The Walter and Eliza Hall Institute of Medical Research

The role of chemokine networks in severe malaria and the control of parasite density

Project type

Honours and/or PhD

Supervisor(s)	Division	Email
Dr Diana Hansen (Primary)	Infection and Immunity	.(JavaScript must be enabled to view this email address)
Associate Professor Louis Schofield (Co-supervisor)	Infection and Immunity	.(JavaScript must be enabled to view this email address)

 

Details of project

Two contributing factors have been identified as the main determinants of severe malaria: high parasite densities and host pro-inflammatory responses. To date it is not clear if inflammation is a cause or a consequence of high parasite density.

Whereas cytokine responses to malaria have been extensively investigated, the role of chemokines in severe disease has only recently started to receive attention. Amongst these molecules, CXCL10 or IFN-gamma-inducible protein 10 (IP-10) has emerged as a biomarker strongly associated with increased risk of severe malaria in Africa and Papua New Guinea. Consistent with its role in human disease, we found that the absence of IP-10 protects from malaria-infected mice from severe disease and significantly reduces parasite densities in the infected host.

We therefore propose that IP-10 produced in response to malaria is not only detrimental for its involvement in organ-specific syndromes but also contributes to the development of high parasite densities by compromising the induction of protective immunity. The aim of this study is to determine if locally produced IP-10 has a detrimental effect for the development of immune responses required to control parasitemia. The cellular sources of IP-10 involved in this process will be identified.

Previous work in the lab showed that anti-IP-10 treatment alleviates brain inflammation and prevents fatalities in a pre-clinical model of severe malaria. This project will provide evidence that such treatment could be also beneficial to improve induction of protective immunity and reduce parasite biomass.

Project references

1. Nie CQ, Bernard NJ, Norman MU, Amante FH, Lundie RJ, Crabb BS, Heath WR, Engwerda CR, Hickey MJ, Schofield L and Hansen DS. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection, PLoS Path. 2009 5(4): e1000369.
2. Van den Steen PE, Deroost K, Van Aelst I, Geurts N, Martens E, Struyf S, Nie CQ, Hansen DS, Matthys P, Van Damme J, Opdenakker G. CXCR3 determines strain-susceptibility to murine cerebral malaria by mediating T-lymphocyte migration toward IFN-gamma-induced chemokines. Eur J Immunol. 2008 38:1082-1095.
3. Hansen DS, Bernard NJ, Nie CQ and Schofield L. Natural Killer cells control CXCR3-dependent T cell recruitment to the brain during Plasmodium berghei-mediated cerebral malaria. J Immunol. 2007 178:5779-5788.
4. Sexton AC, Good RT, Hansen DS, Buckingham L, Simpson K and Schofield L. Microarray analysis reveals novel transcriptional pathways in murine malaria pathogenesis. J. Infec. Dis. 2004, 189: 1245-1256.

Research interests

Malaria is a major global disease responsible for over a million deaths each year. Clinical symptoms of malaria include respiratory distress, renal failure, pulmonary oedema and cerebral involvement.

Blood-stage forms of Plasmodium parasites are responsible for such disease syndromes. Mature forms of malaria parasites express surface proteins on the red blood cell membrane, which allow them to bind to blood vessels and avoid clearance in the spleen. This process, called sequestration, is known to induce severe disease syndromes in target organs such as the brain and results in recruitment of host inflammatory leukocytes.

Recent findings have revealed that the spleen is the source of such inflammatory cells that migrate to target organs. Thus immune responses appear to play a dual role in malaria by mediating protection against the parasite and contributing to pathogenesis, which highlights the balance that should take place to protect the host from infection without resulting in harmful inflammation.

Our group investigates the mechanisms by which inflammatory factors produced in response to infection modulate the balance between pathogenic organ-specific inflammation and spleen-mediated protective immunity to malaria. Understanding the mechanisms that control these inflammatory processes is highly relevant, as it could lead to the development of new therapeutic strategies to alleviate severe malaria syndromes and enable immune responses to be generated more effectively.

 

 

Selected publications

1. Hansen DS and Schofield L. Natural T regulatory cells in malaria: host or parasite allies? PLoS path. 2010 Apr 29;6(4):e1000771.
2. Nie CQ, Bernard NJ, Schofield L and Hansen DS. CD25+ CD4+ T regulatory cells suppress T cell function and inhibit the development of parasite-specific to TH1 responses involved in cerebral malaria pathogenesis. Infect. Immun. 2007 75:2275-2282.
3. Hansen DS, Evans KJ, D’ombrain MC, Bernard NJ, Sexton AC, Buckingham L, Scalzo AA and Schofield L. The Natural Killer Complex regulates malarial pathogenesis and influences acquired immune responses to Plasmodium berghei. Infect. Immun. 2005 73: 2288-2297.
4. Hansen DS, Siomos M-A, Buckingham L, Scalzo AA and Schofield L. Regulation of murine malarial pathogenesis by CD1d-restricted NKT Cells and the Natural Killer Complex. Immunity. 2003 18: 391-402.
5. Hansen DA, Siomos M-A, de Koning-Ward T, Buckingham L, Crabb BS and Schofield L. CD1d-restricted NKT cells contribute to the splenomegaly associated with B cell expansion and enhance parasite-specific antibody responses in murine malaria. Eur. J. Immunol. 2003 33: 2588-2598.

Research theme

Infectious diseases

Scientific discipline

• Immunology