Malaria parasite liver stages
2021; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês
10.1016/j.jhep.2021.05.034
ISSN1600-0641
AutoresDebashree Goswami, Nana Minkah, Stefan H.I. Kappe,
Tópico(s)Hepatitis B Virus Studies
ResumoMalaria, caused by Plasmodium (P.) parasite species, poses a significant global health burden. There were 229 million malaria cases reported in 2019 and 95% of the 409,000 global malaria-caused fatalities occurred in sub-Saharan Africa (World Malaria Report 2020). Infection of the human host begins with a Plasmodium-infected mosquito bite that deposits sporozoites in the skin. Sporozoites enter blood vessels, are transported to the liver and invade hepatocytes. Within a hepatocyte, each sporozoite transforms into a liver stage (LS), which differentiates into tens of thousands of exo-erythrocytic merozoites. The hepatocyte takes center stage throughout this asymptomatic phase of infection; it initiates with hepatocyte surface interactions that mediate sporozoite entry, it continues with the complex remodeling of the infected hepatocytes and the defense mechanisms that have evolved to alert the immune system against the silent invader and ends with hepatocyte death and exo-erythrocytic merozoite release. Only recently, robust in vivo and in vitro models have been developed to study liver infection by the two most important human malaria parasites, P.falciparum (Pf) and P.vivax (Pv). Thus, we highlight our general knowledge of LS biology and immunology, mainly garnered from rodent malaria research but also insights directly gained from human parasite LS research. Sporozoites of human malaria parasites have an exclusive hepatocyte tropism and appear to further select specific hepatocytes for infection. Sporozoites first traverse multiple hepatocytes before selecting one for invasion and residence.[1]Loubens M. Vincensini L. Fernandes P. Briquet S. Marinach C. Silvie O. Plasmodium sporozoites on the move: switching from cell traversal to productive invasion of hepatocytes.Mol Microbiol. 2020; : 1-12https://doi.org/10.1111/mmi.14645Crossref Scopus (9) Google Scholar The molecular switch from sporozoite traversal to invasion remains poorly understood but might be determined by sulfation levels of hepatocyte heparan sulfate proteoglycans (HSPGs).[1]Loubens M. Vincensini L. Fernandes P. Briquet S. Marinach C. Silvie O. Plasmodium sporozoites on the move: switching from cell traversal to productive invasion of hepatocytes.Mol Microbiol. 2020; : 1-12https://doi.org/10.1111/mmi.14645Crossref Scopus (9) Google Scholar Both involve the release of unique effector proteins from the sporozoite secretory organelles. Surface-positioned proteins engage host receptors for infection and these receptors might differ for Pf and Pv sporozoites.[2]Manzoni G. Marinach C. Briquet S. Grand M. Tolle M. Gransagne M. et al.Plasmodium P36 determines host cell receptor usage during sporozoite invasion.Elife. 2017; 6https://doi.org/10.7554/eLife.25903.001Crossref PubMed Google Scholar In addition, hepatocyte heterogeneity might render some hepatocytes more conducive to sporozoite infection, for example degrees of hepatocyte ploidy. Successful invasion establishes the sporozoite inside a parasitophorous vacuole (PV) with a hepatocyte-derived PV membrane (PVM) forming the interface with the hepatocyte cytoplasm. The PV is essential for parasite survival and is extensively remodeled by the parasite, both to evade the hepatocyte defenses such as the autophagosomal machinery[3]Real E. Rodrigues L. Cabal G.G. Enguita F.J. Mancio-Silva L. Mello-Vieira J. et al.Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes.Nat Microbiol. 2017; 3: 17-25https://doi.org/10.1038/s41564-017-0054-xCrossref PubMed Scopus (50) Google Scholar and to use it as a conduit for uptake of host cell-derived nutrients.[4]Nyboer B. Heiss K. Mueller A. Ingmundson A. The Plasmodium liver-stage parasitophorous vacuole : a front-line of communication between parasite and host.Int J Med Microbiol. 2021; 308: 107-117https://doi.org/10.1016/j.ijmm.2017.09.008Crossref Scopus (27) Google Scholar If these initial perturbations are successful, the parasite undergoes extensive organellar and genome replication without cytokinesis, resulting in the formation of a multinucleated schizont.[5]Vaughan A.M. Kappe S.H.I. Malaria parasite liver infection and exoerythrocytic biology.Cold Spring Harb Lab Press. 2017; 7https://doi.org/10.1101/cshperspect.a025486Crossref Scopus (48) Google Scholar Cytokinesis occurs at the end of LS development and results in formation of exo-erythrocytic merozoites. All Pf LS immediately undergo schizogony, while in Pv liver infection, a subpopulation of LS become dormant stages called hypnozoites.[5]Vaughan A.M. Kappe S.H.I. Malaria parasite liver infection and exoerythrocytic biology.Cold Spring Harb Lab Press. 2017; 7https://doi.org/10.1101/cshperspect.a025486Crossref Scopus (48) Google Scholar Hypnozoites can remain dormant for weeks to years and then activate to undergo secondary schizogony and cause relapses of blood infection. It remains unclear whether natural parasite liver infection engenders protective immunity but if it does, immunity is incomplete. In contrast, vaccination with whole attenuated parasites engenders complete immune protection, which is mainly mediated by hepatic resident memory CD8 T cells (Trm)[6]Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902https://doi.org/10.1016/j.immuni.2016.08.011Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar eliminating infected hepatocytes, and humoral immune responses to sporozoites, and potentially LS.[7]Sack B.K. Keitany G.J. Vaughan A.M. Miller J.L. Wang R. Kappe S.H.I. Mechanisms of stage-transcending protection following immunization of mice with late liver stage-arresting genetically attenuated malaria parasites.Plos Pathog. 2015; 11e1004855https://doi.org/10.1371/journal.ppat.1004855Crossref PubMed Scopus (26) Google Scholar How innate immune responses to LS influence the development of the cellular and humoral adaptive immune responses is not fully understood, but accumulating evidence indicates that hepatocytes play an integral role: recognition of LS infection induces a type I interferon response (IFN-1) in hepatocytes, which promotes immune cell recruitment to the liver[8]Liehl P. Zuzarte-Luís V. Chan J. Zillinger T. Baptista F. Carapau D. et al.Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.Nat Med. 2014; 20: 47-53https://doi.org/10.1038/nm.3424Crossref PubMed Scopus (174) Google Scholar but also compromises the durability of hepatic CD8 T cell immunity.[9]Minkah N.K. Wilder B.K. Sheikh A.A. Martinson T. Wegmair L. Vaughan A.M. et al.Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites.Nat Commun. 2019; 10: 1-14https://doi.org/10.1038/s41467-019-11819-0Crossref PubMed Scopus (12) Google Scholar In addition, infected hepatocyte cell death leads to the release of LS antigens that are acquired by infiltrating monocyte-derived antigen presenting cells which in turn prime naïve CD8 T cells.[10]Kurup S.P. Anthony S.M. Hancox L.S. Vijay R. Pewe L.L. Moioffer S.J. et al.Monocyte-derived CD11c + cells acquire Plasmodium from hepatocytes to prime CD8 T cell immunity to liver-stage malaria.Cell Host Microbe. 2019; 25 (565-577.e6)https://doi.org/10.1016/j.chom.2019.02.014Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Whether the induction of infected hepatocyte cell death is dependent on IFN-1 signaling remains to be determined. Linking all findings to achieve a comprehensive understanding of LS infection and immunity is a priority for future malaria research. Research of the authors is funded by the NIH . DG, NKM and SHIK conceived the idea, DG and NKM designed the figure and drafted the manuscript. SHIK contributed to figure design, writing and editing. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.18 MB) Help with pdf files Multimedia component 1
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