Multicellular organisms evolved sophisticated immune systems to protect themselves against infection. We are interested in understanding how our immune system regulates its responses to microbial challenges. We focus on specialized antimicrobial cells known as neutrophils, since these play central microbicidal and regulatory roles during the course of infection. We are trying to understand the mechanisms that allow these cells become activated and kill a variety of different microbes. We are focusing our attention on the mechanism that allows these cells to release large web like structures that capture and kill bacteria and fungi. These NETs, as they are called, are thought to protect against infection but are also thought to trigger autoimmunity. We plan to investigate the role of NETs in autoimmune disease. We are exploring whether NETs play a detrimental role in inflammatory disease and sepsis.

The association between Human Papillomavirus (HPV) infection and cervical cancer is well established. While HPVs by themselves cannot cause cancer, their continued presence increases the risk of such a development, and as infectious agents, their spread within the population augments the potential problem considerably. Efforts to contain and eventually abolish this virus are concentrated at two fronts. The first is the development of a vaccine against HPV, which has been a recent success, and the second is to develop anti-viral drugs to eliminate viruses that have already gained access into the cervical tissue. To address the latter, one needs to first understand how HPVs infect, replicate and persist in the tissue for years. Hence we have elected to study and be well acquainted with these processes which constitute the life-cycle of this virus with the tenet that this knowledge may provide channels to intervene and to rid tissues of this pathogen. While it is difficult to be certain whether continued presence of HPV DNA is due to persistence or continuous infections, it is nevertheless possible (and important) to determine the mechanism/s employed by HPV to remain in the host tissue for prolonged periods, if not indefinitely.

Toxoplasma gondii is a pathogen related to the malaria parasite with a wide range of host specificity that includes humans. It can cause brain disease and is a serious health threat to individuals with a poorly functioning immune system, including newborns. No vaccines or drugs to fight the disease are available and once infected the parasite remains with the host its whole life. We don't exactly know how Toxoplasma maintains the intricate balance between survival inside a host and elimination. We study how the host cell redesigns and controls the composition of its membrane system and the sites to which the parasite has access directly following infection. These same controls enable the immune system to "see" which cells are infected. Proteins called large GTPases are upregulated in infected cells and brought to the membrane of the enclosure in which the parasites multiply. We investigate how this recruitment contributes to the parasites’s survival or elimination. Moreover, we have created mice that bear large numbers of immune cells, capable of specific recognition of Toxoplasma. We will ask how these specific immune cells control the infection with Toxoplasma in the chronic phase. This is especially important, as clinically the parasite lies permanently dormant due to the pressure these cells exert in normal individuals. Understanding these parameters of parasite control will contribute to the design of effective countermeasures against Toxoplasma.

Rheumatoid arthritis (RA) is a common human autoimmune disease, which is characterized by chronic inflammation of the synovial joints and progressive destruction of cartilage and bone. Localized inflammatory responses, in this case in blood vessel walls, are similarly important in atherosclerosis, a leading cause of morbidity and mortality in industrialized countries. An understanding of the mechanism by which inflammatory responses are controlled is important for development of new therapies for these major diseases.The initiation of inflammatory responses depends on the NF-?B family of intracellular proteins, which regulate the expression of multiple genes that are switched on in both RA and atherosclerosis. The activation of NF-?B involves several distinct signalling pathways and my laboratory concentrates on one of these that is dependant on the protein NF-B1 p105. Our recent work has shown that this controls not only the activation of NF-B proteins but also of another signalling protein, TPL-2. We are currently investigating in more detail how p105 regulates TPL-2 activation and how both of these proteins control immune and inflammatory responses. It is hoped that our work might identify novel targets for the development of anti-inflammatory drugs for the treatment of inflammatory diseases such as RA and atherosclerosis.

Two classes for anti-influenza drugs are effective in prophylaxis and treatment of influenza.||Amantadine and rimantadine prevent infection of cells by blocking the M2 ion channel in the virus particle which is essential for entry into cells and subsequent replication of the virus. Our investigations have explained the basis of the selective antiviral activity of the drugs and further elucidated key stages in virus infection. Our current studies of the activities of the NB and CM2 ion channels of influenza B and C viruses, respectively, which differ from that of the M2 channel of influenza A and are not blocked by the two anti-influenza A drugs, will increase our fundamental understanding of their functional roles in virus replication and may provide the basis for developing other, broader spectrum, channel-blocking drugs which are more effective against influenza A, B and C viruses.||Oseltamivir and zanamivir inhibit the neuraminidase (NA), which is involved in the release of virus from infected cells and in the spread within and between individuals. X-ray crystallography of different NA subtypes has identified an additional cavity within the active site of the enzyme which provides an additional target for development of other drugs. These structural studies also provide explanations for differences in the emergence of drug-resistant mutants and contribute to our understanding of their potential clinical and epidemiological significance.