INDIVIDUAL RESEARCHER
Meenakshi Malik
, D.V.M.
, Ph.D.
Research Assistant Professor
e-mail: malikm@mail.amc.edu
Education
1989 - D.V.M. from College of Veterinary Sc. & A.H.1998 - Ph.D. from Indian Veterinary Research Institute
Current Research
Our long term research goal is to understand the host mediated mechanisms of innate immunity against intracellular bacterial pathogens. Over the past several years, our research has focused on elucidating the many complexities of innate immunity against Francisella tularensis, a category A biothreat agent. Our findings have yielded important insights into the role of TLRs in protective immunity against Francisella infection. We have reported a pivotal role for TLR2 in innate immune recognition of F. tularensis demonstrating that TLR2 deficiency leads to enhanced susceptibility to infection in mice. While many TLRs, including TLR2, are expressed on the cell surface and are involved in the extracellular recognition of pathogen-associated molecular patterns (PAMPs), another family of pattern recognition receptors (PRRs), the Nod-like Receptors (NLRs) can detect bacterial products in the cytoplasm. Since F. tularensis invades and replicates within the intracellular environment of several cell types including macrophages and dendritic cells, the role of NLRs in innate immunity against this pathogen assumes great importance. However, little is known regarding the role of NLR proteins, their ligands and the composition of the inflammasome (a cytosolic multi-protein complex that activates caspase-1 to produce proinflammatory cytokines such as IL-1ß and IL-18) in host defense against F. tularensis. Current work is focused on investigating the NLR(s) being activated in response to F. tularensis and the specific Francisella component(s) responsible for triggering these intracellular signaling events. Furthermore, we are also exploring the relationship that exists between the external and internal sensors detecting F. tularensis. The objective of this project is to understand the cell biology of signal integration between key components of innate immunity and how these processes at the cellular level contribute to the host’s ability to resist microbial challenge. Defining the molecular mechanism(s) of innate immunity will be an essential first step towards development of immunotherapeutic, as well as effective vaccine strategies to combat a variety of intracellular bacterial pathogens.References
- Bakshi, C. S., Malik, M., Kirimanjeswara, G. S., Hazlett, K. R. O., Melendez, J. A., Sellati, T. J., and Metzger, D. W. An improved vaccine for the prevention of respiratory tularemia caused by F. tularensis SchuS4. Vaccine, 26:5276-5288, 2008.
- Forestal, C.A., Malik, M., Benach, J.A., Sellati, T.J., and Furie, M.B. Francisella tularensis in the blood of tularemic mice is localized predominantly in the plasma. Journal of Infectious Diseases.196:134-137, 2007.
- Malik, M., Bakshi, C. S., McCabe, K., Catlett, S. V., Shah, A., Sahay, B., Singh, R., Metzger, D. W., Melendez, J.A., and Sellati, T. J. Matrix Metalloproteinase 9 (MMP-9) activity enhances host susceptibility to pulmonary infection with Type A and B strains of Francisella tularensis. Journal of Immunology. 178:1013-1020, 2007.
- Bakshi, C. S., Malik, M., Regan, K., Melendez, J. A., Metzger, D. W., Pavlov, V. M., and Sellati, T. J. Superoxide dismutase-B (sodB) deficient mutants of Francisella tularensis demonstrate hypersensitivity to oxidative stress and attenuated virulence. Journal of Bacteriology. 188 (17): 6443-6448, 2006.
- Malik, M., Bakshi, C. S., Sahay, B., Shah, A., Lotz, S. A., and Sellati, T. J. Toll-like receptor 2 is required for control of pulmonary infection with Francisella tularensis. Infection and Immunity. 74 (6): 3657-62, 2006.
