I studied biology in the school, did B.Sc. in Zoology and M.Sc. in Cell Biology, and went on to carry out PhD research in molecular biology from Delhi. After a short stint at Salk Institute, San Diego as a NASA fellow, I joined in 1996 Department of Biochemistry, Oxford, first as a Wellcome Trust Overseas Fellow, and then as a Research Associate within Medical Research Council Immunochemistry Unit. At Oxford, I became interested in pattern recognizing innate immune molecules such as complement protein C1q and pulmonary surfactant proteins SP-A and SP-D. The identification of a major role of SP-D in controlling pulmonary inflammation and infection by our group took me further into host-pathogen interaction. I became involved in a range of projects that culminated in demonstrating that recombinant SP-D can have therapeutic potential again pulmonary hypersensitivity and invasive infection. Since then, I have been concentrating on clinical aspects of the above mentioned proteins that have ramifications as far as asthma, infection, autoimmunity, transplantation and a number of neonatal conditions.
My current interest lies in role of innate immunity in host defence using a model fungal pathogen, Aspergillus fumigatus. This pathogen causes allergic bronchopulmonary aspergillosis (ABPA) in immunocompetent individuals, while being capable of causing fatal invasive aspegillosis in immunocompromised subjects. Human SP-D is a pulmonary surfactant-associated innate immune molecule. Our studies have established its potent anti-microbial and anti-inflammatory properties in vitro, in vivo and ex vivo. Using a murine model of severe lung infection (invasive pulmonary aspergillosis, IPA) caused by a fungal pathogen, Aspergillus fumigatus (Afu), we found that treatment with rhSP-D can rescue mice from certain death. All untreated IPA mice died within 5-7 days, the rhSP-D treated group showed >90% survival (without any side effects). The SP-D mediated protective mechanisms include agglutination of pathogen, fungistasis, enhanced killing by phagocytes and predominant Th1 response. Increased susceptibility of SP-D gene deficient mice to IPA supports our view. Patients, who are immunocompromised or immunodeficient due to chemotherapy, cancer, transplantation or AIDS are high risk IPA groups.
Using animal models of asthma caused by Afu and dust mite, we have shown that rhSP-D has a long term therapeutic value in dampening asthmatic symptoms in mice. The therapeutic mechanisms include inhibition of allergen-IgE binding and histamine release by sensitized mast cells, dramatic downregulation of specific IgG and IgE antibodies and pulmonary and peripheral eosinophilia, a shift from pathogenic Th2 to a protective Th1 cytokine response, inhibition of mechanisms that cause airway remodelling, and apoptosis induction in sensitised eosinophils. This is consistent with inherent hypereosinophilia and Th2 predominance, and hence increased susceptibility of SP-D gene deficient mice, to allergic hypersensitivity. Thus, another important milestone in sight is to evaluate therapeutuc efficacies of a recombinant form of human SP-D in patients suffering from asthma and lung infection. I aim to further understand how SP-D modulates immune responses, and how it maintains persistence of its therapeautic effect. Using animal models of ABPA and IPA in wild type and SP-D knock out mice, we will try to understand how SP-D modulates eosinophils, dendritic cells (DC), and helper T cell polarisation to protective Th1 response that are so central to therapeutic mechanisms.
In addition, I remain interested in structural and functional aspects of the globular head region of human C1q, the first subcomponent of the classical complement pathway. The potential application of the recombinant forms of C1q globular head domains in dampening complement activation in a range of inflammatory conditions including neurodegenerative diseseaes is also being explored on my laboratory. A number of above mentioned studies have led to setting up of clinical trials, which remain at the core of my translational research.
- PhD (1995): Department of Zoology, University of Delhi and CSIR Institute of Genomics and Integrative Biology, Delhi, Indi Thesis: Chemical gene synthesis and expression of Human Epidermal Growth Factor in Escherichia coli.
BB2405 Genetic Engineering and Immunobiology;
BB3216 Microbial Pathogenesis
Deputy Postgraduate Admission Tutor, Biosciences
Personal tutor to a number of undergraduate and postgraduate students
Newest selected publications
DeCordova, S., Shastri, A., Tsolaki, A., Yasmin, H., Klein, L., Singh, SK. and (2020) 'Molecular heterogeneity and immunosuppressive microenvironment in Glioblastoma'. Frontiers in Immunology. ISSN: 1664-3224 Open Access Linket al.
Murugaiah, V., Agostinis, C., Vargheses, P., Belmonte, B., Vieni, S., Alaql, F., (2020) 'Hyaluronic acid present in the tumour microenvironment can negate the pro-apoptotic effect of a recombinant fragment of Human Surfactant Protein-D on breast cancer cells'. Frontiers in Immunology. ISSN: 1664-3224 Open Access Linket al.
Kale, K., Vishwekar, P., Balsarkar, G., Jassawalla, M., Alkahtani, S., Kishore, U., (2020) 'Serum levels of collectins are sustained during pregnancy: Surfactant protein D levels are dysregulated prior to missed abortion'. Reproductive Sciences. pp. 1 - 33. ISSN: 1933-7191 Open Access Linket al.
Riaz, M., Kaur, A., Shwayat, S., Behboudi, S., Kishore, U. and Pathan, A. (2020) 'Dissecting the mechanism of intracellular Mycobacterium smegmatis growth inhibition by Platelet activating factor C-16'. Frontiers in Microbiology. ISSN: 1664-302X Open Access Link
Madan, T. and Kishore, U. (2020) 'Surfactant protein D Recognizes Multiple Fungal Ligands: A Key Step to Initiate and Intensify the Antifungal Host Defense'. Frontiers in Cellular and Infection Microbiology, 10. ISSN: 2235-2988 Open Access Link