Research Abstract
Few
infectious diseases have had as profound an impact on the course of human
civilization as the bacterium Yersinia pestis, the cause of plague.
Historically, Y. pestis has been a source of significant human
morbidity and mortality, being the repeated causative agent of epidemics and
pandemics, and becoming known as the “black death” during the Middle Ages.
More recently, Y. pestis has re-emerged as a public health concern in
multiple countries, including Malawi, Mozambique, and the Democratic
Republic of Congo. In addition, the potential exists for Y. pestis to
be used as a weapon of bioterrorism or biowarfare, thus the bacterium is
classified as a category A select agent by the U.S. government.
Y. pestis infection in humans is an acute febrile disease that can have
a number of different presentations depending upon the route of inoculation;
these include bubonic plague, pneumonic plague, and septicemic plague.
Although a Y. pestis infection is readily treatable with antibiotics,
the disease is aggressive and delays in treatment or misdiagnosis are almost
universally fatal. This is especially true of primary pneumonic plague,
which would be the most likely presentation of victims of a biological
warfare attack that utilized Y. pestis. Unfortunately, little is
known about the interaction between Y. pestis and its mammalian host,
especially during a respiratory infection. Thus, the focus of my
laboratory’s research is to understand and define the molecular mechanisms
by which Y. pestis causes the most severe form of disease, pneumonic
plague.
A key molecule that is required for the
development of a severe respiratory infection by Y. pestis is the
bacterial plasminogen activating protease Pla. Indeed, in a mouse model of
pneumonic plague, the absence of Pla eliminates the development of a
pneumonia and shifts the disease from the respiratory form to a septicemic
one. Quite unexpectedly, we found that Pla has considerably different
effects on the course of disease during mammalian infection depending on the
route of entry and organs colonized, one of the only examples of a bacterial
virulence factor to exhibit such profound differences in this manner. Thus,
it appears that the mechanisms by which Y. pestis employs Pla to
cause pneumonic plague are distinct from those during bubonic plague. In
addition, Pla is required for Y. pestis to initiate an overwhelming
and destructive pulmonary inflammatory response in the latter half of the
infection, which likely contributes to the eventual death of the animal.
However, the mechanisms by which Pla contributes to disease during pneumonic
plague are completely unknown, including the effects of Pla on lung
function, bacterial replication, and the host immune response, particularly
the coagulation and fibrinolytic cascades.
Y. pestis also requires for virulence a
type III secretion system to inject a set of six effector proteins directly
into host cells. While it has been demonstrated that bacteria lacking the
entire system are avirulent and are cleared from the lungs, it is unclear
which of the six secreted proteins is required to cause pneumonic plague.
Therefore, another area of study in the laboratory is centered on
determining which of these proteins is necessary to cause disease during
respiratory infection, at what stages during the progression of the
infection these proteins are required, what host cells in the lungs are
affected, and the effects of these bacterial proteins on pulmonary function.
In the long term, I anticipate that these studies will be applicable to
other systems, with the goal of identifying common themes and unique aspects
among bacterial respiratory infections.
Yersinia
pestis bacteria
(brown) overwhelm the lungs of mice (yellow) during pneumonic plague.
