The mere mention of the plague brings to mind
the devastating “Black
Death” pandemic that spread across
Europe in the 1300s. Mass graves were piled
high with the corpses of its millions of
victims, while the disease rampaged across
Europe for many decades. Yersinia pestis ,
the bacterium responsible for that plague
pandemic, still persists in the environment
among rodent and flea populations today, and
human outbreaks regularly occur around the
world. Most recently, an outbreak of plague
was confirmed late last year in Madagascar
as well as within a prairie dog colony in Colorado
just this June.
The
various routes of transfer between hosts
of Y. pestis bacteria, which are
the cause of bubonic plague in the United
States. CDC ,
CC
BY
Click to enlarge
Y. pestis can cause three different
forms of plague :
bubonic, pneumonic and septicemic. Pneumonic
plague infects the lungs, causing severe
pneumonia. It’s the most serious form of the
disease, with fatality rates approaching 100%
if untreated, although recovery is possible
with antibiotics if caught in time. While
increased basic hygiene and developments in
modern medicine have greatly reduced the
severity of plague outbreaks, the symptoms of
pneumonic plague are so similar to that of the
flu that misdiagnosis or delays in treatment
can have fatal consequences.
Y. pestis is known to have evolved
from the relatively mild gut pathogen Yersinia
pseudotuberculosis sometime within the
last 5,000
to 10,000 years – very recently on an
evolutionary timescale. Sometime during this
evolution Y. pestis developed new
modes of transmission and disease
manifestations, which allowed it to adapt to
new animals and environments. Rather than
simply causing an upset stomach, the bacterium
became the killer we know from the Middle
Ages.
A mother
and son, suspected carriers of the
pneumonic plague, share a bed in an Indian
hospital. Kamal
Kishore / Reuters
Click to enlarge
One of our
lab’s major research goals is to figure
out how Y. pestis developed its
ability to specifically cause pneumonic
plague. Our research, recently
published in Nature Communications ,
offers new insights into how small genetic
changes fundamentally affected the emergence
of Y. pestis as a severe respiratory
pathogen.
Prior to our study, the consensus in the
field has been that pneumonic plague was a
secondary byproduct of the invasive disease
associated with bubonic plague. As pneumonic
plague represents only 5%–10% of current
plague infections in humans, the field has
presumed that pneumonic plague occurs only
once Y. pestis reaches the lungs
following systemic infection, as might occur
during bubonic plague. While this may be the
case now, it may not necessarily represent
what occurred in the past, especially as Y.
pestis was just emerging from its
ancestor Y. pseudotuberculosis .
Plague
infection in the lungs. Untreated, death
results within a week. CDC/
Dr Jack Poland , CC BY
Click to enlarge
First, target the lungs
Therefore, we began our study by asking a
relatively simple question: “When did Y.
pestis develop the ability to infect
the lung and cause pneumonic plague?”
Remember, it was only recently, evolutionarily
speaking, that it started targeting the lungs
rather than the gut. Y. pestis is
believed to have emerged as a species
5,000–10,000 years ago, but the first known
pandemic of plague in humans didn’t occur
until the Justinian
Plague that afflicted the Byzantine
empire about 1,500 years ago.
Excavation
of skeletal remains of victims of the
Black Death. Museum
of London, Schuenemann et al PNAS vol.
108 no. 38
Click to enlarge
A recent discovery helped us investigate.
Scientists successfully recovered DNA from Y.
pestis from human skeletons in a Black
Death mass grave in London, England. The
genetic material from the historic site is
very similar to DNA isolated from recent
modern plague outbreaks. The fact that the DNA
from then is similar to the DNA from now
indicates that today’s Y. pestis has
maintained its devastating disease-causing
capability.
To answer the question of how Y. pestis
made that crucial leap to targeting the lung
and therefore being able to cause pneumonic
plague, we used strains of both ancestral and
modern Y. pestis in our study. These
ancestral
strains of Y. pestis , isolated
from voles in the Transcauscaian highland,
carry characteristics of both modern, pandemic
Y. pestis and the relatively benign
predecessor species Y. pseudotuberculosis
that still exists today.
Thus, these ancestral versions can be
considered “intermediate” strains, trapped
somewhere between the gut Yersiniae
and modern, virulent Y. pestis .
Indeed, these “intermediate” lineage ancestral
strains are as closely related to Y.
pseudotuberculosis as we can get while
still technically representing species of Y.
pestis . Because of their unique genetic
characteristics, these ancestral strains can
provide crucial insights into how this
bacterium may have adapted to new host
environments as it evolved from Y.
pseudotuberculosis .
Surprisingly, we found that these ancestral
strains were able to cause pneumonic plague in
a manner indistinguishable from that of modern
Y. pestis in mice – but only if the
bacteria carried the gene for a single protein
called Pla. Pla is unique to Y. pestis
and was acquired very early in the evolution
of the species.
Almost all ancestral strains of Y.
pestis carry the gene for Pla, but
there still exist a few that represent
ancestral Y. pestis just prior to
acquisition of Pla. We were able to test if
these pre-Pla strains were able to cause
pneumonic plague – and they did not. But as
soon as Y. pestis picked up this
gene, the bacteria could cause epidemics of
pneumonic plague. No further changes were
necessary, even though there are dozens of
additional differences between these ancestral
strains and modern Y. pestis . So Y.
pestis was able to cause pneumonic
plague much earlier in its history than had
previously been thought – as soon as it
acquired this single gene for Pla.
Scanning
electron micrograph of Yersinia pestis.
Justin Eddy,
Lindsay Gielda, et al , CC
BY-ND
Click to enlarge
Second, increase infectiousness
But that’s not where the story ends. It turns
out that all modern pandemic strains of Y.
pestis contain a single amino acid
mutation in Pla compared to ancestral Y.
pestis . This change slightly alters the
function of the Pla protein. The mutation,
however, plays no role in the ability of any Y.
pestis isolates to cause pneumonic
plague – ancestral or modern.
Quite surprisingly, this modification allowed
the Y. pestis to spread deeper into
host tissue following a bite from an infected
flea or rodent, leading to the development of
bubonic plague with its trademark swollen
lymph nodes. This suggests that Y. pestis
was first a respiratory pathogen before it was
able to efficiently cause invasive infections.
This discovery challenges our traditional
notion of how plague evolved. Rather than
pneumonic plague being a late addition to Y.
pestis ’s arsenal as commonly believed,
its ability to target the lung came before the
change that makes it such an infectious
pathogen. Our research suggests that the
acquisition of Pla and its ability to cause
pneumonic plague occurred well before
1,500–5,000 years ago. But the amino acid
modification didn’t occur until just prior to
1,500 years ago, allowing Y. pestis
to become much more deadly. All strains of Y.
pestis from the time of the Justinian
Plague and after have the deadly modification
of Pla, while strains prior do not.
Physician
attire for protection from the Black
Death. Paul
Fürst
Click to enlarge
Our results may explain how, through one
small amino acid change, Y. pestis
quickly transitioned from causing only
localized outbreaks of disease to the pandemic
spread of Y. pestis as seen during
the Justinian Plague and the Black Death.
And it raises the ominous possibility that
other respiratory pathogens could emerge from
similar small genetic changes.