The National Institutes of Health has awarded University of Texas Medical Branch at Galveston professor Ashok Chopra $1.7 million over the next five years, renewing NIH support for his efforts to find new ways to fight plague.
The organism that causes plague, Yersinia pestis, has been the focus of Chopra’s research since just after the post-9/11 anthrax attacks. Found in nature all over the world (including the American Southwest), Yersinia pestis circulates between rats and fleas, normally affecting only humans who are bitten by infected fleas. Although most natural plague infections are controllable with antibiotics, human modifications can make the bacteria suitable for use by bioterrorists — both resistant to antibiotics and easily spread through aerosolization.
“In the case of terrorist activity, chances are that transmission would occur through an aerosol route, resulting in pneumonic plague, which is highly contagious — the organism is transmitted from person to person through aerosols charged with highly virulent Yersinia pestis,” said Chopra. “The mortality rate for pneumonic plague can approach 100 percent.”
Chopra aims to forestall this nightmare scenario by helping develop an effective vaccine against pneumonic plague. (A vaccine against bubonic plague, another form of the disease, was withdrawn in 1999 because of its inconsistent effectiveness and high rate of adverse side effects.). Currently, there is no vaccine against plague.
“Vaccines work by sensitizing the immune system to respond strongly to particular pathogens,” Chopra said. “One way to do this is to develop a live attenuated vaccine using a strain of the pathogen that’s nonvirulent. Another is to employ one or more components of the organism to make what is called a subunit vaccine. We are looking for both new live attenuated vaccine strains and new antigens — components of the pathogen that induce an immune response — which can be used for subunit vaccines.”
Early in the project, Chopra’s group zeroed in on a particular protein found on the surface of Yersinia pestis. In previous work with the related Salmonella bacteria, Chopra’s group had determined that this component, known as Braun lipoprotein, was closely associated with virulence, and he found a similar connection in Yersinia pestis. Yersinia pestis bacteria with the gene for Braun lipoprotein deleted along with other bacterial virulence factors were far less virulent in mice and still conferred protective immunity—key characteristics for a potential live attenuated vaccine.
“We’ve provided a detailed mechanism for how deleting the gene for this lipoprotein reduces the virulence of the bacteria, and now we’re looking at some other genes which can be deleted to further attenuate Yersinia pestis,” Chopra said. “We’ve also identified some new antigens which we think can be used for subunit vaccines.”
Chopra will use the additional NIH support to continue this work, taking advantage of the unique resources of UTMB’s Galveston National Laboratory and the support of the university’s Sealy Center for Vaccine Development, Institute of Human Infections and Immunity and Center for Tropical Diseases.
“The infrastructure we have developed at UTMB helps us tremendously,” Chopra said. “We have the containment facilities and expertise to do cutting-edge research, and along with hard work and perseverance, that’s made it possible for us to be very productive.”