Research Groups
Mammalian Biology: Malaria
Research Interests and Description
Research Scientist: Paushali Mukherjee, PhD
Group Leader: Virander Chauhan
Research Interests
Blood stage malaria, dendritic cell, CD4+ T cells, B cells, immunological memory.
Description of Research
The interaction of blood stage malaria parasites with innate immune system
The innate immune system provides the early phases of host defenses against malaria and is important in shaping the adaptive immune response. In this connection we are looking at the TLR responses during acute P. yoelii nigeriensis murine infection. We compared the expression of TLR on macrophages and dendritic cells and found that expression of all the TLRs were lower on both dendritic cells and macrophages of infected mice compared with uninfected mice. We determined whether the altered TLR expression in dendritic cells and macrophages of infected mice translated to functional dimunition in responses to TLR ligands, stimulated DC and macrophages isolated from the spleens of naive animals, infected mice at day 10 p.i with the ligands for TLR2 (Pam3Cys), TLR4 (LPS), TLR6 (zymosan) and TLR9 (CpG) and examined the DC and macrophages response by flow cytometry. TLR2, 4, 6 and 9 ligands induced a significant up-regulation of CD80, CD86 (except Pam3Cys), and MHC class II molecules in uninfected macrophages and dendritic cells. There was no upregulation in the expression of CD80 and CD86 on the DCs and macrophages from infected mice. Further, we observed no TNF-a, IL-6, and IL-12 in macrophages and dendritic cells isolated from P. yoelii nigeriensis infected mice in response to Pam3Cys, LPS, zymosan and CpG DNA. These results suggest that the functional responses measured correlate with the expression patterns of TLR in infected and uninfected mice.
The cellular basis of immunological memory in experimental model of malaria
Understanding the basis of protective immunity in terms of its induction, effector mechanisms and memory is critical for designing candidate malaria vaccines. An effective immune response to malaria infection depends on the CD4+ helper T cell regulated development of high-affinity B cell memory. The cognate CD4+ T cell helps comprise peptide-MHC interactions, cytokines and co-stimulatory molecules that regulate commitment B cell to antibody isotype switch, plasma cell development and the germinal center pathway. We are elucidating the mechanisms that underline the differentiation of memory CD4+ T cell during an acute, versus chronic, malaria infection. A model of acute and chronic P. berghei infection was established. We have shown that CD4+ T cells responded to an acute as well as chronic blood-stage infection with P. berghei and persisted in an activated state. CD4+ T cells showed dynamic expression of the surface protein interleukin (IL)-7R (CD127) and programmed death-1 (PD-1). Additionally, there was high expression of T-box transcription factor TBX21 (T-bet) and predominant Th1 response in malaria-activated CD4+ T cells indicated an early T helper type 1 (Th1)-skewed immune response during both acute and chronic infection. Our data demonstrated that blood-stage malaria infection resulted in a striking T-cell response and that activated CD4+ T cells have phenotypic and functional characteristics that are consistent with conventional antigen specific effector and memory T cells. Central CD4+ memory cells (CD44hiCD62L+CCR7+) developed during the chronic infection and were distinct from effector (CD44hiCD62L−CCR7−) cells during the acute infection. In parallel, we are investigating the kinetics, duration and characteristics of the Plasmodium-specific memory B cell response during chronic and acute P. berghei infection.
Recent Publications
Chandele, A., Mukherjee, P., Das, G., Ahmed, R., Chauhan, V.S. 2011. Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii. Immunology 132, 273-286 PubMed link
Mazumdar, S., Mukherjee, P., Yazdani, S.S., Jain, S.K, Mohmmed, A., Chauhan, V.S. 2010. Plasmodium falciparum merozoite surface protein 1 (MSP-1)-MSP-3 chimeric protein: immunogenicity determined with human-compatible adjuvants and induction of protective immune response. Infect Immun 78, 872-883 PubMed link
Singh, M., Mukherjee, P., Narayanasamy, K., Arora, R., Sen, S.D., Gupta, S., Natarajan, K., Malhotra, P. 2009. Proteome analysis of Plasmodium falciparum extracellular secretory antigens at asexual blood stages reveals a cohort of proteins with possible roles in immune modulation and signaling. Mol Cell Proteom 8, 2102-2118 PubMed link
Mukherjee, P., Chuahan, V.S. 2008. Blood stage malaria antigens induce different activation induced cell death programs in splenic CD4 T cells. Parasite Immunol, 30, 497-514 PubMed link
Mukherjee, P., Chuahan, V.S. 2008. Plasmodium falciparum free merozoites and infected RBCs distinctly modulate soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells. J Leukoc Biol 84, 244-254 PubMed link
Devi, Y.S., Mukherjee, P., Yazdani, S.S., Shakri, A.R., Mazumdar, S., Pandey, S., Chitnis, C.E,, Chauhan, V.S. 2007. Immunogenicity of Plasmodium vivax combination subunit vaccine formulated with human compatible adjuvants in mice. Vaccine 25, 5166-5174 PubMed link
