Cerebral malaria: insights from host-parasite protein-protein interactions.
BACKGROUND
Cerebral malaria is a form of human malaria wherein Plasmodium falciparum-infected red blood cells adhere to the blood capillaries in the brain, potentially leading to coma and death. Interactions between parasite and host proteins are important in understanding the pathogenesis of this deadly form of malaria. It is, therefore, necessary to study available protein-protein interactions to identify lesser known interactions that could throw light on key events of cerebral malaria.


METHODS
Sequestration, haemostasis dysfunction, systemic inflammation and neuronal damage are key processes of cerebral malaria. Key events were identified from literature as being crucial to these processes. An integrated interactome was created using available experimental and predicted datasets as well as from literature. Interactions from this interactome were filtered based on Gene Ontology and tissue-specific annotations, and further analysed for relevance to the key events.


RESULTS
PfEMP1 presentation, platelet activation and astrocyte dysfunction were identified as the key events influencing the disease. 48896 host-parasite along with other host-parasite, host-host and parasite-parasite protein-protein interactions obtained from a disease-specific corpus were combined to form an integrated interactome. Filtering of the interactome resulted in five host-parasite PPI, six parasite-parasite and two host-host PPI. The analysis of these interactions revealed the potential significance of apolipoproteins and temperature/Hsp expression on efficient PfEMP1 presentation; role of MSP-1 in platelet activation; effect of parasite proteins in TGF-beta regulation and the role of albumin in astrocyte dysfunction.


CONCLUSIONS
This work links key host-parasite, parasite-parasite and host-host protein-protein interactions to key processes of cerebral malaria and generates hypotheses for disease pathogenesis based on a filtered interaction dataset. These hypotheses provide novel and significant insights to cerebral malaria.
Life Sciences Division, TCS Innovation Labs Hyderabad, Tata Consultancy Services Ltd, 1, Software Units Layout, Madhapur, Hyderabad-500081, India. adityar.rao@tcs.com
Aditya
A
Rao
Mayil K
MK
Kumar
Thomas
T
Joseph
Gopalakrishnan
G
Bulusu
D001053:Apolipoproteins / Q000378:metabolism*; D001253:Astrocytes; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D004912:Erythrocytes / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D016779:Malaria, Cerebral / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology*; D020066:Merozoite Surface Protein 1 / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000502:physiology*; D015539:Platelet Activation; D011485:Protein Binding / Q000502:physiology*; D025941:Protein Interaction Mapping; D015800:Protozoan Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D001053:Apolipoproteins; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; D016212:Transforming Growth Factor beta; C085731:erythrocyte membrane protein 1, Plasmodium falciparum