Bug’s “To-do”: Lose a few genes; Cause the Black Death
Yersinia pestis (YP) is a rod-shaped bacterium associated with the pandemic plagues that have devastated human civilization multiple times. According to available genetic evidence, an ancestral bacterium called Yersinia pseudotuberculosis (YPT) gave rise to this bug in China, from where it spread repeatedly westward to the rest of the world causing disease in both animals and humans.
Infections due to both YPT and YP are classified as “zoonoses”, transmissible from animals (mostly rodents) to other animals and humans. YPT is transmitted by fecal contamination of food and water; in contrast, YP is vector-borne, and is transmitted via bites of infected fleas. Genetically, YP possesses a restricted subset of genes compared to its more diverse progenitor YPT. And yet, while YPT causes a relatively mild disease in various mammals, YP causes types of plague, a severe, inflammatory disease that may be fatal if left untreated.
Diagram courtesy PHIL, CDC: Modalities of transfer between various hosts of Yersinia pestis involving a wide variety of mammals - including rodents, rabbits, wild and domestic carnivores, and humans. Red circles show intersections with rodent-inhabiting fleas.
Although YPT and YP share many similarities in their genetic signatures, the differences in those signatures hide clues about the differences in their transmission and the ability to cause disease. In a fascinating new study published recently in Cell Host & Microbe, Yi-Cheng Sun and colleagues, from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, used genetic tools to trace how these differences, especially the shift to flea-borne transmission in YP, gradually occurred as a net effect of gain and loss of certain genes.
Based on their observations and analyses, the authors propose a model conforming to the ecological theory called adaptive radiation, which explains rapid evolutionary divergence and the formation of new species. According to this theory, an organism in a given environmental niche sometimes incurs a change in its genetic make-up. This change may – (a) be ‘neutral’ i.e. may do nothing in that niche; (b) be ‘deleterious’ i.e. may make the present environment inhospitable for it – causing it to die or move to a new niche; (c) be ‘neutral’ and adapt to the new environment; or even (d) ‘increase fitness’ i.e. confer the ability to exploit the new niche maximally to thrive. Such adaptive genetic changes, therefore, establish a new habitat for the organism, and may lead to the emergence of a new species.
The key genetic mechanisms involved in this process are not currently well-understood in general. However, in this paper, the authors present convincing evidence that adaptive genetic changes may be responsible for the increased fitness of YP to thrive in the flea internal environment, compared to YPT.
The bug YPT gets to its primary host, rodent gut, via mouth, establishing a gut infection but not usually causing disease. However, if the animal ingests too many bugs or has diminished immunity, YPT can reach its bloodstream, and thence to the lower digestive tract (‘hindgut’) of the parasitic fleas that regularly feed on the animal’s blood. These rodent fleas harbor YPT in the hindgut and shed them continuously via their feces, but do not get sick from it. In sharp contrast, YP – which lacks a sticky protein (adhesin) from YPT – can’t attach to the flea hindgut, but is able to lodge itself in the flea’s middle (‘midgut’) and upper digestive tracts (foregut or ‘proventriculus’) by virtue of an enzyme-producing gene called ymt absent in YPT. If YPT is given this gene, it gains YP’s ability to reach midgut and further up.
Again, YP bugs (like many other disease-causing bacteria) produce a polymeric substance, called ‘biofilm’, with which they cover the inner surfaces of the flea gut; embedding themselves in the biofilm allows the establishment of flea infection, and is an important determinant of rodent-to-flea transmission of YP (as well as of its disease-causing ability). The production of this material – a genetic function in YP – is actively suppressed in YPT by another set of three genes which don’t work in YP. Giving these functional YPT suppressor genes to YP robbed the latter of its ability to make biofilms, whereas removing the suppressor genes from YPT allowed it to behave more like YP, and show similar rates of transmission.
Both of these functional expressions of genetic characteristics of YP - the ability to colonize the midgut and the foregut, i.e. areas closer to the mouth, and the production of the biofilm that retains it in the gut and enriches its numbers - provide a tremendous advantage in transmissibility over YPT, making YP a more efficient and deadly pathogen ("Increased fitness").
The species divergence of YP from YPT (approximately 6400 years ago) was demonstrated via analysis of the genetic signatures in 133 YP strains collected globally; this analysis also provided evidence for more recent YP lineages arising out of China beginning about 1,500 years ago. Sun and colleagues found that the adaptive genetic changes which enabled the flea-borne transmission of YP were likely switched on early after/around the divergence, and conferred upon all these bug lineages the ability to cause human and animal plagues.
Dependence on the flea-vector does impose some selection pressure on YP. For a successful transmission, YP needs to multiply aggressively in the host rodent bloodstream, so as to load the fleas with sufficient bugs, and also to kill the host, so that the fleas would be forced to find a new host. However, it is expected that with time, YP in the wild would lose some of these adaptive changes; already, some strains have lost the gene for an enzyme, and with it, the ability to cause the same severity of disease in guineapigs and primates as they can in mice and rats.