Malaria is a highly inflammatory and oxidative disease. The production of reactive oxygen species by host phagocytes is an essential component of the host response to Plasmodium infection. Moreover, host oxidative enzymes, such as xanthine oxidase, are upregulated in malaria patients. Although increased production of reactive oxygen species contributes to the clearance of the parasite, excessive amounts of these free radicals can mediate inflammation and cause extensive damage to host cells and tissues, probably contributing to severe pathologies. Plasmodium has a variety of antioxidant enzymes that allow it to survive amidst this oxidative onslaught. However, parasitic degradation of hemoglobin within the infected red blood cell generates free heme, which is released at the end of the replication cycle, further aggravating the oxidative burden on the host and possibly contributing to the severity of life-threatening malarial complications. Additionally, the highly inflammatory response to malaria contributes to exacerbate the oxidative response. In this review, we discuss host and parasite-derived sources of oxidative stress that may promote severe disease in P. falciparum infection. Therapeutics that restore and maintain oxidative balance in malaria patients may be useful in preventing lethal complications of this disease.
Highlights d S. aureus leukocidins target DARC on endothelial cells to cause vascular dysfunction d Targeting DARC leads to organ damage during S. aureus bloodstream infection d Primary human endothelial cells are susceptible to S. aureus leukocidins d Leukocidins target host leukocytes, red blood cells, and endothelial cells
Leukocidin ED (LukED) is a pore forming toxin produced by Staphylococcus aureus which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which is dependent on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers, LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton-Valentine Leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC, and the role this plays in hemolysis, are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE-LukS-PV chimeras, in which areas of sequence divergence (divergence regions or DRs) were swapped between the toxins. We found that two regions of LukE’s rim domain contribute to hemolysis, namely residues 57-75 (DR1) and residues 182-196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE-DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.
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