Steven Zeichner, MD, PhD
We study infectious disease pathogenesis and work to develop new therapies and diagnostics for infectious diseases and cancers using the new insights that we develop.
In one set of projects, we are working to develop new platform technologies that will enable the very rapid development of inexpensive and easily produced vaccines that will be appropriate both in rich and in developing countries. We use a synthetic biology approach in which vaccine antigens are expressed on the surfaces of bacteria that have had a very large fraction of their genomes removed. We have found that expressing vaccine antigens in bacteria with a large fraction of their genomes removed greatly enhances their immunogenicity. The approach can enable the production of vaccine concepts testable in animals in only a few weeks. We are applying this new technology to produce concept vaccines for a variety of important viral diseases, from HIV to COVID-19.
In another set of projects, we are working to turn the gastrointestinal (GI) immune system of a mouse into a technology called Intestinal Selection of Immunogenic Antigens (ISIA) that can distinguish highly immunogenic antigens from less immunogenic antigens. The technology employs a combination of synthetic biology, new insights into the microbiome, the notion of DNA barcoding, and Gram-negative autotransporters to interrogate, without any advance assumptions or biases, the entire, intact GI immune system of a mouse. In ISIA, we synthesize a set of plasmids, each of which carries a unique DNA barcode and places a test protein on the surface of bacteria capable of long-term colonization of the GI tract using a Gram-negative autotransporter. We inoculate mice with bacteria transformed with the set of barcoded plasmids expressing the different test proteins and then assay for the abundance of the different barcodes in the feces of mice. If the GI immune system of the mice identifies a surface test protein as being particularly immunogenic it will, in a Darwinian sense, “select against” the bacteria expressing the immunogenic antigen and eliminate it from the GI tract. We detect elimination from the GI tract using assays for the DNA barcodes.
The technology has applications in the development of new vaccines for infectious diseases and therapeutic cancer vaccines, and for working to make biologics, such as therapeutic proteins, minimally antigenic. In this context, we are actively working on developing new prophylactic vaccines for HIV and therapeutic cancer vaccines.
In other projects, we seek to understand the control of Human Immunodeficiency Virus and herpesvirus latency. We have recently shown that Kaposi Sarcoma-associated Herpesvirus (KSHV) and other herpesviruses, and HIV can sense the health of their host cells. When the viruses sense that their host cells are about to undergo apoptosis, they respond by starting to replicate. If the viruses were not able to reproduce before the host cell died an apoptotic death, then the viruses would be unable to produce progeny, so presumably, there is a strong evolutionary imperative for viruses to evolve ways to sense and respond to impending host cell apoptosis. These studies have implications for attempts at curing HIV and for understanding some of the complications that accompany cytotoxic exposures like cancer chemotherapy and bone marrow transplantation.
We also are working on more clinically-oriented projects related to infectious disease pathogenesis. For example, we recently showed that the community of microbes present in the appendix of appendicitis patients differed from the community of microbes present in the appendix of patients without appendicitis, that the microbes present in the appendix differed from the microbes present in the rectum, and perhaps most interestingly, that the microbes present in the rectum of patients with appendicitis differed from the microbes present in the rectum of patients who did not have appendicitis. This finding suggested that it might be possible to design a diagnostic test for appendicitis based on identifying and quantitating the microbes in the rectum of patients who might possibly have appendicitis. This would be helpful because such a microbe-base test would be less expensive, faster, easier, and safer than the current methods used to diagnose appendicitis, such as CT scan, which administers significant doses of radiation. We are currently conducting a larger prospective study to try to confirm whether there might be a distinctive community of microbes in the rectum of patients that could be used to diagnose appendicitis.