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Major Research Projects

Funding

We are funded by ERC, MRC, BBSRC, EMBO, British Council, Newton Bhabha, Erasmus and Wellcome Trust.

European Research Council
Medical Research Council
BBSRC
EMBO
British Council
Newton Bhabha
Wellcome Trust

Overview

The research in the group has undertaken genome wide functional studies using rodent malaria model P. berghei to understand parasite developmental biology and the crucial novel molecules that are part of the signalling cascades, cell division, polarity during parasite development.

Major projects undertaken in the group are:

1. Understanding molecular mechanism regulating unusual cell division and cell polarity in malaria parasite

Cell division and proliferation require a process of chromosome replication and segregation that ensure that the two daughter cells obtain identical copies of the genome. Malaria parasites representing divergent eukaryote divide and proliferate within host cells in a unique way that is different from that of many model eukaryotes. Many of the regulators as part of reversible phosphorylation (kinases and phosphatases) and motor proteins required for progression through cell development and polarity, mitosis and meiotic division are either diverged or missing from Plasmodium. Most of our studies are also focussed on understanding the cell biology of the sexual and sporogony stages of parasite development occurring within mosquito vector. These are difficult stages to study in many apicomplexan parasites, including malaria parasites. Our recent research has given us an important insight to understand the mechanism and function of some of these molecules as described below:

1A. Kinesins - Molecular motors in cell division
Role of Kinesins as molecular motor in spindle dynamics and axoneme dynamics. (For details see Zeeshan et al PLOS Pathogens 2019; 2019b)
Figure 1. Role of Kinesins as molecular motor in spindle dynamics and axoneme dynamics (For details see Zeeshan et al (: 10.1371/journal.ppat.1008048 ) and : 10.26508/lsa.201900488 ).
1B. Condensin core subunits - SMC2/SMC4 in Plasmodium cell division
Localization, protein complex and functional analysis of SMC2/4 during proliferative stages in Plasmodium. (Pandey et al Cell Reports 2020)
Figure 2. Localization, protein complex and functional analysis of SMC2/4 during proliferative stages in Plasmodium. Pandey et al et al (: 10.1016/j.celrep.2020.01.033 ).
1C. Kinetochore complex – Plasmodium NDC80 dynamics in chromosome segregation during proliferative stages
Unusual features of Plasmodium Ndc80 reveals atypical modes of chromosome segregation during parasite proliferation. Zeeshan et al JCS 2020
Figure 3. Unusual features of Plasmodium Ndc80 reveals atypical modes of chromosome segregation during parasite proliferation. Zeeshan et al (: 10.1242/jcs.245753 ).
1D. Cyclins - Cyclin3 in Plasmodium
Only three cyclins present in Plasmodium (A); shows cyclin expression during sporogony (B) and the deletion of P type cyclin affects sporogony (C) (Roques et al PLOS Pathogens 2015)
Figure 4. Only three cyclins present in Plasmodium (A); shows cyclin expression during sporogony (B) and the deletion of P type cyclin affects sporogony (C). Roques et al (: 10.1371/journal.ppat.1005273 ).

2. Reversible phoshorylation and parasite development in malaria parasite

2A. Kinases and Phosphatases functional screen
Stage specific function of various kinases and phosphatases in mosquito stages of parasite development (Tewari et al Cell Host & Microbe 2010: Guttery et al Cell Host & Microbe 2014)
Figure 5. Stage specific function of various kinases and phosphatases in mosquito stages of parasite development. Tewari et al (: 10.1016/j.chom.2010.09.006) and Guttery et al (: 10.1016/j.chom.2014.05.020 ).
2B. Plasmodium specific Cyclin dependent protein kinase CRK5-cyclin complex and function during male gametogenesis
Plasmodium specific CRK5-Soc2-Cdkr complex (A and B) and its role during male gamete formation (Balestra, Zeeshan et al eLife 2020)
Figure 6. Plasmodium specific CRK5-Soc2-Cdkr complex (A and B) and its role during male gamete formation. Balestra, Zeeshan et al (: 10.7554/eLife.56474 ).
2C. Phosphatase PP1 in male gametogenesis and ookinete formation
PP1 is present at schizogony and male gametogenesis (A and B) and is required both for male gametogenesis and ookinete formation as well as transcription of other phosphatase and cell motility genes when knockdown (C and D) (Zeeshan et al 2021)
Figure 7. PP1 is present at schizogony and male gametogenesis (A and B) and is required both for male gametogenesis and ookinete formation as well as transcription of other phosphatase and cell motility genes when knockdown (C and D). Zeeshan et al (: 10.1101/2021.01.15.426883 ).

3. Cell polarity during motile and invasive stages in Plasmodium

3A. Myosin gene family
Systematic functional screen of Plasmodium Myosins reveals differential localisation and function during invasive stages. (Wall et al 2019)
Figure 8. Systematic functional screen of Plasmodium Myosins reveals differential localisation and function during invasive stages. Wall et al (: 10.1111/cmi.13082 ).
3B. Phil1 is novel complex present during invasive stages
Phil1 as component of inner membrane complex showing both basal and apical polarity during invasive stages. (Saini, Zeeshan et al 2017)
Figure 9. Phil1 as component of inner membrane complex showing both basal and apical polarity during invasive stages. Saini, Zeeshan et al (: 10.1038/s41598-017-15781-z ).

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