Biology subjects

Marques-da-Silva, C.

Publications and source records attributed to Marques-da-Silva, C..

4 recordsLinked to original sources

bioRxiv2024

Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria

Plasmodium parasites undergo development and replication within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1 disruption of the PV activates caspase-1 inflammasome, inducing pyroptosis to remove the infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium; their pharmacologic or genetic inhibition led to profound malarial susceptibility, and are essential in vivo. In addition to identifying the IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, this study extends our understanding of how non-immune cells are integral to protective immunity against malaria.

immunology↗

bioRxiv2023

Inherently reduced expression of ASC restricts caspase-1 processing in hepatocytes and promotes Plasmodium infection

Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in the hepatocytes and precludes the generation of mature IL-1{beta} or IL-18, unlike in other cells. Why this is so, or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule ASC (apoptosis-associated speck-like protein containing CARD) is responsible for the incomplete proteolytic processing of caspase-1 in hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell-death, maturation of the proinflammatory cytokines IL-1{beta} and IL-18 that was otherwise absent, and resulted in better overall control of Plasmodium infection in the liver mice. This however impeded the protection offered by live-attenuated anti-malarial vaccination. Tempering ASC expression in macrophages on the other hand resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.

immunology↗

bioRxiv2022

Direct type I Interferon signaling in hepatocytes control malaria

Malaria is a devastating disease impacting over half of the worlds population. Plasmodium parasites that cause malaria undergo obligatory development and replication in hepatocytes before infecting red blood cells and initiating clinical disease. While type I interferons (IFNs) are known to facilitate innate immune control to Plasmodium in the liver, how they do so has remained unresolved, preventing the manipulation of such responses to combat malaria. Utilizing transcriptomics, infection studies, and a novel transgenic Plasmodium strain that exports and traffics Cre recombinase, we show that direct type I IFN signaling in Plasmodium-infected hepatocytes is necessary and sufficient to control malaria. We also show that the majority of infected hepatocytes naturally eliminate Plasmodium infection, revealing the potential existence of anti-malarial cell-autonomous immune responses in such hepatocytes. These discoveries challenge the existing paradigms in Plasmodium immunobiology and are expected to inspire new anti-malarial drugs and vaccine strategies.

immunology↗

bioRxiv2021

Altered cleavage of Caspase-1 in hepatocytes limits control of malaria in the liver

Malaria, caused by Plasmodium parasites, is a devastating disease that kills over half a million people each year1. Plasmodium sporozoites inoculated by mosquitoes into mammalian hosts undergo a clinically silent phase of obligatory development and replication in hepatocytes before initiating the life-threatening blood-stage of malaria2. Thus, understanding the immune responses elicited by Plasmodium infection in the liver is key to controlling clinical malaria and transmission3,4. Here, we show that Plasmodium DNA can be detected by AIM2 (absent in melanoma 2) sensors in the infected hepatocytes, resulting in Caspase-1 activation and pyroptotic cell-death. However, Caspase-1 was observed to undergo only partial cleavage in hepatocytes, limiting pyroptosis, and the maturation of pro-inflammatory cytokines classically associated with Caspase-1 activation. We discovered that the extent of Caspase-1 cleavage in cells is determined by the expression of ASC (apoptosis-associated speck-like protein containing a CARD). ASC expression is inherently low in hepatocytes, and transgenically enhancing it in the hepatocytes induced complete processing of Caspase-1, efficient secretion of pro-inflammatory cytokines, enhanced pyroptotic cell-death, and markedly improved control of malaria infection in the liver. In addition to describing a novel pathway of natural immunity to malaria, our findings uncover a key aspect of liver biology that may have been exploited during evolution by successful hepatotropic pathogens.

immunology↗