Sequestration and histopathology in
            <i>
              <scp>P</scp>
              lasmodium chabaudi
            </i>
            malaria are influenced by the immune response in an organ‐specific manner

Brugat, Thibaut; Cunningham, Deirdre; Sodenkamp, Jan; Coomes, Stephanie M.; Wilson, Mark S.; Spence, Philip J.; Jarra, William; Thompson, Joanne; Scudamore, Cheryl L.; Langhorne, Jean

doi:10.1111/cmi.12212

Cited by 72 publications

(120 citation statements)

References 50 publications

(94 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…Also blood leukocytes infiltrate the liver and produce inflammatory mediators thereby enhancing hepatic inflammation. A recent paper by Brugat et al confirmed the inflammatory etiology of liver pathology in Pc AS-infected C57BL/6 mice, as they found that the increase of serum ALT levels is abrogated in rag −/− and IFN-γ receptor −/− mice [23]. Furthermore, the liver also has an important role in the induction of immune tolerance and it produces high amounts of anti-inflammatory molecules.…”

Section: Discussionmentioning

confidence: 88%

Hemozoin Induces Hepatic Inflammation in Mice and Is Differentially Associated with Liver Pathology Depending on the Plasmodium Strain

et al. 2014

View full text Add to dashboard Cite

Malaria is a global disease that clinically affects more than two hundred million people annually. Despite the availability of effective antimalarials, mortality rates associated with severe complications are high. Hepatopathy is frequently observed in patients with severe malarial disease and its pathogenesis is poorly understood. Previously, we observed high amounts of hemozoin or malaria pigment in livers from infected mice. In this study, we investigated whether hemozoin is associated with liver injury in different mouse malaria models. C57BL/6J mice infected with the rodent parasites Plasmodium berghei ANKA, P. berghei NK65 or P. chabaudi AS had elevated serum liver enzymes without severe histological changes in the liver, in line with the observations in most patients. Furthermore, liver enzymes were significantly higher in serum of P. chabaudi AS-infected mice compared to mice infected with the P. berghei parasite strains and a strong positive correlation was found between hepatic hemozoin levels, hepatocyte damage and inflammation in the liver with P. chabaudi AS. The observed liver injury was only marginally influenced by the genetic background of the host, since similar serum liver enzyme levels were measured in infected C57BL/6J and BALB/c mice. Intravenous injection of P. falciparum-derived hemozoin in malaria-free C57BL/6J mice induced inflammatory gene transcription in the liver, suggesting that hemozoin may be involved in the pathogenesis of malaria hepatopathy by inducing inflammation.

show abstract

Section: Discussionmentioning

confidence: 88%

Hemozoin Induces Hepatic Inflammation in Mice and Is Differentially Associated with Liver Pathology Depending on the Plasmodium Strain

et al. 2014

View full text Add to dashboard Cite

show abstract

“…34,35 Liver damage has also been observed in mice infected with P. yoelii 17XNL, Plasmodium chabaudi, and Plasmodium berghei. [36][37][38] In particular, apoptosis of hepatocytes has been shown to be induced by infection-associated oxidative stress and liver metabolic dysfunction can result from immunopathology during malaria. 39,40 The spleen is crucial to clearance of Plasmodiuminfected RBCs.…”

Section: Resultsmentioning

confidence: 99%

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Glennon¹,

Adams²,

Hicks³

et al. 2016

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Nearly half of the world's population is at risk for malaria. Increasing drug resistance has intensified the need for novel therapeutics, including treatments with intrinsic transmission-blocking properties. In this study, we demonstrate that the isoprenoid abscisic acid (ABA) modulates signaling in the mammalian host to reduce parasitemia and the formation of transmissible gametocytes and in the mosquito host to reduce parasite infection. Oral ABA supplementation in a mouse model of malaria was well tolerated and led to reduced pathology and enhanced gene expression in the liver and spleen consistent with infection recovery. Oral ABA supplementation also increased mouse plasma ABA to levels that can signal in the mosquito midgut upon blood ingestion. Accordingly, we showed that supplementation of a Plasmodium falciparum-infected blood meal with ABA increased expression of mosquito nitric oxide synthase and reduced infection prevalence in a nitric oxide-dependent manner. Identification of the mechanisms whereby ABA reduces parasite growth in mammals and mosquitoes could shed light on the balance of immunity and metabolism across eukaryotes and provide a strong foundation for clinical translation.

show abstract

“…Liver is one of organs in which iRBCs preferentially accumulate to avoid immune system surveillance inside the spleen, and iRBC sequestration within the liver endothelium is now emerging as another factor that promotes liver damage [40][41][42]. Several studies suggest that iRBC sequestration contributes to the intrahepatic obstruction of blood flow, which leads to hepatocellular hypoxia and excessive intravascular hemolysis, causing increased oxidative stress and leukocyte infiltration [40,[43][44][45]. Infiltrated leukocytes also produce inflammatory mediators, thereby enhancing hepatic inflammation [43,46].…”

Section: Discussionmentioning

confidence: 99%

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Kim

Wang

Lee

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver’s response to malarial infection. Methods: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. Results: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. Conclusion: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

show abstract

Sequestration and histopathology in P lasmodium chabaudi malaria are influenced by the immune response in an organ‐specific manner

Cited by 72 publications

References 50 publications

Hemozoin Induces Hepatic Inflammation in Mice and Is Differentially Associated with Liver Pathology Depending on the Plasmodium Strain

Hemozoin Induces Hepatic Inflammation in Mice and Is Differentially Associated with Liver Pathology Depending on the Plasmodium Strain

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Contact Info

Product

Resources

About