Nilofer Qureshi

Inspiring and motivated Professor brings advanced research and teaching skills and department leadership experience. Goal-oriented to advance department, improve research. Extensive background in research and university fundraising.

Purification and Structure-function of Lipid A. Then Dr. Qureshi started her project on lipid A to detoxify and characterize lipid A for immunotherapy of cancer. That was considered impossible at the time because methods of purification of lipid A were not available. Dr. Coley had found that heat-killed S. pyogenes and Serratia marcescens could be used for immunotherapy for cancer and to prevent infections. The rationale for Dr. Qureshi’s studies was to develop an effective and well-characterized adjuvant for activating the immune system for immunotherapy of cancer based on Coley’s toxins. Since LPS was too toxic for human use, so she prepared and purified monophosphoryl lipid A, which was relatively 100-fold less toxic than

LPS antagonists: Once the agonists were characterized, Dr. Qureshi wanted to design an ideal antagonist. For this purpose, she purified only one lipid A from Rhodobacter sphaeroides (obtained from the soil) and functionally it was relatively non-toxic, as compared to the LPS from E. coli and monophosphoryl lipid A (Salmonella and E. coli). She, therefore, purified the diphosphoryl lipid A from the LPS of Rhodobacter sphaeroides (RsDPLA) and determined if it would act as an antagonist. She and her colleagues found that RsDPLA did not possess much inflammatory activity in RAW 264.7 cells, but it acted as a potent antagonist in both human and murine cells and inhibited many of the activities of ReLPS. She used RsDPLA in many biological systems and established it to be a potent LPS antagonist. Later, she established the mechanisms that revealed that RsDPLA acts as an antagonist, by inhibiting the binding of gold labelled LPS to the surface receptors, and the internalization of LPS into the cell, as observed by electron microscopy. RsDPLA also bound to membrane complex and blocked the LPS-mediated signal transduction. Therefore, for all future studies, LPS (E. coli D31m4) was used as an agonist, and RsDPLA as an antagonist. It also worked in lethality models for shock in mice. The identification of Rhodobacter sphaeroides lipid A as a lipid A structural analog antagonist was also a seminal finding by Dr. Qureshi and colleagues. This ultimately led to the synthetic development of TLR4 antagonists such as Eritoran.

Mechanisms Involved in Cell Activation by Toxins: Dr. Qureshi also synthesized and characterized a novel radioactive and photoactivable LPS probe to provide new insights regarding the activation of immune cells. She was trying to establish the identity of the LPS receptor and studying early steps in the signal transduction of LPS in macrophage cell lines. She characterized some LPS-binding proteins and determined the role of the proteasome complex in the LPS-initiated signal transduction process and inflammation.

Dr. Qureshi and colleagues were the first to show that the proteasome is involved in degradation of mediators involved in many signal-transduction steps and the entire process of inflammation using proteasome subunit knockout mice and specific inhibitors. LPS, CpG DNA and peptidoglycan prime the cells to be activated by changing the subunits of the proteasomes. The subunits of the proteasomes have definite functions. Her conclusion from these studies was that the proteasome is a central regulator of macrophage function and inflammation and is involved in several diseases. Proteasomes are involved in differentiation of all cells. On this basis she has suggested a novel mechanism for inflammation and tolerance based on the proteasome. These studies will ultimately lead to a cure for preventing inflammation-linked diseases.