence that it can be spread from person to person, or we would be dealing with a large problem.  But this might well be, in some sense, only a matter of time. 

In the case of the newly diagnosed "swine flu", we may have breached this wall.  We appear to be dealing with a new strain of the old H1N1 influenza A virus; but one that is capable of human-to-human transmission.  It appears to be an assortment of human, swine and avian elements.  This is why the World Health Organisation is so worried right now, although there's still no reason to panic at the moment.

If you'd like to know more about the current swine flu epidemic, you can read the informative Wikipedia article, or else for a more humanised version, I'd recommend the Aetiology blog.

HIV and cell-to-cell infection

There's a fiercely interesting post over at Pure Pedantry, where Jake Young taught me something today.  He took the words right out of my mouth:

It's funny how my biases work. I mean, I am not a microbiologist, but here is the bias that I had about how infections like HIV work: I figure that you have large quantities of virus floating around in your blood. These viruses invade whatever cells they happen upon, forcing them to produce more virus. Eventually those cells explode (lysis) from too much virus, setting them free into the blood to wreak more chaos. We could call this the carpet-bombing theory of viral action: limited selectivity, maximum damage.

It turns out that HIV doesn't work like this (mostly). In fact, it operates more much more sneakily -- like special forces -- viral ninjas, if you will. Instead of spreading out in the blood, HIV viruses transfer between infected cells through a structure called a virological synapse. (To be accurate, HIV does infect cells in a cell-free form -- this is discussed in the Introduction of the paper. However, cell-to-cell transfer of HIV is up to a thousand times more efficient and inhibiting it inhibits viral replication.)

But don't stop reading there.  Go take a look at the whole article, and finish off by watching HIV infect another cell:

This video, as well as many others, can be found at the same address (above).

Why do the cysts in neurocystcercosis end up in the brain? Accident or design?

Life cycles can be complicated things.  One of my pathology lecturers used to reassure us that he wouldn't test us on the life cycle of some of the parasitic worms, because every time he tried to work them out, he ended up with carnivorous sheep!

I think some of the difficulty stems from not being able to distinguish the woods from the trees. Fundamentaly, Taenia solium, like certain other parasitic worms (helminths), needs an intermediate host before it can settle down in a definitive host.  

A definitive host is where the worm goes to retire in its old age.  Therefore, it is in the definitive host that it exists in its adult form.  It must also replicate (like all evolutionary organisms), and so it must be producing eggs.  It makes sense that T. solium therefore sits in the human intestine, shedding eggs for as long as it can. 

The intermediate host is a temporary vehicle that the helminth needs in order to prepare for its glorious days in the definitive host.  It therefore exists in this vehicle in something other than adult form.  It must also stand a reasonable chance of getting to the definitive host.  In this case, T. solium tries to burrow its way into the nice juicy meat of the intermediate host, hoping to be eaten by the definitive host.  If that occurs, the infectious cysts in the skeletal muscle of the poor dead intermediate host get awoken, and try to find their way into the intestine, ultimately to stay there as mature adults. Thus, the cycle is completed.  Got it?

In the case of T. solium, the definitive host is one of us humans, while the intermediate host is a pig.  That's what is supposed to happen, at least.  This all goes a bit haywire on occasion, if we happen to ingest one of the infectious eggs (made from an adult tapeworm sitting in our, or somebody else's, intestine).  Put another way, things go belly up if we accidentally act as the intermediate host, instead of as the definitive one.  

Under the belief that they have been successfully ingested by a pig (which is false, or at least only metaphorically true), the eggs go into cyst-making mode.  They thus wait expectantly to be eaten by the definitive host, a day that will never come.  They can wait for years on end, and are so successful at hiding from the immune system that they almost never evoke a response until they die of old age.

Oh, and why do they go to the brain (or eye) in  humans, and not the skeletal muscle like they are programmed to?  Simple: they are programmed to go to the skeletal muscle of a pig, and being in the wrong host messes up their plans.  Making cysts in the brain or eye is a mistake (not many of us are cannibals).  It is a mistake they make because they think they are in the correct intermediate host (i.e. a pig), rather than in a human.

In the brain they most commonly cause seizures and headaches.  Here's a MRI of a brain infected with neurocysticercosis.  The think to look for is the ring-shaped lesion towards the bottom, which is causing all the problems.

 

What is a virus?

Viruses are by far and away the cheekiest life form, since they have fundamentally outsourced all of life to other organisms.  All they contribute to their own life are orders!  Let me explain.

By many definitions of life, viruses don't make the cut.  They consist of:

• a nucleic acid (DNA or RNA)
• encased in a protein capsule called a capsid,
  
• which, in some viruses, is coated by a lipid envelope (derived from one of the host cell's membranes)

In other words, they are the only type of organism not to be cellular.  They also don't appear to have machinery for the absorption of nutrients, for the excretion of waste products, or for almost any metabolism at all.  They are fundamentally a chunk of DNA or RNA surrounded by a rudimentary covering.  

They get away with this, of course, by hijacking the resources of an honest, hard-working cell. Why have your own mitochondria when you can use someone else's?  All other organisms, even prokaryotes, are bafflingly complicated assemblies of prodigious complexity - all of which is simply stolen and turned against the organism by a virus.

The virus can therefore be functionally divided into two aspects: the instructions that it wants the host cell to follow (i.e. the DNA or RNA) and the way of getting the instructions into the right place in the cell (i.e. the capsid and/or envelope).  The host cell is of course blind, and simply follows whatever instructions it gets from DNA/RNA  in the belief that these instructions come from the cell's 'own' DNA.  Viruses exploit this weakness by pretending to be just this 'honest' DNA/RNA, and the cell's complicated machinery dutifully follows the instructions of the virus.

What do these instructions say?  On the whole, they simply say: replicate me by building more virus particles (called virions).  The host cell therefore recreates the original virus particle, nucleic acid plus capside, thousands and thousands of times over.  The virions then exit the cell to infect others like it.  Sometimes they cause the host cell to burst, scattering the tens of thousands of virions far and wide, but sometimes the virus forces the cell to export it in a more dignified manner, often collecting its envelope from the cell membrane on the way out.

It is interesting to note that although viruses are the simplest type of organism, they could not have been the first, at least in their present form.  They depend entirely on already extant cells, which must have preceded them, to do the hard work.  As I said, they are such efficient parasites that they have outsourced all of life barring a few orders, to the point where they are not even considered alive anymore.  Remarkable!

Image from: Harrison's Image Library

How infectious is Hepatitis B virus?

Hepatitis B virus (HBV) is transmitted by exposure to body fluids, and the common ways of doing this are: via unprotected sex, blood transfusions, needlesticks and from mother to child during childbirth.  It is regarded as highly infectious:

• A needlestick injury (i.e. the patient's infected blood is on a needle, which you then prick yourself with, accidentally [e.g. a doctor] or non-accidentally [e.g. drug users sharing needles]) carries roughly a 30% transmission risk.  Compare this with a roughly 0.3% risk of HIV transmission in the same circumstances.
• A mother who has actively replicating HBV can have up to a  90% risk of transmission to her child.
• HBV retains infectivity when stored at 30°C to 32°C for at least 6 months and when frozen at –15°C for 15 years.
• HBV present in blood can withstand drying on a surface for at least a week.

(The last two terrifying points are from the WHO's page on the HBV.)

So, basically - it's very infectious.

What are the likely causative organisms in a patient with COPD and pneumonia?

Any patients with chronic obstructive pulmonary disease (COPD) are predisposed to pneumonia, and because of the underlying damage to their lungs, a pneumonia in these patients takes longer to go away, and carries a higher mortality rate than average.

Any patient with a pneumonia in the context of COPD needs to have their sputum cultured, so that you can tailor your antibiotics specifically to their requirements. However, before such results come back, you need to start empiric therapy, which implies that you have to know which organisms are common in this situation.

And the answer is... Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The first two are common enough causes of pneumonia, but perhaps I should introduce you to the third one quickly.

M. catarrhalis was first discovered 112 years ago, and is a Gram negative aerobic diplococcus. (A diplococcus is a coccus that generally goes around with a partner, so that if you look down a microscope, you usually see two little spheres clinging tightly to each other.) It is fundamentally a 'respiratory tract organism', causing infections in both the upper and lower tracts. When it causes pneumonia, it often gives an 'atypical' picture, with a tendency to produce a more patchy and bilateral picture than with, say S. pneumoniae.

It is often resistant to penicillins, and so a macrolide, like erythromycin, usually has to do the trick instead.

Chemotaxis - in action!

In a post a while back, I offered a brief overview of how it is that our immune cells get from the the blood to the site of inflammation: rolling, adhesion, activation, transmigration and chemotaxis. By far the best (if detailed) visual demonstration of this was the one I wrote about here.

But I've recently been sent two lovely clips focusing on the last step: chemotaxis. Basically, chemotaxis, in the context of our immune cells, refers to their ability to move towards a chemical substance. These are usually signals from either other immune cells or from foreign microorganisms. If you're really nasty and want to see your own neutrophils run around in circles, you can do what these researchers did: introduce a chemotactic substance by a constantly moving pipette, and watch the poor neutrophils go on a wild goose chase:




Of course, this is highly artificial, but it does show how amazingly, well, dextrous these tiny cells can be in pursuit of (what they think is) their prey. The following video clip, more than 50 years old now, shows a ferocious car chase between the local police and an intruder. Spoiler: the police get their man.

HIV-infected man 'cured' with bone marrow transplant

This story is doing the rounds at the moment, so I thought I'd add my two cents worth. A German man happened to have both HIV and leukaemia. After failing first-line chemotherapy for his leukaemia, he was booked for a bone marrow transplant. His astute doctor remembered that a rare few people have a mutation in the gene for CCR5, a receptor found on our immune cells. Most stains of HIV bind to the CCR5 receptor and thereby trick the cell into letting them inside. However, those few people with two 'defective' copies of the gene have the serendipitous effect of not allowing HIV in, and are thus 'immune' to the disease.

What the doctor did was to specifically seek out a matching donor for his patient who also had these mutations in his CCR5 gene. The result: almost 2 years after the transplant, HIV is undetectable in the patient's body. It may still be 'hiding' somewhere there, but even if this is the case, the man has been 'functionally cured' at the very least.

This is very promising news, although it doesn't mean that a cure (or 'vaccination') is around the corner. Bone marrow transplantations arguably carry a greater risk to the patient than HIV does, and so repeating this feat on a routine basis isn't feasible. However, it does suggest that if we could alter people's CCR5 receptors artificially, we would make them immune to HIV. The way to do this, of course, is via gene therapy. That takes time to develop and test, so we're a long way off. But this finding is nonetheless certainly good news.

There's a really good article on the matter here.

Why is a tetanus toxoid booster given with open wounds?

The questioner goes on to note, correctly, that Clostridium tetani is an obligate anaerobe - oxygen is toxic to it. Open wounds would therefore seem to be an area that would be safe from C. tetani then, wouldn't they?

Alas, the part of the wound exposed to the outside air isn't the part that we worry about. During traumatic injuries of sufficient magnitude (especially with deep wounds) the blood flow to the tissue is often disrupted. This renders local parts of the would ischaemic, and therefore (since oxygen is carried around in the blood) hypoxic as well. In some of the particularly hypoxic areas, the oxygen tension falls to a low enough level for C. tetani to replicate, raising the prospects of tetanus being the result.

The ways to prevent tetanus are:

• Vaccination - most vaccination programmes around the world include the tetanus vaccine. It's efficacious period lasts about 10 years, and so a booster vaccine should be given at decade intervals. Booster vaccines may also be given at the time of a new injury (if the patient isn't covered already).
• Passive immunisation with antitetanus immunoglobulin - This isn't usually necessary in terms of prevention unless the wound is particularly badly contaminated.
• Penicillin - The drug of choice against C. tetani, this is also used if the wound is badly contaminated.

Take care not to confuse this prophylactic regimen with the treatment regimen that one needs to embark on if the patient is unlucky enough to get tetanus. That can be the topic for another day, if requested.

The opportunism of Hepatitis D virus

Although it may offend our aesthetic sensibilities, evolution frequently removes parts of an organism that aren't paying their way. It will do this even if the result is what we would judge to be an inferior organism. To clarify, let's look at an example completely tangential to the hepatitis D virus.

It is well known that there is a 'window period' during which we optimally learn a language - namely, the first few years of childhood. Of course, it is quite possible to learn a language later on in life, but the process is much harder and much less perfect. Why is this? Why would the brain so quickly lose what would seem to be a massive asset? Steven Pinker, in his brilliant book The Language Instinct, answers as follows:

The genes, shaped by natural selection, control bodies throughout the lifespan; designs hang around during the times of life that they are useful, not before or after. The reason that we have arms at age sixty is not because they have stuck around since birth, but because arms are as useful to a sixty-year-old as they were to a baby.

This inversion (an exaggeration, but a useful one) flips the critical-period question with it. The question is no longer "Why does a learning ability disappear?" but "When is the learning ability needed?" We have already noted that the answer might be "As early as possible," to allow the benefits of language to be enjoyed for as much of life as possible. Now note that learning a language - as opposed to using a language - is perfectly useful as a one-shot skill. Once details of the local language have been acquired from the surrounding adults, any further ability to learn (aside from vocabulary) is superfluous. [...] So language-acquisition circuitry is not needed once it has been used; it should be dismantled if keeping it around incurs any costs. And it probably does incur costs. Metabolically, the brain is a pig. It consumes a fifth of the body's oxygen and similarly large portions of its calories and phospholipids. Greedy neural tissue lying around beyond beyond its point of usefulness is a good candidate for the recycling bin.

(Wasn't that masterfully explained?) So, one helpful way of looking at the bits of organisms is to view them as a trade-off between their costs and their benefits. If some new innovation (or 'old' innovation, as Pinker shows) is too costly, it will tend to be removed by natural selection even if the new innovation made the organism 'better' in other ways.

And so to hepatitis D. This RNA virus is actually unable to replicate itself, which makes it a rather odd inhabitant of the microbiological world. You don't need to understand much about evolution to realise that an 'species' that can't replicate its genetic code isn't going to be around long. Yet, hepatitis D virus (HDV) is clearly still with us. What's going on?

It turns out that Hepatitis D piggy-backs on some of the machinery brought by hepatitis B when it infects liver cells. Without hepatitis B coinfection, HDV it is utterly helpless. Now this is often perjoratively described in textbooks, which cruelly label HDV 'defective', 'degenerative' or even, in echoes of Hitlerian narrative, as 'subviral'. But by now the opposing view should be clear. Far from being in some way the runt of the litter, HDV may equally be seen as the cleverest of the hepatitis viruses, since its enslaving of hepatitis B obviates the need to carry all its own heavy replication machinery.

It's a nice inversion of vantage points, I think.

In the news... Turning Bacteria into Plastic Factories

There's an interesting article in the latest Scientific American magazine. Amazingly, scientists at a company called Genomatica, Inc., in San Diego, have managed to coax some E. coli to produce something named butanediol. Now butanediol is a chemical that is used to make, as the article states, "everything from spandex to car bumpers". The nice part of this whole deal is that the bacteria are apparently able to make it significantly more efficiently than factories can - and this translates into lesser energy expenditure and hence lower costs. It's also a more environmentally friendly process, apparently.

This is certainly not the first time bacteria have been commandeered into producing a nice substance for us. They have been used to produce insulin for us for decades, for instance. But this latest success shows us just how malleable these organisms are, and how slavishly any organism can follow the dicates of its genes, given the right circumstances.

How infectious is TB?

TB, caused by the bacterium Mycobacterium Tuberculosis, has reached epidemic proportions in many poor, overcrowded regions of the world, like sub-Saharan Africa and India. But how does it's infectiousness compare with that of meningococcus (Neiserria meningitidis)?

The short answer (and contrary to what might initially be expected) is this: much more infectious.

When a person infected with active TB coughs, he will expectorate numerous droplets. If the TB patient's disease is eroding into the airways, some of these droplets will contain active M. tuberculosis organisms. The very big droplets will fall to the floor harmlessly within seconds, and if the medium sized droplets (which stay afloat a while longer) are inhaled, they are merely trapped in the upper respiratory tract, from which they are cleared without causing infection. The smaller droplets, on the other hand, evaporate almost immediately, leaving 'naked' organisms that stay afloat in the room (or whatever) until something blows them away.

In this way, TB spreads, and it is actually quite a rare way for respiratory pathogens to be transmitted. Yet it is devastatingly effective.

First the good news: as with meningococcus, casual social contact doesn't seem to increase your risk of contracting the disease. But anything more than this, and you are at significant risk. For instance:

When active tuberculosis developed in a school-bus driver, 30 percent of the children who rode his bus had a positive tuberculin skin test. After one student contracted active disease in a school that had a large, open dormitory, 19 percent of the others converted to tuberculin positivity, regardless of how close their beds were to that of the index patient.

The closer the contact, the worse of course. Sharing a home with someone who has active TB entails about 1:3 chance of getting the disease.

So, contrary to expectations (and media hype), TB is a far more contagious disease than meningococcal meningitis.

However, you must bear in mind that these figures are for TB infection, not active TB disease. Only a small percentage of people who have latent TB infection will end up with active TB disease. In the vast majority, the infection is soon controlled and quarantined without symptoms or residual dysfunction. If this didn't occur, M. tuberculosis would never be able to sustain such high infectivity odds - we would all be dead.

How infectious is meningococcus?

This'll be the first of two posts - the following one will ask the same question of TB, and the contrast is actually fascinating.

But let's not prejudge the conclusion - we shall start with Neiserria meningitidis, affectionately known as meningococcus. The crucial question in determining it's infectivity is this: how does it spread?

Neiserria meningitiditis doesn't survive for long outside the human body, and nor does it have an animal vector to act as a storage vessel until it can get back into a human. Therefore it must go from one human more or less straight to the next. People are infected when they come into direct contact with the organism (usually from the nasal secretions of infected patients) or when they inhale respiratory droplets containing it. Both of these methods of contagion are vastly facilitated by viral upper respiratory infections, which frequently induce both nasal secretions and coughing.

So, what are the odds of getting it? The matter is of some importance, since Neiserria meningitidis is capable of producing a nasty meningitis (hence it's name!). Worried family members and health care workers need to know whether or not they should take antibiotic prophylaxis to try to prevent the same fate.

Here are the facts, courtesy of a fantastically interesting article from the New England Journal of Medicine, entitled "How contagious are Common Respiratory Tract Infections?" (N Engl J Med 2003;348:1256-66). Close family members of a person infected with meningococcus have anywhere between a 1:400 to a 1:50 risk of contagion, which is actually lower than most people think. Schoolmates and work colleagues are better off still - with only a 1:3000 to a 1:200 chance. And casual social contacts (those who might come into contact with the infected person infrequently for short periods of time) have no increased risk of getting the disease when compared with someone on the other side of the country.

These figures may surprise you, because there is often a good deal of panic when meningococcus is diagnosed. This is probably because of the meningitis that it causes. As these figures show, however, this risk is rather exaggerated. The author of the article states:

Despite the public fear, bordering on hysteria, that may follow a case of meningococcal disease, more than 95 percent of cases in the United States and other developed countries are sporadic. Thus, in the majority of instances, a second case does not follow a first one. This is why, when a single case occurs in a schoolchild, the Centers for Disease Control and Prevention recommends prophylactic treatment for family contacts but not schoolmates.

And health care workers? The best thing, as always, is hand washing. In the case of meningitis, unless the patient is coughing profusely (which is decidedly unlikely), it is only really upper respiratory tract secretions that are infectious. Nurses, for instance, are at a slightly increased risk of catching the disease, since they often directly exposed to secretions. On the other hand, doctors who spend only a few minutes per day by a particular patient's bedside are usually at no greater risk of infection than the population at large.

The genetic susceptibility of HIV

There's an interesting new journal article that has made the news recently. An international team has found that a particular protein - the Duffy Antigen Receptor for Chemokines (DARC) seems to offer limited but significant protection against HIV. Most people in the world have it, but unfortunately once particular group - sub-Saharan Africans - seems to largely lack this protein. People lacking in this regard are 40% more likely to contract HIV in any given situation than the rest of the world are.

The real tragedy here is that this variant is so common in sub-Saharan Africa because it offers protection against some forms of malaria. Thus, over the millennia this mutation has been selected for by evolution and has steadily become more numerous throughout the populations there.

But now, faced with a new virus, this decision is backfiring somewhat. This sort of discovery is no doubt one of the factors needed to explain why it is that sub-Saharan Africa carries such a heavy HIV burden compared with comparable areas elsewhere in the world.

AIDS vaccines...

There's a nice article from Scientific American on the progress (or lack thereof) towards an AIDS vaccine.

The next two years will reveal whether researchers are on the right track for at least a partially effective vaccine. Three clinical trials are underway to test the effectiveness of coaxing the immune system's disease-killing T cells into attacking the virus more aggressively. Experts say that such a vaccine is unlikely to prevent the HIV infection. But they hope it will weaken the virus enough to delay the complications of AIDS and reduce the need for expensive antiretroviral drugs.

Increased funding and more sophisticated organization have played a key role in getting this far. "By the early to mid- 1990s, the AIDS vaccine effort was relatively moribund," says IAVI president Seth Berkley, who founded the group in 1996. "It's 100 percent a scientific problem. However, without an enabling environment, you can't solve the science."

It's a nice summary, should you be interested.