Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF- B Activation and Inducible NO Synthase Expression (original) (raw)
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Infection and immunity, 1997
The elimination of liver-stage malaria parasites by nitric oxide (NO)-producing hepatocytes is regulated by T cells. Both CD8 ؉ and CD4 ؉ T cells, which surround infected hepatocytes, are evident by 24 h after sporozoite challenge in Brown Norway rats previously immunized with irradiated Plasmodium berghei sporozoites. While the number of CD4 ؉ T cells remained the same beyond 24 h postchallenge, the number of CD8 ؉ T cells increased three-and sixfold by 31 and 44 h, respectively. This increase in the number of CD8 ؉ T cells correlated with a decrease in the number of intrahepatic parasites. In immunized rats, intrahepatic parasites were reduced in number by 31 h after sporozoite challenge and cleared from the liver by 44 h, as visualized by P. berghei-specific DNA in situ hybridization. If immunized rats were treated with aminoguanidine, a substrate inhibitor of NO synthase, at the time of challenge, liver-stage protection was blocked, as shown by the increase in parasite liver burden. Further histological examination of infected livers from immunized animals treated with aminoguanidine revealed fewer and smaller cellular infiltrates surrounding the infected hepatocytes, and the number of CD8 ؉ T cells that normally accumulate within the infiltrates was drastically reduced. Consequently, the infected hepatocytes were not cleared from the liver. We hypothesize that the early production of NO may promote the influx and/or enhance local proliferation of malaria parasite-specific CD8 ؉ T cells or a CD8 ؉ T-cell subset which is required for parasite clearance.
Microbes and Infection, 2013
Infection of mice with Plasmodium berghei NK65 represents a well-recognized malaria model in which infection is accompanied by an intense hepatic inflammatory response. Enzyme-inducible nitric oxide synthase is an important regulator of inflammation and leukocyte recruitment in microvessels, but these functions have yet to be evaluated in experimental malaria. In this study, we assessed the involvement of inducible nitric oxide synthase in inflammatory responses to murine experimental malaria induced by P. berghei NK65. We observed that wild type (WT) and nitric oxide synthase (iNOS)-deficient mice (iNOS À/À ) mice showed similar levels of parasitemia following P. berghei NK65 infection, although infected iNOS À/À mice presented early mortality. Inducible nitric oxide synthase deficiency led to increased leukocyte rolling and adhesion to the liver in iNOS À/À mice relative to the WT animals, as observed via intravital microscopy. Infected iNOS À/À mice also exhibited increased hepatic leukocyte migration and subsequent liver damage, which was associated with high serum levels of the cytokines TNF-a, IL-6 and IL-10. Our data suggest potential role for the iNOS enzyme as a regulator of hepatic inflammatory response induced by P. berghei NK65-infection, and its absence leads to exacerbated inflammation and sequential associated-hepatic damage in the animals.
NO as an affector molecule of parasite killing: modulation of its synthesis by cytokines
Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology, 1994
It has recently been appreciated that NO, a molecule previously known to play a physiologic role in blood pressure regulation, is a major effector molecule of macrophage cytotoxicity against a variety of microbial targets, including protozoan and helminth parasites. NO production by macrophages is argininc dependent and catalyzed by a cytokine-indncible form of the NO synthase. This activity is positively controlled by several up-regulatory stimuli (including IFN-y, TNF-~, IL-2) and negatively controlled by others (principally IL-10, IL-4, TGF-~). Other cell types, such as endothelial cells and hepatocytes, display a similar capacity for NO production in response to cytokine stimulation. In murine models of leishmaniasis and schistosomiasis, in vivo NO synthesis correlates with protective immunity against infection. The effector molecule that plays a similar role in cell-mediated immunity in man has not yet been identified.
Cytokines and nitric oxide as effector molecules against parasitic infections
Philosophical Transactions of the Royal Society B: Biological Sciences, 1997
Nitric oxide (NO) derived from L-arginine by the catalytic action of inducible NO synthase (iNOS) plays an important role in killing parasites. Many cell types express high levels of iNOS when activated by a number of immunological stimuli which include interferon-gamma (IFN-), tumour necrosis factor alpha, and lipopolysaccharide. IFN-is typically produced by the Th1 subset of CD4+ T cells, whose di¡erentiation depends on interleukin-12 (IL-12) produced by macrophages. Mice with a disrupted iNOS gene were highly susceptible to Leishmania major infection compared with similarly infected control wild-type mice.The mutant mice developed signi¢cantly higher levels of TH1-cell response compared with the control mice, suggesting that NO is likely to be the e¡ector molecule in the immunological control of this and other intracellular parasitic infections. To ensure their survival, the Leishmania parasites have evolved e¡ective means to inhibit NO synthesis. The highly conserved major surface glycolipids, glycoinositol-phospholipids and lipophosphoglycan (LPG), of Leishmania are potent inhibitors of NO synthesis. Furthermore, LPG can also inhibit IL-12 synthesis, thereby indirectly blocking the induction of iNOS. The evolutionary and therapeutic implications of these ¢ndings are discussed.
Hepatocyte growth factor and its receptor are required for malaria infection
Nature Medicine, 2003
Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. Sporozoites migrate through several hepatocytes, by breaching their plasma membranes, before infection is finally established in one of them. Here we show that wounding of hepatocytes by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploits MET not as a primary binding site, but as a mediator of signals that make the host cell susceptible to infection. HGF/MET signaling induces rearrangements of the host-cell actin cytoskeleton that are required for the early development of the parasites within hepatocytes. Our findings identify HGF and MET as potential targets for new approaches to malaria prevention. NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1363
Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens
Immunology Letters, 1994
ence and quantity of IFN-y at the time of infection. The relationship between NO production in vivo and host resistance to infection was demonstrated with M. bovis (BCG). These studies confirmed that both IFN-y and TNF are required for induction of NO-mediated nonspecific host defense in vivo. The presumed source of NO in these studies was the activated macrophage, however, other cells infected with parasites can also be stimulated to produce NO. In studying acquired immunity to malaria induced by irradiated sporozoites, we found that IFN-y provided by malaria-specific CD8 ÷ T cells stimulated sporozoite-infected hepatocytes to produce NO for destruction of either infected hepatocytes or the parasite, P. berghei, within these cells.
Cytokine genes expression in mice hepatocytes during malaria infection
The aim of this study was to investigate the inflammation genes (IL-1β, IL-6, TNF-α and iNos) responses to Plasmodium chabaudi malaria in the liver of female C57BL/6 hepatocytes via mRNA expression due to infection with P. chabaudi at different time points. Mice were injected intraperitoneally (ip) with 10 6 P. chabaudi-infected erythrocytes and then scarified at days (0, 1, 4 and 8 respectively). RT-PCR was used to quantify liver inflammation genes. The levels of IL-1β, IL-6 and TNFα were significantly increased at days 1 and 8. The total iNos were significantly increased at all days after infection. In conclusion, present data has shown that infection with P. chabaudi stimulated infalammation genes in the liver. Thus, we suggest the implication of oxidative stress due to outcome of malaria in mice hepatocytes according to its natural function need to be confirmed with a larger number of samples to be used as a reliable inflammation detection method.