Neuroimmunological Blood Brain Barrier Opening in Experimental Cerebral Malaria

Nacer, Adela; Movila, Alexandru; Baer, Kerstin; Mikolajczak, Sebastian A.; Kappe, Stefan H. I.; Frevert, Ute
October 2012
PLoS Pathogens;Oct2012, Vol. 8 Issue 10, Special section p1
Academic Journal
Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB.


Related Articles

  • Effective induction of high-titer antibodies by viral vector vaccines. Draper, Simon J.; Moore, Anne C.; Goodman, Anna L.; Long, Carole A.; Holder, Anthony A.; Gilbert, Sarah C.; Hill, Fergal; Hill, Adrian V. S. // Nature Medicine;Aug2008, Vol. 14 Issue 8, p819 

    Protein-in-adjuvant vaccines have shown limited success against difficult diseases such as blood-stage malaria. Here we show that a recombinant adenovirus–poxvirus prime-boost immunization regime (known to induce strong T cell immunogenicity) can also induce very strong antigen-specific...

  • Daily Plasmodium yoelii infective mosquito bites do not generate protection or suppress previous immunity against the liver stage. Pollock, Tzvi; Leitao, Ricardo; Galan-Rodriguez, Cristina; Wong, Kurt A.; Rodriguez, Ana // Malaria Journal;2011, Vol. 10 Issue 1, p97 

    Background: Human populations that are naturally subjected to Plasmodium infection do not acquire complete protection against the liver stage of this parasite despite prolonged and frequent exposure. However, sterile immunity against Plasmodium liver stage can be achieved after repeated exposure...

  • Modelos animales para la malaria cerebral y su aplicabilidad para la investigación de nuevos fármacos. Mendiola, Bárbara Judith // Revista de Ciências Farmacêuticas Básica e Aplicada;2012, Vol. 33 Issue 2, p189 

    Cerebral malaria is one of the most important complications of Plasmodium falciparum infections. Forty percent of the worldwide population is at risk of being infected of malaria. These infections produced approximately 243 millions of clinical cases and 863000 deaths in 2008, the majority of...

  • Plasmodium berghei ANKA causes intestinal malaria associated with dysbiosis. Taniguchi, Tomoyo; Miyauchi, Eiji; Nakamura, Shota; Hirai, Makoto; Suzue, Kazutomo; Imai, Takashi; Nomura, Takahiro; Handa, Tadashi; Okada, Hiroko; Shimokawa, Chikako; Onishi, Risa; Olia, Alex; Hirata, Jun; Tomita, Haruyoshi; Ohno, Hiroshi; Horii, Toshihiro; Hisaeda, Hajime // Scientific Reports;10/30/2015, p15699 

    Gastrointestinal symptoms, such as abdominal pain and diarrhea, are frequently observed in patients with Plasmodium falciparum malaria. However, the correlation between malaria intestinal pathology and intestinal microbiota has not been investigated. In the present study, infection of C57BL/6...

  • Pre-clinical evaluation of a P. berghei-based whole-sporozoite malaria vaccine candidate. Mendes, António M.; Reuling, Isaie J.; Andrade, Carolina M.; Otto, Thomas D.; Machado, Marta; Teixeira, Filipa; Pissarra, Joana; Gonçalves-Rosa, Nataniel; Bonaparte, Dolores; Sinfrónio, João; Sanders, Mandy; Janse, Chris J.; Khan, Shahid M.; Newbold, Chris I.; Berriman, Matthew; Lee, Cynthia K.; Wu, Yimin; Ockenhouse, Christian F.; Sauerwein, Robert W.; Prudêncio, Miguel // NPJ Vaccines;2018, Vol. 3 Issue 1, pN.PAG 

    Whole-sporozoite vaccination/immunization induces high levels of protective immunity in both rodent models of malaria and in humans. Recently, we generated a transgenic line of the rodent malaria parasite P. berghei (Pb) that expresses the P. falciparum (Pf) circumsporozoite protein (PfCS), and...

  • Alpha-tocopherol transfer protein gene inhibition enhances the acquired immune response during malaria infection in mice. Herbas, Maria; Natama, Magloire; Suzuki, Hiroshi // Parasitology Research;Mar2014, Vol. 113 Issue 3, p1019 

    Immune response to malaria infection is complex and seems to be regulated by innate and adaptive immune response as well as environmental factors such as host genetics and nutritional status. Previously, we have reported that α-tocopherol transfer protein knockout (α-ttp) mice, showing low...

  • Robust contour reconstruction of red blood cells and parasites in the automated identification of the stages of malarial infection. Kumarasamy, Saravana Kumar; Ong, S. H.; Tan, K. S. W. // Machine Vision & Applications;May2011, Vol. 22 Issue 3, p461 

    We present a novel method for detecting malaria parasites and determining the stage of infection from digital images comprising red blood cells (RBCs). The proposed method is robust under varying conditions of image luminance, contrast and clumping of RBCs. Both strong and weak boundary edges of...

  • Site-Specific Integration and Expression of an Anti-Malarial Gene in Transgenic Anopheles gambiae Significantly Reduces Plasmodium Infections. Meredith, Janet M.; Basu, Sanjay; Nimmo, Derric D.; Larget-Thiery, Isabelle; Warr, Emma L.; Underhill, Ann; McArthur, Clare C.; Carter, Victoria; Hurd, Hilary; Bourgouin, Catherine; Eggleston, Paul // PLoS ONE;2011, Vol. 6 Issue 1, p1 

    Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the...

  • A structural annotation resource for the selection of putative target proteins in the malaria parasite. Joubert, Yolandi; Joubert, Fourie // Malaria Journal;2008, Vol. 7, Special section p1 

    Background: Protein structure plays a pivotal role in elucidating mechanisms of parasite functioning and drug resistance. Moreover, protein structure aids the determination of protein function, which can together with the structure be used to identify novel drug targets in the parasite. However,...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics