Blood-stage malaria of Plasmodium chabaudi induces differential Tlr expression in the liver of susceptible and vaccination-protected Balb/c mice

ABSTRACT The killing of blood-stage malaria parasites in vivo has been attributed to reactive intermediates of oxygen (ROI) and of nitrogen (RNI). However, in the case of the latter, this contention is challenged by recent observations that parasitemia was not exacerbated in nitric oxide synthase (NOS) knockout (KO) (NOS2−/− or NOS3−/−) mice or in mice treated with NOS inhibitors. We now report that the time course shows that Plasmodium chabaudi parasitemia in NADPH oxidase KO (p47phox−/−) mice also was not exacerbated, suggesting a minimal role for ROI-mediated killing of blood-stage parasites. It is possible that the production of protective antibodies during malaria may mask the function of ROI and/or RNI. However, parasitemia in B-cell-deficient JH −/− × NOS2−/− or JH −/− × p47phox−/− mice was not exacerbated. In contrast, the magnitude of peak parasitemia was significantly enhanced in p47phox−/− mice treated with the xanthine oxidase inhibitor allopurinol, but the duration of patent parasitemia was not prolonged. Whereas the time course of parasitemia in NOS2−/− × p47phox−/− mice was nearly identical to that seen in normal control mice, allopurinol treatment of these double-KO mice also enhanced the magnitude of peak parasitemia. Thus, ROI generated via the xanthine oxidase pathway contribute to the control of ascending P. chabaudi parasitemia during acute malaria but alone are insufficient to suppress parasitemia to subpatent levels. Together, these results indicate that ROI or RNI can contribute to, but are not essential for, the suppression of parasitemia during blood-stage malaria.

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Differential miRNA Expression in the Liver of Balb/c Mice Protected by Vaccination during Crisis of Plasmodium chabaudi Blood-Stage Malaria

Frontiers in Microbiology ◽

10.3389/fmicb.2016.02155 ◽

2017 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Mohamed A. Dkhil ◽

Saleh A. Al-Quraishy ◽

Abdel-Azeem S. Abdel-Baki ◽

Denis Delic ◽

Frank Wunderlich

Keyword(s):

Mirna Expression ◽

Blood Stage ◽

Plasmodium Chabaudi ◽

Blood Stage Malaria

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Faculty Opinions recommendation of The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14264093.15777219 ◽

2012 ◽

Author(s):

Robert Menard ◽

Daniel Youssef Bargieri

Keyword(s):

Neutralizing Antibody ◽

Blood Stage ◽

Malaria Antigen ◽

Blood Stage Malaria

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Immunogenicity and structural efficacy of P41 of Plasmodium sp. as potential cross-species blood-stage malaria vaccine

Computational Biology and Chemistry ◽

10.1016/j.compbiolchem.2021.107493 ◽

2021 ◽

Vol 92 ◽

pp. 107493

Author(s):

Kevin Nathanael Ramanto ◽

Rizky Nurdiansyah

Keyword(s):

Malaria Vaccine ◽

Blood Stage ◽

Blood Stage Malaria

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The Structure of the Cysteine-Rich Domain of Plasmodium falciparum P113 Identifies the Location of the RH5 Binding Site

mBio ◽

10.1128/mbio.01566-20 ◽

2020 ◽

Vol 11 (5) ◽

Author(s):

Ivan Campeotto ◽

Francis Galaway ◽

Shahid Mehmood ◽

Lea K. Barfod ◽

Doris Quinkert ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Binding Site ◽

Structural Information ◽

Blood Stage ◽

Site Directed Mutagenesis ◽

Effective Vaccine ◽

Binding Region ◽

Fab Fragment ◽

Content Type ◽

Blood Stage Malaria

ABSTRACT Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA, and RIPR can inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or noninhibitory for RH5 binding. Using a Fab fragment as a crystallization chaperone, we determined the crystal structure of the RH5 binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in guiding the development of blood-stage malaria vaccines that target RH5. IMPORTANCE Malaria is a deadly infectious disease primarily caused by the parasite Plasmodium falciparum. It remains a major global health problem, and there is no highly effective vaccine. A parasite protein called RH5 is centrally involved in the invasion of host red blood cells, making it—and the other parasite proteins it interacts with—promising vaccine targets. We recently identified a protein called P113 that binds RH5, suggesting that it anchors RH5 to the parasite surface. In this paper, we use structural biology to locate and characterize the RH5 binding region on P113. These findings will be important to guide the development of new antimalarial vaccines to ultimately prevent this disease, which affects some of the poorest people on the planet.

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