One of the things I love about science–but that can also be frustrating–is that every new piece of information leads to a new unanswered question. We’ve learned so much about microbiology and human disease since the time of Koch and Pasteur, but in many other ways, we’re still at square one. One reason is because research over the last century has largely focused on disease-causing organisms–and within those, many studies have focused on identifying factors that allow these organisms to cause disease. This concentration has led to many breakthroughs (such as vaccine targets), but it has also left a number of notable shortcomings in our knowledge. For instance, I’ve written previously mentioning just how little we know about our own commensal flora. Another area where we have a surprising dearth of knowledge is the transmission of infectious agents.
To back up a bit, when we look at the components of an infectious disease, we often break it down into a few steps. (Note that I’m simplifying quite a bit here, but bear with me). The organism must first colonize the host, which means either being able to avoid or otherwise escape the host’s intrinsic defenses. These defenses include “mechanical” barriers (such as the mucus layer) as well as more specific defenses, including the various cells and proteins of the immune system. They then must be able to replicate. Depending on the organism, this may require additional invasion into host tissues or the host cells themselves (such as viruses and intracellular bacteria). These organisms then may either persist in the host for years (such as the Pseudomonas I described here), or they may cause an acute infection and be quickly cleared by the host. In either case, the host will be a “dead end” unless the organism is then transmitted to another host.
Examining the phenomenon of transmission isn’t as easy one may think. Generally, there are two ways we can approach it (and again, I’m simplifying). We can carry out epidemiological studies, looking at how an organism passes between individuals, and then working to correlate that to the biology of the organism (and/or the host). Occasionally, we can use human volunteers, but this frequently isn’t possible. Alternatively, we can model this in animals. This is how typical studies of pathogen virulence have been carried out: inoculate a model animal with the organism of interest, and observe whatever parameters are of interest. Many permutations, of course, exist: the investigator can knock out a putative “virulence gene” in one strain of pathogen and inoculate them into one group of animals, while infecting a second group of animals with the wild-type strain to see whether the knocked out gene affects the course of disease. There are dozens of possibilities, but generally they involve an artificial administration of the pathogen (for example, by injection). This allows the investigator to control the dose of the organism the animal receives, but real life is obviously much more messy. These types of animal studies have taught us a lot about factors that contribute to colonization and virulence, but not as much about the other important part of disease development: transmission of the agent to a new host. Additionally, for transmission studies, it’s difficult to directly extrapolate from animals living in cages to the human population. Therefore, while we can glean a great deal from these types of studies, they’re certainly not perfect.
This gap has recently been highlighted by the outbreak of H5N1. We have a few clues suggesting why it’s so virulent, but the million dollar question is: what will make it more easily transmissible between humans? This is when the trouble really starts: when it spreads among humans without any need for birds as a reservoir.
There has been at least one aspect of the host-virus interaction that has been proposed to play a role in effective transmission. As reviewed at Effect Measure, two groups of scientists have suggested that the specific types of sugars on cells of our lungs–and where they appear within the lobes of our lungs–play a role in the binding of H5N1 to mammalian cells, and therefore may effect how efficiently transmitted these viruses are. However, the basis of this is rather sketchy: we don’t have enough information about other influenza viruses that were present in the human population but not effectively transmissible to know if this is a valid generalization or not. Additionally, animal models of influenza transmission have been less than optimal. Mice don’t consistently transmit the virus from one animal to another, and influenza viruses generally have to be “mouse adapted” (for example, by serial passage) in order to efficiently infect the animal. (The 1918 “Spanish” influenza strain, and several recent H5N1 strains, have been notable exceptions). Additionally, even when using a mouse-adapted strain (WSN), it wasn’t found to be transmitted between mice in an experimental setting.
The other animal model commonly used in studies of influenza–ferrets–are more naturally susceptible, but present other difficulties as far as acquisition and housing of animals. Therefore, a new study went back to the animal whose very name is synonymous with medical research–the guinea pig.
They found that this served as an improved model. Virus was transmitted between guinea pigs that were housed together, both in the same cage and when separated by a distance of ~3 feet (meaning you might want to stay a little farther away from those infected co-workers…) However, I don’t think this paper was PNAS material. Yes, the guinea pig model seems to be less cumbersome than the ferret one, and perhaps more biologically similar to humans than a mouse one, but it’s not a huge breakthrough, nor a particularly novel piece of research. Still, anything that draws more attention to this critical gap in our understanding of agent transmission is a good thing, IMO. If we had a better handle on the factors that caused an avian strain of influenza virus to be more efficiently transmitted among humans, then we could better focus our resources and know when to really sound the alarm–unlike now, when we’re flying blind in many ways.
Lowen et al. 2006. The guinea pig as a transmission model for human influenza viruses. PNAS. 103:9988-92.
Image from http://www.awionline.org/pubs/cq02/gui-3.jpg