Research Groups

Mammalian Biology: Malaria

Research Interests and Description

Research Scientist: Paushali Mukherjee

Group Leader: Virander Chauhan

Research Interests

Blood stage malaria, dendritic cell, CD4⁺ T cells, B cells, immunological memory.

Description of Research

Dendritic cell (DCs) are the immune system's decision-makers since these cells are equipped to sense pathogens or vaccines and orchestrate appropriate immune responses to them. Recently we have shown that P. falciparum free merozoites and iRBCs distinctly regulate the sCD40L-induced maturation of human monocyte-derived DCs (MDDCs) and define the outcome of CD40-CD40L interaction on cytokine production. Whereas P.falciparum infected RBC-infected DCs retain their responsiveness to sCD40L stimuli, producing appreciable levels of IL-6, TNF-a and IL-12p70, infection with P.falciparum free merozoites fails to induce DC activation (Fig. 1A). Our results suggest that the marked alteration in the responsiveness of iRBC or free merozoite infected DCs to sCD40L stimulation is due to activation of different key molecules of MAPK pathways. Down-modulation of DC activation following free merzoites infection was associated with increased phosphorylation of extracellular signal–regulated kinase (ERK), whereas the increased responsiveness of iRBC infected DCs to sCD40L stimulation was due to increase phosphorylation of of p38 MAPK (Fig. 1B, C). Taken together the data reveal that plasmodium parasites have evolved complex strategies to evade DC functions by regulating host cell signaling pathways.
Prior exposure to blood stage malaria parasites has been shown to provide incomplete protection against subsequent infection. In another set of experiments, we assessed longevity of antibody-response and maintenance of the memory B and T cells to two blood stage merozoite surface proteins, PfMSP-1₁₉ and PfMSP-3 and P. yoelii nigeriensis infected mice. After immunization with either PfMSP-1₁₉ or PfMSP-3, maximum levels of circulating antibody observed three weeks after the second and third boost remained stable for three to four weeks before decreasing to nearly baseline by 10 to 12 weeks (Fig. 2A). The number of splenic antigen-specific IgG secreting AFCs response peaked after second booster dose and then rapidly declined. Concomitantly, the number of BM AFCs slowly grew, such that by 8 weeks after primary immunization the frequency of antigen-specific AFCs in the BM was 4-5-fold higher than in the spleen before decreasing to nearly baseline by 8 to 10 weeks. The response to the booster dose was consistent with the development of memory B cells by primary vaccination. After a rest of 8-10 weeks, the booster dose of soluble antigen elicited a recall of the immune memory established by the two (PfMSP-3) or three-dose (PfMSP-1₁₉) regimen of recombinant vaccine but the recall response was not sustained for long period of time.
Examining the dynamics of CD4+ T cell response to infection with P. yoelii nigeriensis (PYN), we observed that CD4+ T-cell response consists of expansion, contraction, and memory phases. To study endogenous memory CD4+ T cell responses to secondary infection, immune mice were challenged with P. yoelii nigeriensis on day 42 postinfection. Kinetic analysis revealed that during secondary response after its peak response at day 5, the frequency of PYN-specific IFN-γ+ cells started to decline rapidly and by day 14, there were very few parasite-specific IFN-γ+ cells left in the spleen after 3 or 4 week after challenge. Although the recall response to PYN peaked earlier than it did during the primary response (day 5 vs day 10 p.i.), the secondary response was found to be significantly smaller than that of the primary response (Fig. 2A). These results are in contrast to what is seen for other pathogen-specific responses where recall is significantly enhanced, compared with the primary response. 

Recent Publications

Mukherjee, P., Devi, Y.S., Chauhan, V.S. 2008. Blood stage malaria antigens induce different activation-induced cell death programs in splenic CD4+T cells. Parasite Immunol. 30, 497-514

Mukherjee, P., Chauhan, V.S. 2008. Plasmodium falciparum-free merozoites and infected RBCs distinctly affect soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells. J Leukoc Biol. 84, 244-254

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