IFN-γ protects hepatocytes against<i>Plasmodium vivax</i>infection via LAP-like degradation of sporozoites

Lelliott, Patrick M.; Coban, Cevayir

doi:10.1073/pnas.1607007113

Cited by 9 publications

(11 citation statements)

References 19 publications

(19 reference statements)

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“…Gene expression profiling of stem and progenitor cell populations highlighted the central role of interferon in driving the observed phenotypes. IFN-g is highly expressed in response to multiple strains of human and murine Plasmodium and it has an important role in controlling the strength of infection (Meding et al, 1990;John et al, 2004;Lelliott & Coban, 2016). It has, however, also been reported to mediate and exacerbate the disease itself, causing damage to the host (King & Lamb, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…To test the hypothesis obtained from the scRNAseq data, and to gain an indication of the strength of IFN signalling in the BM microenvironment, we measured the levels of IFN-g in the serum and BM supernatant of control and infected mice. We focused on IFN-g because this is the IFN type most widely associated with responses to Plasmodium infection in mice and humans (Meding et al, 1990;John et al, 2004;King & Lamb, 2015;Lelliott & Coban, 2016).…”

Section: (Supplementarymentioning

confidence: 99%

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Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

Haltalli

Watcham

Wilson

et al. 2018

Preprint

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Severe infections are a major source of stress on haematopoiesis, where consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow niches, which have been shown to be altered during ageing and haematopoietic malignancies. Whether the bone marrow (BM) microenvironment plays a role in mediating the effects of infection on HSCs remains an open question. Here we used an murine model of malaria coupled with intravital microscopy, single cell RNA-Seq, mathematical modelling and transplantation assays to obtain a quantitative understanding of the proliferation dynamics of haematopoietic stem and progenitor cells (HSPCs) during Plasmodium infection. We uncovered that during Plasmodium infection the HSC compartment turns over significantly faster than in steady state, and that a global interferon response and loss of functional HSCs are linked to alterations in BM endothelium function and osteoblasts number. Interventions that targeted osteoblasts uncoupled HSC proliferation and function, thus opening up new avenues for therapeutic interventions that may improve the health of survivors of severe infections.

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Section: Discussionmentioning

confidence: 99%

Section: (Supplementarymentioning

confidence: 99%

Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

Haltalli

Watcham

Wilson

et al. 2018

Preprint

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“…The IFN-γ responses seem to be important in early control of P. falciparum infection and protection against severe malaria ( Prakash et al, 2006 ). In fact, the peripheral levels of IFN-γ seem to reduce before onset of severe malaria symptoms in humans ( Lelliott and Coban, 2016 ). IFN-γ has recently found to inhibit the liver stage sporozoite invasion and the mechanism seems to be similar to LC3 associated phagocytosis in which primarily LC3 attaches to the membrane of vacuole containing pathogen leading to the fusion of lysosome and resulting in phagocytosis ( Lelliott and Coban, 2016 ).…”

Section: Indirect Interactionmentioning

confidence: 99%

“…In fact, the peripheral levels of IFN-γ seem to reduce before onset of severe malaria symptoms in humans ( Lelliott and Coban, 2016 ). IFN-γ has recently found to inhibit the liver stage sporozoite invasion and the mechanism seems to be similar to LC3 associated phagocytosis in which primarily LC3 attaches to the membrane of vacuole containing pathogen leading to the fusion of lysosome and resulting in phagocytosis ( Lelliott and Coban, 2016 ). Interleukin IL-18 has been shown to have a protective role during malaria infection which it mediates through the IFN-γ production ( Angulo and Fresno, 2002 ).…”

Section: Indirect Interactionmentioning

confidence: 99%

Host–Parasite Interactions in Human Malaria: Clinical Implications of Basic Research

et al. 2017

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The malaria parasite, Plasmodium, is one of the oldest parasites documented to infect humans and has proven particularly hard to eradicate. One of the major hurdles in designing an effective subunit vaccine against the malaria parasite is the insufficient understanding of host–parasite interactions within the human host during infections. The success of the parasite lies in its ability to evade the human immune system and recruit host responses as physiological cues to regulate its life cycle, leading to rapid acclimatization of the parasite to its immediate host environment. Hence understanding the environmental niche of the parasite is crucial in developing strategies to combat this deadly infectious disease. It has been increasingly recognized that interactions between parasite proteins and host factors are essential to establishing infection and virulence at every stage of the parasite life cycle. This review reassesses all of these interactions and discusses their clinical importance in designing therapeutic approaches such as design of novel vaccines. The interactions have been followed from the initial stages of introduction of the parasite under the human dermis until asexual and sexual blood stages which are essential for transmission of malaria. We further classify the interactions as “direct” or “indirect” depending upon their demonstrated ability to mediate direct physical interactions of the parasite with host factors or their indirect manipulation of the host immune system since both forms of interactions are known to have a crucial role during infections. We also discuss the many ways in which this understanding has been taken to the field and the success of these strategies in controlling human malaria.

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“…Autophagy (canonical or macroautophagy) is a cellular process that help cells to degrade and recycle their own components through an intracellular engulfment process which involves the formation of double membrane vesicles known as autophagosomes, which fuse with lysosomes for the final enzymatic digestion of components for their nutrient content [ 31 , 32 ] ( Figure 3 ). This final acidic lysosomal activity is a key step in autophagy and its neutralization by weak alkaline chloroquine, or inhibition with bafilomycin A1 (that inhibits the lysosomal proton pump) disturbs lysosomal function, and either event leads to the failure of autophagy.…”

Section: Introductionmentioning

confidence: 99%

The host targeting effect of chloroquine in malaria

Coban

2020

Current Opinion in Immunology

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Highlights Chloroquine/hydroxychloroquine is an old anti-malarial drug belongs to 4-aminoquinolines. Chloroquine has additional anti-virus, anti-bacteria, anti-protozoan, anti-autoimmunity and anti-cancer effects. Mechanism of action of chloroquine in malaria and other diseases is not understood well. Chloroquine directly targets Plasmodium hemoglobin degradation pathway. In addition, chloroquine may directly target host’s autophagy, innate and adaptive immunity in malaria.

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IFN-γ protects hepatocytes againstPlasmodium vivaxinfection via LAP-like degradation of sporozoites

Cited by 9 publications

References 19 publications

Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

Host–Parasite Interactions in Human Malaria: Clinical Implications of Basic Research

The host targeting effect of chloroquine in malaria

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