Malaria-associated acute respiratory distress syndrome:a neglected complication of malaria

Philippe Van den SteenImmunoparasitology

Rega InstituteKU Leuven - University of Leuven

Belgium

216 million clinical cases in 2016

445 000 deaths in 2016

Mortality despite antimalarial drugs:due to complications:- Cerebral malaria- Severe malaria anemia- Placental malaria- Malaria-associated ARDS- Metabolic disturbances

Malaria: a world-wide burden

No adjunctive treatments

N.J. White, Science 2008; 320:330-334

Complicated malaria

Plasmodium genus

The ‘classical four’:Plasmodium falciparumPlasmodium vivaxPlasmodium ovalePlasmodium malariae

The Plasmodium genus: more than 150 species!

Shearer FM (2016) PLOS Neglected Tropical Diseases 10(8): e0004915.

P. knowlesi: a neglected zoonotic malaria species

- Macaques as main host

- Discovered in 2004 as human pathogen

- Previously misdiagnosed as P. malariae

- Main malaria species in Borneo

- Problematic for elimination

- Rapid progression (24 h cycle)

- 10-40% of cases are complicated ~60% MA-ARDS

Singh et al. (2004) Lancet 363: 1017–24William et al. (2011) Emerg Inf Dis 17: 1248-55World Malaria Report 2018, WHO.

Malaria-associated Acute Respiratory Distress Syndrome (MA-ARDS)

Taylor et al., Chest, 2012

ARDS

HealthyP. falciparum P. vivax

Valecha et al., Am J Trop Med Hyg, 2009

- excessive alveolar edema and inflammation

- 2-25% of adult patients with complications

- most common complication of P. knowlesi malaria

- 2nd cause of ARDS in India

- high mortality risk: 80% without mechanical ventilation10-40% with mechanical ventilation

- antimalarial drugs do not help, ARDS develops often after parasite clearanceVan den Steen et al., Trend Parasitol 2013

Sharma et al., Indian J Med Res. 2016

Uninfected P. berghei NK65

P. berghei NK65 as a novel model for MA-ARDS

Lungs(C57Bl/6)

Control

Van den Steen et al., Am J Resp Crit Care Med 2010

Pathogenesis

Parasite factors:- Hemozoin

Host factors:- Leukocytes- Cytokines,

Chemokines, …- Adrenal hormones

Develop therapeutic strategies

Endothelial activation and VWF in MA-ARDS

Effect of VWF KO on alveolar edema

VWF in murine MA-ARDS

Kraisin (2019) J Thromb Haemost 17(8):1372-1383

CON

VWF: Von Willebrand Factor

Collaboration with Prof. Simon De Meyer

Parasites produce hemozoin(malaria pigment)

Pisciotta et al., Biochem. J. (2007) 402, 197-204

hemoglobin

large peptides

small peptides

dipeptides

Heme

AA in cytoplasm

Hemoglobin degradation food vacuole

Hemozoin

Malaria pigment or hemozoin in MA-ARDS

Deroost et al., Am J Resp Cell Mol Biol 2013

MA-ARDS patient

Pham et al., unpublishedIn collaboration with Dr. P. Viriyavejakul

10 µm

MA-ARDS (polarisation)

Role of VEGF and PlGF in MA-ARDS

VEGF and PlGF: consequence of pathology, not the cause!

Neutralization with anti-VEGFR2 Inhibition with sunitinib

Pham et al., 2017, Front Cell Inf Microbiol.

Role of VEGF and PlGF in MA-ARDS

Neutralization with anti-VEGFR2 Inhibition with sunitinib

Depletion of pathogenic CD8+ T cells

Pham et al., 2017, Front Cell Inf Microbiol.

VEGF and PlGF: consequence of pathology, not the cause!

Role of VEGF and PlGF in MA-ARDS

1. Parasite cytoadherence

2. Localized release of hemozoin (and other “toxins”)

3. Endothelial activation

4. Leukocyte recuitment and activation

5. Damage to endothelial barrier interstitial edema

6. Damage to epithelial barrier alveolar edema

Van den Steen et al., Trends Parasitol 2013

Conclusions

1. MA-ARDS is a neglected complication of malaria

2. Endothelial activation and VWF increase in MA-ARDS

3. Hz is a crucial pathogenic factor in MA-ARDS

4. VEGF and PlGF: consequence but not cause of MA-ARDS

References

1. Van den Steen PE, Geurts N, Deroost K, Van Aelst I, Verhenne S, Heremans H, Van Damme J, Opdenakker G: Immunopathology and Dexamethasone Therapy in a New Model for Malaria-Associated Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2010, 181:957-968.2. Deroost K, Lays N, Noppen S, Martens E, Opdenakker G, Van den Steen PE: Improved methods for haemozoinquantification in tissues yield organ- and parasite-specific information in malaria-infected mice. Malar J 2012, 11:166.3. Van den Steen PE, Deroost K, Deckers J, Van Herck E, Struyf S, Opdenakker G: Pathogenesis of malaria-associated acute respiratory distress syndrome. Trends Parasitol 2013, 29:346-359.4. Deroost K, Tyberghein A, Lays N, Noppen S, Schwarzer E, Vanstreels E, Komuta M, Prato M, Lin JW, Pamplona A, et al: Hemozoin induces lung inflammation and correlates with malaria-associated acute respiratory distress syndrome. Am J RespirCell Mol Biol 2013, 48:589-600.5. Deroost K, Pham TT, Opdenakker G, Van den Steen PE: The immunological balance between host and parasite in malaria. FEMS Microbiol Rev 2016, 40:208-257.6. Vandermosten L, Pham TT, Possemiers H, Knoops S, Van Herck E, Deckers J, Franke-Fayard B, Lamb TJ, Janse CJ, Opdenakker G, Van den Steen PE: Experimental malaria-associated acute respiratory distress syndrome is dependent on theparasite-host combination and coincides with normocyte invasion. Malar J 2018, 17:102.7. Vandermosten L, Pham TT, Knoops S, De Geest C, Lays N, Van der Molen K, Kenyon CJ, Verma M, Chapman KE, Schuit F, et al: Adrenal hormones mediate disease tolerance in malaria. Nat Commun 2018, 9:4525.8. Kraisin S, Verhenne S, Pham TT, Martinod K, Tersteeg C, Vandeputte N, Deckmyn H, Vanhoorelbeke K, Van den Steen PE, De Meyer SF: von Willebrand factor in experimental malaria-associated acute respiratory distress syndrome. J ThrombHaemost 2019, 17:1372-1383.

ImmunoparasitologyImmunobiology

Leiden Malaria

Research group

Chris Janse

Blandine Franke-Fayard

Jai Ramesar

Thy PhamHendrik Possemier

Emilie PollenusLeen Vandermosten

Katrien DeroostSofie Knoops

Ghislain Opdenakker

Faculty of

Tropical Medicine

Parnpen Viriyavejakul

Chuchard Punsawad

Acknowledgements

Nuclear Receptor Lab

Ghent University

Karolien De Bosscher

Endocrinology Unit

University of Edinburgh

Karen Chapman

Cardiovascular Sciences

KU Leuven

Simon De Meyer