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Plasmodium Falciparum Var Gene/ Important Role of the EPCR-Activated Protein C (APC) Pathway in P

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Plasmodium Falciparum Var Gene/ Important Role of the EPCR-Activated Protein C (APC) Pathway in P Severe adult malaria is associated with specific PNAS PLUS PfEMP1 adhesion types and high parasite biomass Maria Bernabeua, Samuel A. Danzigera, Marion Avrila, Marina Vazb, Prasad H. Babarc,d, Andrew J. Braziera, Thurston Herricksc,d, Jennifer N. Makic,d, Ligia Pereirac,d, Anjali Mascarenhasc,d, Edwin Gomesb, Laura Cheryc,d, John D. Aitchisona, Pradipsinh K. Rathodc,d, and Joseph D. Smitha,1 aCenter for Infectious Disease Research, Seattle, WA 98109; bDepartment of Medicine, Goa Medical College & Hospital, Bambolim, Goa 403202, India; cDepartment of Chemistry, University of Washington, Seattle, WA 98195; and dDepartment of Global Health, University of Washington, Seattle, WA 98195 Edited by Mats Wahlgren, Karolinska Institutet, Stockholm, Sweden, and accepted by the Editorial Board April 7, 2016 (received for review December 10, 2015) The interplay between cellular and molecular determinants that This subset of PfEMP1s includes mediators of distinct infected lead to severe malaria in adults is unexplored. Here, we analyzed erythrocyte adhesion categories, including “rosetting” and endo- parasite virulence factors in an infected adult population in India thelial protein C receptor (EPCR) binding. Rosetting involves ad- and investigated whether severe malaria isolates impair endothe- hesion to uninfected red blood cells (20, 21), possibly leading to lial protein C receptor (EPCR), a protein involved in coagulation greater microvascular obstruction (22). EPCR binding involves in- and endothelial barrier permeability. Severe malaria isolates overex- fected erythrocyte adhesion to vascular endothelial cells (23). The pressed specific members of the Plasmodium falciparum var gene/ important role of the EPCR-activated protein C (APC) pathway in P. falciparum PfEMP1 ( erythrocyte membrane protein 1) family that regulating coagulation, inflammation, and endothelial barrier prop- var bind EPCR, including DC8 genes that have previously been linked erties (24) has led to the hypothesis that EPCR-binding parasites to severe pediatric malaria. Machine learning analysis revealed that may drive pathogenic mechanisms by inhibiting the APC–EPCR DC6- and DC8-encoding var transcripts in combination with high par- interaction (23, 25–28), thus increasing vascular dysfunction and asite biomass were the strongest indicators of patient hospitalization permeability. Indeed, cerebral swelling is a major risk factor for and disease severity. We found that DC8 CIDRα1 domains from pediatric death (29) and there is loss of EPCR and fibrin depositions severe malaria isolates had substantial differences in EPCR binding MICROBIOLOGY affinity and blockade activity for its ligand activated protein C. at sites of cerebral sequestration in pediatric autopsies (30). How- Additionally, even a low level of inhibition exhibited by domains ever, the extent to which severe malaria isolates disrupt EPCR from two cerebral malaria isolates was sufficient to interfere with function is poorly understood. A better understanding of adhesion- activated protein C-barrier protective activities in human brain based pathogenic mechanisms may inform novel targeted adjunctive endothelial cells. Our findings demonstrate an interplay between drug therapies to improve patient survival and outcomes. parasite biomass and specific PfEMP1 adhesion types in the devel- Another factor that determines malaria disease severity is total opment of adult severe malaria, and indicate that low impairment parasite burden. Plasma levels of P. falciparum histidine rich of EPCR function may contribute to parasite virulence. Significance malaria | Plasmodium falciparum | var | PfEMP1 | EPCR The clinical presentation of severe malaria differs between evere malaria caused by Plasmodium falciparum is responsi- children and adults, but the factors leading to these differences Sble for at least 400,000 deaths every year (1), mainly affecting remain poorly understood. Here, we investigated parasite vir- children younger than 5 y old. However, in areas of low and un- ulence factors in adult patients in India and show that specific stable transmission, severe malaria affects both children and adults endothelial protein C receptor (EPCR)-binding parasites are (2), although disease symptomatology varies according to patient age. associated with severe adult malaria and act together with Whereas severe anemia, metabolic acidosis, and cerebral malaria are parasite biomass in patient hospitalization and disease sever- the major severe syndromes in children, multisystem disease is more ity. We found substantial differences in EPCR binding activity common in adults, including renal impairment, jaundice, respiratory from severe malaria isolates. However, even parasite domains distress, metabolic acidosis, and cerebral malaria (3, 4). In addition, that partially obstructed the interaction between EPCR and its disease mortality sharply increases with the age of the patient (4). ligand activated protein C were sufficient to interfere with The factors that drive age-related differences are unknown. activated protein C-barrier protective activities in human brain A central process in severe falciparum pathology is the seques- endothelial cells. Thus, restoration of EPCR functions may be a tration of infected erythrocytes to microvascular endothelial cells key target for adjunctive malaria drug treatments. (5). Extensive tissue-specific sequestration results in organ pathol- ogy, such as cerebral malaria and placental malaria, and contributes Author contributions: M.B., S.A.D., M.A., and J.D.S. designed research; M.B., M.A., P.H.B., A.J.B., and T.H. performed research; M.V., J.N.M., L.P., A.M., E.G., L.C., and P.K.R. contrib- to metabolic acidosis and endothelial dysfunction (6, 7). Proteins uted new reagents/analytic tools; M.B., S.A.D., M.A., J.D.A., and J.D.S. analyzed data; M.B., of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) S.A.D., and J.D.S. wrote the paper; M.V. and E.G. conducted patient enrollment and data family, encoded by the var genes, are responsible for infected management; J.N.M., A.M., L.C., and P.K.R. designed the clinical study; J.N.M., L.P., A.M., – and L.C. designed the clinical study data management; and P.K.R. was responsible for the red blood cell binding to the microvasculature (8 10). PfEMP1s study site. are classified into three main groups—A, B, and C—basedonup- The authors declare no conflict of interest. stream sequence (UpsA, UpsB, UpsC) and chromosome location This article is a PNAS Direct Submission. M.W. is a guest editor invited by the Editorial (11). The extracellular domain of PfEMP1s presents a modu- Board. lar structure composed of adhesion domains, called Duffy binding- Freely available online through the PNAS open access option. like (DBL) and cysteine-rich interdomain region (CIDR) (12), Data deposition: The sequences reported in this paper have been deposited in the Gen- which sometimes can be found in conserved tandem arrange- Bank database (accession nos. KU843600–KU843604). mentsknownasdomaincassettes(DC)(13).Expressionof 1To whom correspondence should be addressed. Email: [email protected]. – group A PfEMP1 variants (14 18) and PfEMP1 encoding DC8 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (15, 19) have been strongly linked with pediatric severe malaria. 1073/pnas.1524294113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1524294113 PNAS Early Edition | 1of10 Downloaded by guest on October 2, 2021 protein 2 (PfHRP2), a surrogate of parasite biomass, can predict target groups A, B, or C (VarA, UpsB1, UpsB2, UpsC1, and disease severity and fatality rates in both children and adults (31, UpsC2) (16) and 40 degenerate primers that target specific ad- 32), the probability of disease deterioration (33), retinopathy-posi- hesion domains (15). Overall, patients in the study presented tive cerebral malaria (34), and whether a fever is caused by malaria a complex population of parasites that transcribed a mixture of (35). Nevertheless, a recent longitudinal study in Tanzanian children A, B, and C var genes (Fig. 2A and Table 2). However, the showed that high PfHRP2 levels did not necessitate severe disease median VarA transcript level was higher than groups B and C in (36), suggesting severe disease requires additional factors. all patient groups, and SM patients had significantly elevated In this study, statistical and machine-learning approaches were VarA and UpsB1 transcripts in comparison with OP (Fig. 2A and used to explore the relationship between PfEMP1 expression, Table 2). parasite biomass, and disease severity in adults with P. falciparum To gain further insight into parasite binding phenotypes as- infections treated at the Goa Medical College, and we investigated sociated with adult SM, domain-specific primers were used to whether severe malaria isolates impair the APC–EPCR pathway. identify adhesion subtypes expressed in patients, also taking advantage of the functional specialization of PfEMP1 proteins Results to infer parasite binding traits. In particular, the N-terminal Characteristics of the Study Population. A total of 59 P. falciparum- PfEMP1 head structure (DBL–CIDR tandem) has diversified infected patients from the Goa Medical College were enrolled in between group A (EPCR binding or rosetting) and groups B and the study. Among them, 26 patients had severe malaria (SM) and C (CD36 binders). Head structures containing CIDRα1 subtypes presented at least one WHO SM criterion (37), 13 patients
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