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Fulltext Expression of full-length Plasmodium falciparum P48/45 in P. berghei blood stages: A method to express and evaluate vaccine antigens

Othman AS, Lin JW, Franke-Fayard BM, Kroeze H, van Pul FJA, Chevalley-Maurel S, et al.

Mol Biochem Parasitol, 2018 Sep;224:44-49.
PMID: 30053393 DOI: 10.1016/j.molbiopara.2018.07.009

The transmission-blocking vaccine candidate Pfs48/45 from the human malaria parasite Plasmodium falciparum is known to be difficult to express in heterologous systems, either as full-length protein or as correctly folded protein fragments that retain conformational epitopes. In this study we express full-length Pfs48/45 in the rodent parasite P. berghei. Pfs48/45 is expressed as a transgene under control of the strong P. berghei schizont-specific msp1 gene promoter (Pfs48/45@PbMSP1). Pfs48/45@PbMSP1 schizont-infected red blood cells produced full-length Pfs48/45 and the structural integrity of Pfs48/45 was confirmed using a panel of conformation-specific monoclonal antibodies that bind to different Pfs48/45 epitopes. Sera from mice immunized with transgenic Pfs48/45@PbMSP1 schizonts showed strong transmission-reducing activity in mosquitoes infected with P. falciparum using standard membrane feeding. These results demonstrate that transgenic rodent malaria parasites expressing human malaria antigens may be used as means to evaluate immunogenicity and functionality of difficult to express malaria vaccine candidate antigens.

Matched MeSH terms: Plasmodium berghei/genetics*
Pathologic activity of Plasmodium berghei prevented but not reversed by dexamethasone

Franz DR, Lim TS, Baze WB, Arimbalam S, Lee M, Lewis GE

Am J Trop Med Hyg, 1988 Mar;38(2):249-54.
PMID: 3281490

Dexamethasone has recently been shown to block the production of cachectin (implicated in the pathogenesis of cerebral malaria) if administered prior to endotoxin induction of mouse macrophages. Using the hamster cheek pouch-cerebral malaria model, we tested the hypothesis that dexamethasone is effective as a therapeutic agent in severe malaria if given before some yet undefined trigger point in the disease. Infected hamsters were treated with dexamethasone (0.7 mg/kg) daily on days 7-12, 4-12, or 1-12 post-challenge. When treatment was started on day 1, whole body oxygen consumption (used as a measure of erythrocyte transport to sites of diffusion) on day 12 was greater than (P less than 0.05) that of infected control animals, though the degree of anemia was no different in treated and untreated groups. Furthermore, treatment produced a reduction in monocyte accumulation, capillary malfunction, and monocyte/red blood cell aggregate formation observable in the cheek pouch in vivo and a similar reduction in monocyte presence, capillary pathologic change, and multifocal hemorrhage in the brain on postmortem. These data suggest that mediator(s), whose production can be blocked by pretreatment with dexamethasone, are involved in the pathogenesis of disease leading to death of the Plasmodium berghei infected hamster.

Matched MeSH terms: Plasmodium berghei/immunology
Effects of testosterone on blood leukocytes in plasmodium berghei-infected mice

Kamis AB, Ibrahim JB

Parasitol Res, 1989;75(8):611-3.
PMID: 2671986

Gonadectomized male mice aged 5 weeks were given 5 mg testosterone propionate daily for 14 days. The treatment significantly decreased the number of blood leukocytes. The number of all individual types of leukocytes except basophils in vehicle-treated gonadectomized mice was increased. Testosterone-treated mice consistently had a lower number of leukocytes after being infected with Plasmodium berghei than did vehicle-treated mice. The results suggest that testosterone suppresses the production of leukocytes and that testosterone-treated mice become more susceptible to parasite infection.

Matched MeSH terms: Plasmodium berghei
Histopathology of Brugia pahangi and Plasmodium berghei ANKA co-infection in the Gerbil (Meriones unguiculatus)

Junaid OQ, Wong KT, Khaw LT, Mahmud R, Vythilingam I

Trop Biomed, 2018 Dec 01;35(4):981-998.
PMID: 33601846

Co-infection with multiple different parasites is a common phenomenon in both human and animals. Among parasites that frequently co-infect the same hosts, are the filarial worms and malaria parasites. Despite this, the mechanisms underlying the interactions between these parasites is still relatively unexplored with very few studies available on the resulting pathologies due to co-infection by filarial nematodes and malaria parasites. Hence, this study investigated the histopathological effect of Brugia pahangi and Plasmodium berghei ANKA (PbA) infections in gerbil host. Gerbils grouped into B. pahangi-infected, PbA-infected, B. pahangi and PbA-coinfected, and uninfected control, were necropsied at different time points of post PbA infections. Brugia pahangi infections in the gerbils were first initiated by subcutaneous inoculation of 50 infective larvae, while PbA infections were done by intraperitoneal injection of 106 parasitized red blood cells after 70 days patent period of B. pahangi. Organs such as the lungs, kidneys, spleen, heart and liver were harvested aseptically at the point of necropsy. There was significant hepatosplenomegaly observed in both PbA-infected only and coinfected gerbils. The spleen, liver and lungs were heavily pigmented. Both B. pahangi and PbA infections (mono and coinfections) resulted in pulmonary edema, while glomerulonephritis was associated with PbA infections. The presence of both parasites induced extramedullary hematopoiesis in the spleen and liver. These findings suggest that the pathologies associated with coinfected gerbils were synergistically induced by both B. pahangi and PbA infections.

Matched MeSH terms: Plasmodium berghei
Changes in hepatic phosphoprotein levels in mice infected with Plasmodium berghei

Maniam P, Zainal Abidin Abu Hassan, Noor Embi, Hasidah Mohd Sidek

Sains Malaysiana, 2012;41:721-729.

Hepatic phosphoprotein levels are altered in mouse liver as a manifestation of bacteria, virus or parasite infection. Identification of signaling pathways mediated by these hepatic proteins contribute to the current understanding of the mechanism of pathogenesis in malarial infection. The present study was undertaken to evaluate the changes in hepatic phosphoprotein levels during Plasmodium berghei infection. Our study revealed changes in levels of three hepatic phosphoproteins following P. berghei infection compared to non-infected controls. Peptide fragment sequence analysis using tandem mass spectrometry (MS/MS) showed these hepatic proteins to be homologs to haemoglobin beta (HBB), class
Pi glutathione S-tranferase (GSTPi) and carbonic anhydrase III (CAIII) proteins of Mus musculus species respectively from the NCBInr sequence database. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis predicted the involvement of these proteins in specific pathways in Mus musculus species; GSTPi in glutathione and drug metabolism and CAIII in nitrogen metabolism. This shows that P. berghei infection affects similar signaling pathways as those reported in other pathogenic infections such as that related to GSTPi and CAIII in response to oxidative stress.

Matched MeSH terms: Plasmodium berghei
Fulltext The Antimalarial properties of essential oils of The Leaves of Malaysian Plectranthus Amboinicus (Lour) Spreng in Mice infected with Plasmodium Berghei

Norazsida, R., Pakeer, O., Taher, M.

International Medical Journal Malaysia, 2017;16(1):67-74.
MyJurnal

This study was conducted to evaluate the phytochemical contents and antimalarial properties of the oils extracted from the leaves of Malaysian Plectranthus amboinicus in mice infected with Plasmodium berghei. The essential oils were extracted and prepared by using steam distillation technique and subjected to phytochemical screening by using GC-MS. Antimalarial activity of different extract doses of the essential oil was tested in vivo in ICR mice infected with Plasmodium berghei (PZZ1/100) during early, established and residual infections. In all, 5 compounds made up 88.34% of total oil and the major chemical compounds were carvacrol (85.14%), thymoquinone (1.65%), terpinen-4-ol (0.70%), octenol (0.62%) and thymol (0.23%). Antimalarial assay showed this essential oil as a potential prophylactic agent with the percentage chemosuppression of 45.23%, 18.28%, 45.38% and 58.26% while treated with 50, 200, 400 and 1000 µL/kg respectively of essential oil and curative agent with percentage of chemo suppression of 54.10%, 47.35%, 56.75% and 65.38% while treated with the above dose of essential oil. Statistically no reduction of parasitemia was calculated for suppressive test. The extract has prophylactic and curative effects on P.berghei in mice

Matched MeSH terms: Plasmodium berghei
Fulltext TREM-1 modulation produces positive outcome on the histopathology and cytokines release profile of Plasmodium berghei-infected mice

Chin VK, Asyran AMY, Zakaria ZA, Abdullah WO, Chong PP, Nordin N, et al.

J Parasit Dis, 2019 Mar;43(1):139-153.
PMID: 30956457 DOI: 10.1007/s12639-018-1070-3

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potential molecular therapeutic target for various inflammatory diseases. Despite that, the role of TREM-1 during malaria pathogenesis remains obscure with present literature suggesting a link between TREM-1 with severe malaria development. Therefore, this study aims to investigate the role of TREM-1 and TREM-1 related drugs during severe malaria infection in Plasmodium berghei-infected mice model. Our findings revealed that TREM-1 concentration was significantly increased throughout the infection periods and TREM-1 was positively correlated with malaria parasitemia development. This suggests a positive involvement of TREM-1 in severe malaria development. Meanwhile, blocking of TREM-1 activation using rmTREM-1/Fc and TREM-1 clearance by mTREM-1/Ab had significantly reduced malaria parasitemia and suppressed the production of pro- inflammatory cytokines (TNF-α, IL-6 and IFN-γ) and anti-inflammatory cytokine (IL-10). Furthermore, histopathological analysis of TREM-1 related drug treatments, in particular rmTREM-1/Fc showed significant improvements in the histological conditions of major organs (kidneys, spleen, lungs, liver and brain) of Plasmodium berghei-infected mice. This study showed that modulation of TREM-1 released during malaria infection produces a positive outcome on malaria infection through inhibition of pro-inflammatory cytokines secretion and alleviation of histopathological conditions of affected organs. Nevertheless, further investigation on its optimal dosage and dose dependant study should be carried out to maximise its full potential as immunomodulatory or as an adjuvant in line with current antimalarial agents.

Matched MeSH terms: Plasmodium berghei
Fulltext Pathogenesis of Plasmodium berghei ANKA infection in the gerbil (Meriones unguiculatus) as an experimental model for severe malaria

Junaid QO, Khaw LT, Mahmud R, Ong KC, Lau YL, Borade PU, et al.

Parasite, 2017;24:38.
PMID: 29034874 DOI: 10.1051/parasite/2017040

BACKGROUND: As the quest to eradicate malaria continues, there remains a need to gain further understanding of the disease, particularly with regard to pathogenesis. This is facilitated, apart from in vitro and clinical studies, mainly via in vivo mouse model studies. However, there are few studies that have used gerbils (Meriones unguiculatus) as animal models. Thus, this study is aimed at characterizing the effects of Plasmodium berghei ANKA (PbA) infection in gerbils, as well as the underlying pathogenesis.
METHODS: Gerbils, 5-7 weeks old were infected by PbA via intraperitoneal injection of 1 × 106 (0.2 mL) infected red blood cells. Parasitemia, weight gain/loss, hemoglobin concentration, red blood cell count and body temperature changes in both control and infected groups were monitored over a duration of 13 days. RNA was extracted from the brain, spleen and whole blood to assess the immune response to PbA infection. Organs including the brain, spleen, heart, liver, kidneys and lungs were removed aseptically for histopathology.
RESULTS: Gerbils were susceptible to PbA infection, showing significant decreases in the hemoglobin concentration, RBC counts, body weights and body temperature, over the course of the infection. There were no neurological signs observed. Both pro-inflammatory (IFNγ and TNF) and anti-inflammatory (IL-10) cytokines were significantly elevated. Splenomegaly and hepatomegaly were also observed. PbA parasitized RBCs were observed in the organs, using routine light microscopy and in situ hybridization.
CONCLUSION: Gerbils may serve as a good model for severe malaria to further understand its pathogenesis.

Matched MeSH terms: Plasmodium berghei/physiology*
GSK3β: A plausible molecular target in the cytokinemodulating effect of exogenous insulin in a murine model of malarial infection

Aizuddin NNF, Ganesan N, Ng WC, Ali AH, Ibrahim I, Basir R, et al.

Trop Biomed, 2020 Dec 01;37(4):1105-1116.
PMID: 33612762 DOI: 10.47665/tb.37.4.1105

Malaria is a life-threatening disease caused by the Plasmodium sp. parasite. Infection results in heightened pro-inflammatory response which contributes to the pathophysiology of the disease. To mitigate the overwhelming cytokine response, host-directed therapy is a plausible approach. Glycogen synthase kinase-3β (GSK3β), a serine/threonine kinase plays a pivotal role in the regulation of inflammatory response during pathogenic infections. The present study was conducted to investigate the chemo-suppressive and cytokine-modulating effects of insulin administration in malaria-infected mice and the involvement of GSK3β. Intraperitoneal administrations of 0.3 and 0.5 U/kg body weight insulin each for four consecutive days into Plasmodium berghei NK65 (PbN)-infected mice resulted in chemo-suppression exceeding 60% and improved median survival time of infected mice (20.5 days and 19 days respectively compared to 15.5 days for non-treated control). Western analysis revealed that pGSK3β (Ser9) intensity in brain samples from insulin-treated (0.3 and 0.5 U/kg body weight) infected mice each were 0.6 and 2.2 times respectively than that in control. In liver samples, pGSK3β (Ser9) intensity from insulin-treated infected mice were significantly higher (4.8 and 16.1 fold for 0.3 and 0.5 U/kg bw respectively) than that in control. Insulin administration decreased both brain and liver pNF-κB p65 (Ser536) intensities (to 0.8 and 0.6 times for 0.3 U/kg bw insulin; and to 0.2 and 0.1 times for 0.5 U/kg bw insulin respectively compared to control). Insulin treatment (0.5 U/kg bw) also significantly decreased the serum levels of pro-inflammatory cytokines (TNF-α (3.3 times) and IFN-γ (4.9 times)) whilst significantly increasing the levels of anti-inflammatory cytokines (IL-4 (4.9 fold) and IL-10 (2.1 fold)) in PbN-infected mice. Results from this study demonstrated that the cytokinemodulating effects of insulin at least in part involve inhibition of GSK3β and consequent inhibition of the activation of NF-κB p65 suggesting insulin as a potential adjunctive therapeutic for malaria.

Matched MeSH terms: Plasmodium berghei
Fulltext Median lethal dose, antimalarial activity, phytochemical screening and radical scavenging of methanolic Languas galanga rhizome extract

Al-Adhroey AH, Nor ZM, Al-Mekhlafi HM, Mahmud R

Molecules, 2010 Nov 16;15(11):8366-76.
PMID: 21081857 DOI: 10.3390/molecules15118366

The methanolic extract of Languas galanga rhizomes was investigated for antimalarial activity against Plasmodium berghei (NK65) infections in mice. The median lethal dose was determined to ascertain the safety of the extract in ICR mice of both sexes. The antimalarial activities during early and established infections, as well as the prophylactic activity were evaluated. Phytochemical screening and radical scavenging activity of the extract were also investigated to elucidate the possible mechanism of the antimalarial properties. The acute oral toxicity (LD₅₀) of Languas galanga extract in mice was established to be 4.998 mg/kg. The extract of Languas galanga rhizomes demonstrated significant antiplasmodial activity in all the three models of the antimalarial evaluations. Phytochemical screening revealed the presence of some vital antiplasmodial constituents such as terpenoids and flavonoids. The extract also exhibited a moderate capacity to scavenge the free radicals. The rhizome extract of Languas galanga thus possesses antimalarial activity, which explains the rational usage of this plant in traditional Malaysian medicine.

Matched MeSH terms: Plasmodium berghei

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