Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria
Abstract
:1. Introduction
2. Results
2.1. Number of Unique Sequences per Patient Is Elevated in Association with Chronic PM but Not Gravidity
2.2. Association of Short Peptide Motifs in DBL3X with Gravidity and PM Outcome Parameters
2.3. Sequence Analysis Identifies Four Types That Associate with Gravidity and Infection Parameters
2.4. Association of Infection Outcomes with Sequence Type Dominance
3. Discussion
4. Methods
4.1. Ethics Statement
4.2. Study Population
4.3. Amplification and Sequencing of var2csa DBL3X Domain
4.4. Data Quality Filtering
4.5. Unique Sequence Types Analysis
4.6. Motif Analysis
4.7. VAR2CSA Structure Modeling
4.8. Statistical Analysis and Graph Generation
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Primigravid (n = 23) | Multigravid (n = 26) | p Value a | |
---|---|---|---|
Gravidity (mean, range) | 1 | 4, 3–4.3 | <0.0001 |
Age (years) | 18 (17, 19) | 25 (23, 28.3) | <0.0001 |
Luo ethnicity (%) | 22/23 (96) | 24/26 (92) | 1 |
Resident of Siaya District (%) | 16/23 (70) | 23/26 (88) | 0.16 |
Submicroscopic placental infection (%) b | 3/23 (13) | 7/26 (27) | 0.30 |
% Placental parasitemia b | 1.8 (0.5, 7.0) | 0.5 (0.3, 1.2) | 0.037 |
Placental parasite density/µL b | 15,502 (4723, 50, 521) | 1564 (651, 4410) | 0.0014 |
Chronic placental malaria (%) c | 16/20 (80) | 11/23 (48) | 0.056 |
% Hemozoin-bearing WBC d | 4.3 (1.2, 8.4) | 1.0 (0, 4.3) | 0.041 |
HIV seropositive (%) | 1/23 (4) | 6/26 (23) | 0.10 |
Peripheral hemoglobin level (g/dL) e | 11.6 ± 2.0 | 10.5 ± 2.1 | 0.13 |
Self-reported antimalarial use (%); SP use (%) f | 15/23 (65); 15/23 (65) | 16/26 (62); 12/26 (46) | 1/0.25 |
Infant birth weight (g) | 3009 ± 383 | 3304 ± 436 | 0.015 |
Gestational age (wks) g | 38.3 ± 1.0 | 38.2 ± 1.4 | 0.61 |
Male birth (%) | 10/23 (43) | 16/26 (62) | 0.26 |
Motif | No. Observed | % of Total Population (n = 522) | Primigravid n (%) | Multigravid n (%) | p |
---|---|---|---|---|---|
IISQNDKK | 273 | 51 | 144 (27) | 129 (24) | 0.0571 |
IISRNPMK | 138 | 26 | 52 (9) | 86 (16) | 0.0008 |
EGGEDGKGKQKE | 94 | 18 | 37 (7) | 60 (11) | 0.0313 |
EKANNN | 222 | 41 | 125 (24) | 97 (18) | 0.0049 |
NSNGLP | 328 | 62 | 159 (29) | 169 (32) | 0.4237 |
Continuous Variables | ||||||||||||
Type 1 | Type 2 | Type 3 | Type 4 | |||||||||
Co-efficient | SEM | p | Co-efficient | SEM | p | Co-efficient | SEM | p | Co-efficient | SEM | p | |
Age | 0.737 | 0.973 | 0.453 | −0.877 | 0.586 | 0.142 | 0.764 | 0.616 | 0.222 | −0.806 | 0.414 | 0.0580 |
Gravidity | 0.371 | 0.325 | 0.260 | −0.362 | 0.196 | 0.0711 | 0.306 | 0.206 | 0.145 | −0.170 | 0.138 | 0.225 |
Placental parasite density a | −0.036 | 0.298 | 0.905 | 0.190 | 0.179 | 0.296 | −0.347 | 0.189 | 0.0727 | 0.173 | 0.127 | 0.179 |
Percent placental parasitemia a | −0.0340 | 0.258 | 0.896 | 0.169 | 0.154 | 0.281 | −0.363 | 0.163 | 0.0311 | 0.207 | 0.109 | 0.0648 |
Placental hemozoin burden b | −0.147 | 0.266 | 0.584 | 0.155 | 0.123 | 0.215 | −0.177 | 0.129 | 0.176 | 0.127 | 0.0907 | 0.170 |
Peripheral hemoglobin c | −0.080 | 0.471 | 0.866 | −0.125 | 0.257 | 0.631 | −0.407 | 0.264 | 0.133 | 0.075 | 0.177 | 0.675 |
Infant birth weight | 45.4 | 77.8 | 0.563 | −64.0 | 46.8 | 0.179 | 60.9 | 49.3 | 0.223 | −31.2 | 33.1 | 0.350 |
Gestational age at birth | −0.646 | 0.209 | 0.0036 | −0.0676 | 0.127 | 0.596 | 0.0913 | 0.132 | 0.494 | −0.0219 | 0.0899 | 0.809 |
Categorical Variables | ||||||||||||
Type 1 | Type 2 | Type 3 | Type 4 | |||||||||
OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | |||||
Gravidity group | 3.85 (0.763, 19.4) | 0.103 | 0.621 (0.342, 1.13) | 0.118 | 1.55 (0.872, 2.74) | 0.135 | 0.835 (0.594, 1.17) | 0.298 | ||||
Upper quartile parasite density | 0.231 (0.020, 2.72) | 0.245 | 1.14 (0.698, 1.85) | 0.611 | 0.657 (0.333, 1.30) | 0.226 | 1.12 (0.777, 1.60) | 0.552 | ||||
Upper quartile percent parasitemia | 0.454 (0.064, 3.20) | 0.428 | 1.78 (0.863, 3.68) | 0.118 | 0.184 (0.042, 0.805) | 0.0245 | 1.19 (0.696, 2.04) | 0.524 | ||||
Upper quartile hemozoin-WBCs | 0.684 (0.100, 4.66) | 0.698 | 1.52 (0.852, 2.69) | 0.158 | 1.47 (0.799, 2.71) | 0.215 | 1.02 (.0641, 1.61) | 0.947 | ||||
Placental histology group d | 0.305 (0.073, 1.28) | 0.105 | 4.12 (0.910, 18.6) | 0.0661 | 0.615 (0.305, 1.24) | 0.176 | 3.26 (1.41, 7.52) | 0.0056 | ||||
Anemia | 0.521 (0.135, 2.01) | 0.345 | 1.14 (0.628, 2.05) | 0.674 | 1.43 (0.830, 2.46) | 0.198 | 1.28 (0.892, 1.85) | 0.179 | ||||
HIV serostatus | 0.994 (0.416, 2.37) | 0.990 | 0.315 (0.047, 2.12) | 0.236 | 1.11 (0.601, 2.04) | 0.742 | 1.27 (0.852, 1.91) | 0.239 | ||||
Self-reported antimalarial drug use e | 0.896 (0.427, 1.88) | 0.773 | 1.57 (0.682, 3.63) | 0.288 | 1.14 (0.642, 2.02) | 0.656 | 0.863 (0.604, 1.23) | 0.418 | ||||
Low birth weight | 0.956 (0.258, 3.55) | 0.947 | 1.53 (0.881, 2.65) | 0.132 | 0.907 (0.415, 1.98) | 0.806 | 1.20 (0.754, 1.92) | 0.437 | ||||
Preterm birth | 2.66 (0.891, 7.96) | 0.0797 | 0.884 (0.161, 4.85) | 0.887 | 0.604 (0.114, 3.19) | 0.552 | 0.832 (0.287, 2.41) | 0.735 |
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Talundzic, E.; Scott, S.; Owino, S.O.; Campo, D.S.; Lucchi, N.W.; Udhayakumar, V.; Moore, J.M.; Peterson, D.S. Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria. Pathogens 2022, 11, 520. https://doi.org/10.3390/pathogens11050520
Talundzic E, Scott S, Owino SO, Campo DS, Lucchi NW, Udhayakumar V, Moore JM, Peterson DS. Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria. Pathogens. 2022; 11(5):520. https://doi.org/10.3390/pathogens11050520
Chicago/Turabian StyleTalundzic, Eldin, Stephen Scott, Simon O. Owino, David S. Campo, Naomi W. Lucchi, Venkatachalam Udhayakumar, Julie M. Moore, and David S. Peterson. 2022. "Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria" Pathogens 11, no. 5: 520. https://doi.org/10.3390/pathogens11050520