Hemozoin Directly Induces Inflammation and Upregulation of CD36 in Lung Epithelium and Endothelium. (4th October 2017)

• Record Type: Journal Article
• Authors: Shah, Shivang; Fidock, David; Prince, Alice
• Is Part Of: Open forum infectious diseases. Volume 4(2017)Supplement 1
• Page Start: S224
• Page End: S224
• Publication Date: 2017-10-04
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofx163.464
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Respiratory distress (RD) in severe malaria is a clinical syndrome associated with increased mortality in African children infected with P. falciparum . RD involves inflammation and cellular activation at both the local and systemic level, with cytoadherence between infected red blood cells (RBC) and host endothelial receptors such as CD36 thought to play a key role in disease pathogenesis. The malaria pigment hemozoin (Hz) is found in abundance in tissues involved in severe malaria, including the lungs, and is known to be a potent innate immune effector. However, little is known about the direct role of Hz on host lung tissues independent of immune cell-mediated effects. We sought to investigate whether Hz plays a direct role in inflammation and cellular activation in lung epithelial and endothelial tissues in order to better understand the role of Hz in the molecular pathophysiology of RD. Methods: We report here the results of in vitro work examining the direct effect of synthetic Hz on human airway epithelial (16HBE) and lung microvascular endothelial cells (LHMVEC). Results: Hz induces a pro-inflammatory response in both lung epithelial and endothelial cells via dose-dependent upregulation of mediators such as HMOX1, IL-6, and IL-8 (P < 0.001, linear model). An endothelial-specific response involving upregulation of VEGF and NRF2 (P < 0.001, linear model) was also observed. Additionally, Hz induces cellular activation in both cell types, manifested by dose-dependent upregulation of CD36 expression, a key endothelial cytoadherence receptor for Plasmodium -infected RBC. Upregulation of CD36 by Hz occurs via a post-transcriptional mechanism that is dependent upon Fyn kinase pathway activity. Conclusion: These findings demonstrate a direct role for hemozoin in generating inflammation and cellular activation in lung epithelial and endothelial tissues. Notably, we report the novel finding that hemozoin induces upregulation of CD36, a key cytoadherence receptor associated with severe malaria and RD. Disclosures: All authors: No reported disclosures.