Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis.

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes.

DNA damage independent inhibition of NF-κB transcription by anthracyclines.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse () macrophages.

A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage.

Malaria infection involves an obligatory, yet clinically silent liver stage. Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis, but the effects of hepatocyte zonation on parasite development at the molecular level remain unknown. Here we combine single-cell RNA sequencing and single-molecule transcript imaging to characterize the host and parasite temporal expression programmes in a zonally controlled manner for the rodent malaria parasite Plasmodium berghei ANKA.

The reciprocal influence of the liver and blood stages of the malaria parasite's life cycle.

While the liver and blood stages of the Plasmodium life cycle are commonly regarded as two separate fields of malaria research, several studies have pointed towards the existence of a bidirectional cross-talk, where one stage of mammalian infection may impact the establishment and progression of the other. Despite the constraints in experimentally addressing concurrent liver and blood stage Plasmodium infections, animal models and clinical studies have unveiled a plethora of molecular interactions between the two. Here, we review the current knowledge on the reciprocal influence of hepatic and erythrocytic infection by malaria parasites, and discuss its impacts on immunity, pathology and vaccination against this deadly disease.

Elimination of Hepatic Rodent Parasites by Amino Acid Supplementation.

parasites, causative agents of malaria, scavenge host nutrients to sustain their intracellular replication. Modulation of the host's nutritional status can potentially help control infection by limiting the parasite's access to nutrients, or by boosting the immune system. Here, we show that dietary supplementation of mice employing a combination of arginine (R) with two additional amino acids, lysine (K) and valine (V), termed RKV, significantly decreases liver infection.

Disrupting Plasmodium UIS3-host LC3 interaction with a small molecule causes parasite elimination from host cells.

The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner.

Microbiota, a Third Player in the Host-Plasmodium Affair.

Plasmodium, the causative agent of malaria, is responsible for more than 200 million new infections and 400 000 deaths yearly. While in recent years the influence of the microbiota in homeostasis and a wide variety of disorders has taken center stage, its contribution during malaria infections has only now started to emerge. The few published studies suggest two distinct but complementary directions.

Dietary alterations modulate susceptibility to Plasmodium infection.

The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency . However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection . Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%.

Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.

Before they infect red blood cells and cause malaria, Plasmodium parasites undergo an obligate and clinically silent expansion phase in the liver that is supposedly undetected by the host. Here, we demonstrate the engagement of a type I interferon (IFN) response during Plasmodium replication in the liver. We identified Plasmodium RNA as a previously unrecognized pathogen-associated molecular pattern (PAMP) capable of activating a type I IFN response via the cytosolic pattern recognition receptor Mda5.