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VEGF and LPS synergistically silence inflammatory response to Plasmodium berghei infection and protect against cerebral malaria

Canavese, Miriam; Dottorini, Tania; Crisanti, Andrea


Miriam Canavese

Andrea Crisanti


Malaria infection induces, alongside endothelial damage and obstruction hypoxia, a potent inflammatory response similar to that observed in other systemic diseases caused by bacteria and viruses. Accordingly, it is increasingly recognised that cerebral malaria (CM), the most severe and life threatening complication of Plasmodium falciparum infection, bears a number of similarities with sepsis, an often fatal condition associated with a misregulated inflammatory response triggered by systemic microbial infections.

Using a Plasmodium berghei ANKA mouse model, histology, immunohistochemistry and gene expression analysis, we showed that lipopolysaccharide S (LPS), at doses that normally induce inflammation tolerance, protects P. berghei infected mice against experimental CM (ECM). Vascular endothelial growth factor (VEGF) preserved blood vessel integrity, and the combination with LPS resulted in a strong synergistic effect. Treated mice did not develop ECM, showed a prolonged survival and failed to develop a significant inflammatory response and splenomegaly in spite of normal parasite loads. The protective role of VEGF was further confirmed by the observation that the treatment of P. berghei infected C57BL/6 and
Balb/c mice with the VEGF receptor inhibitor axitinib exacerbates cerebral pathology and aggravates the course of infection. Infected mice treated with VEGF and LPS showed an induction of the anti-inflammatory genes Nrf2 and HO-1 and a suppression to basal levels of the genes IFN-c and TNF-a. These results provide the rationale for developing new therapeutic approaches against CM and shed new light on how the inflammatory process can be modulated in the presence of systemic infectious diseases.


Canavese, M., Dottorini, T., & Crisanti, A. (2015). VEGF and LPS synergistically silence inflammatory response to Plasmodium berghei infection and protect against cerebral malaria. Pathogens and Global Health, 109(6), doi:10.1179/2047773215Y.0000000018

Journal Article Type Article
Acceptance Date Sep 21, 2015
Online Publication Date Sep 21, 2015
Publication Date Sep 21, 2015
Deposit Date Mar 17, 2018
Print ISSN 2047-7724
Electronic ISSN 2047-7732
Publisher Taylor & Francis
Peer Reviewed Peer Reviewed
Volume 109
Issue 6
Keywords Vascular endothelial growth factor; Angiogenesis; Cerebral malaria; Inflammation; Cytokines
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