Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis

Dasari, Prasad; Fries, Anja; Heber, Sophia D.; Salama, Abdulgabar; Blau, Igor‐Wolfgang; Lingelbach, Klaus; Bhakdi, S; Udomsangpetch, Rachanee; Torzewski, Michael; Reiß, Karina; Bhakdi, Sucharit

doi:10.1007/s00430-014-0347-0

Cited by 29 publications

(25 citation statements)

References 35 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Digestive vacuoles activate complement and promote complement deposition on bystander cells, which could include merozoites and neighboring RBCs (37,38). We propose merozoites recruit FH to protect themselves from this additional threat of complement assault.…”

Section: Discussionmentioning

confidence: 92%

“…In bloodstage infection, schizont rupture releases merozoites and digestive vacuoles leading to immune system exposure. A recent study has found digestive vacuoles serve as major complement activation targets with MAC forming on their surface (36)(37)(38). Intriguingly, these studies did not observe terminal pathway formation on merozoites, a strong indication that complement evasion strategies are in place to protect this cell type from complement-mediated attack.…”

mentioning

confidence: 93%

See 1 more Smart Citation

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

Kennedy

Schmidt

Thompson

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The human complement system is the frontline defense mechanism against invading pathogens. The coexistence of humans and microbes throughout evolution has produced ingenious molecular mechanisms by which microorganisms escape complement attack. A common evasion strategy used by diverse pathogens is the hijacking of soluble human complement regulators to their surfaces to afford protection from complement activation. One such host regulator is factor H (FH), which acts as a negative regulator of complement to protect host tissues from aberrant complement activation. In this report, we show that Plasmodium falciparum merozoites, the invasive form of the malaria parasites, actively recruit FH and its alternative spliced form FH-like protein 1 when exposed to human serum. We have mapped the binding site in FH that recognizes merozoites and identified Pf92, a member of the six-cysteine family of Plasmodium surface proteins, as its direct interaction partner. When bound to merozoites, FH retains cofactor activity, a key function that allows it to downregulate the alternative pathway of complement. In P. falciparum parasites that lack Pf92, we observed changes in the pattern of C3b cleavage that are consistent with decreased regulation of complement activation. These results also show that recruitment of FH affords P. falciparum merozoites protection from complement-mediated lysis. Our study provides new insights on mechanisms of immune evasion of malaria parasites and highlights the important function of surface coat proteins in the interplay between complement regulation and successful infection of the host.

show abstract

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 93%

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

Kennedy

Schmidt

Thompson

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The interaction of complement-deposited digestive vacuoles with healthy red blood cells results in the deposition of C3 on the adjacent red blood cells and as a consequence, increased erythrophagocytosis. Increased bystander deposition and erythrophagocytosis were enhanced in the presence of erythrocytes lacking DAF and CD59 (Dasari et al, 2014). A previous study also described hematin promoting opsonisation and clearance of red blood cells with the highest levels of CR1 as potentially leading to increased red blood cell destruction (Pawluczkowycz et al, 2007).…”

Section: Complement Activation By Malaria Parasites: Implications Formentioning

confidence: 90%

More than just immune evasion: Hijacking complement by Plasmodium falciparum

Schmidt

Kennedy

Tham

2015

Molecular Immunology

View full text Add to dashboard Cite

“…In general, however, the complement system seems to play only a minor role in the resolution of a primary infection because even in the absence of complement, parasites are cleared from the circulation (Ward et al 1981;Taylor et al 2001). In contrast, exaggerated complement activation has been observed in severe malaria patients and contributes significantly to pathology, including the promotion of inflammation and anemia (Luginbuhl et al 2007;Silver et al 2010;Dasari et al 2014). Furthermore, the terminal part of the complement pathway is activated in mice with cerebral malaria (CM) as illustrated by increased C5 levels and C9 deposition in mouse CM brains Ramos et al 2011), and deposition of C3d and the assembled C5b-9 complex on sequestering RBCs in brain sections of patients who died from CM (Dasari et al 2014).…”

Section: Activation Of the Complement Systemmentioning

confidence: 99%

“…Increased complement deposition could result from oxidative damage with subsequent band 3 receptor clustering induced by ROS release from phagocytes and/or by transfer of 4-HNE from iRBCs to uninfected RBCs in rosettes (Waitumbi et al 2000;Arese, Turrini and Schwarzer 2005;Odhiambo et al 2008;Uyoga et al 2012). Also direct contact with digestive vacuoles covered with C3 and C5 convertases mediates deposition of activated C3b and C5b components onto the red cell surface (Dasari et al 2014). Furthermore, higher surface deposition of IgG and IgM, directed either against autologous RBC surface proteins or against parasite antigens inserted in the non-infected RBC membrane after their release from the parasite, e.g.…”

Section: Erythrocyte Destruction and Ineffective Erythropoiesismentioning

confidence: 99%

The immunological balance between host and parasite in malaria

Deroost

Pham

Opdenakker

et al. 2015

FEMS Microbiology Reviews

112

143

View full text Add to dashboard Cite

One sentence summary: The intricate balance between anti-malarial immunity and parasite virulence factors including immune evasion mechanisms determine the outcome of malaria infections, as imbalances resulting in exaggerated parasite growth, excessive inflammation or the combination of both result in severe pathology. Editor: Christian van Ooij ABSTRACTCoevolution of humans and malaria parasites has generated an intricate balance between the immune system of the host and virulence factors of the parasite, equilibrating maximal parasite transmission with limited host damage. Focusing on the blood stage of the disease, we discuss how the balance between anti-parasite immunity versus immunomodulatory and evasion mechanisms of the parasite may result in parasite clearance or chronic infection without major symptoms, whereas imbalances characterized by excessive parasite growth, exaggerated immune reactions or a combination of both cause severe pathology and death, which is detrimental for both parasite and host. A thorough understanding of the immunological balance of malaria and its relation to other physiological balances in the body is of crucial importance for developing effective interventions to reduce malaria-related morbidity and to diminish fatal outcomes due to severe complications. Therefore, we discuss in this review the detailed mechanisms of anti-malarial immunity, parasite virulence factors including immune evasion mechanisms and pathogenesis. Furthermore, we propose a comprehensive classification of malaria complications according to the different types of imbalances.

show abstract

Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis

Cited by 29 publications

References 35 publications

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

More than just immune evasion: Hijacking complement by Plasmodium falciparum

The immunological balance between host and parasite in malaria

Contact Info

Product

Resources

About