Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive Molecules

Abstract

One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through heme-oxygenase I (HO-I)-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during both acute parasitemia and up to 2 months after clearance of Py infected red blood cells that was independent of HO-I and IL-10. Py-infected mice were also susceptible to Streptococcus pneumoniae (Sp) bacteremia, a common malaria-bacteria co-infection, with higher blood and spleen bacterial burdens and decreased survival compared to naïve mice. Mechanistically, impaired immunity to Sp was independent of HO-I, but was dependent on Py-induced IL-10. Splenic phagocytes from Py infected mice exhibit an impaired ability to restrict growth of intracellular Lm, and neutrophils from Py-infected mice produce less reactive oxygen species (ROS) in response to Lm or Sp. Analysis also identified a defect in a serum component in Py-infected mice that contributes to reduced production of ROS in response to Sp. Finally, treating naïve mice with Plasmodium-derived hemozoin containing naturally bound bioactive molecules, excluding DNA, impaired clearance of Lm. Collectively, we have demonstrated that Plasmodium infection impairs host immunity to diverse bacteria, including S. pneumoniae, through multiple effects on innate immunity, and that a parasite-specific factor (Hz+bound bioactive molecules) directly contributes to Plasmodium-induced suppression of antibacterial innate immunity.

The spleen: “epicenter” in malaria infection and immunity

“…Therefore, this raises questions about whether this remnant of Plasmodium infection negatively impacts the immune response to other infections. Indeed, there is evidence that hemozoin and the molecules bound to it can impair innate immunity against systemic bacterial infections 190 . As hemozoin and the DNA bound to it can serve as a potent activator of TLR9 and other PRRs, 191 it is possible that the hemozoin that lingers after clearance of the infection serves to tolerize or train innate cells to respond differently to other infections or stimuli.…”

“…Indeed, there is evidence that hemozoin and the molecules bound to it can impair innate immunity against systemic bacterial infections. 190 As hemozoin and the DNA bound to it can serve as a potent activator of TLR9 and other PRRs, 191 it is possible that the hemozoin that lingers after clearance of the infection serves to tolerize or train innate cells to respond differently to other infections or stimuli. Indeed, hemozoin can train monocytes to hyper‐respond to secondary stimulation with a TLR agonist through increased production of proinflammatory cytokines, a response that differs from other infectious stimuli.…”

Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

“…Furthermore, it has been previously reported that HO-1 has a role in suppressing pro-inflammatory Th1 immune responses in experimental colitis, and sickle cell alloimmunization has been reported, and it protects from atherosclerosis [ 40 , 41 ]. Finally, HO-1 can impair the immunity against other pathogens, such as Plasmodium yoelii [ 42 ].…”

Protozoan co-infections and parasite influence on the efficacy of vaccines against bacterial and viral pathogens

“…The protozoan converts it to hemozoin, a novel non-DNA ligand for Toll-like receptor (TLR)9, which can be captured by cells of the reticuloendothelial system (RES) and can activate innate immune responses (Simoes et al, 2015). In response, mammalian host produces heme oxygenase-1 to degrade the heme and mitigate malaria pathology by limiting production of reactive oxygen species (ROS; Gozzelino et al, 2010); however, reduced ROS has counterproductive effect due to decrease in beneficial granulocyte oxidative burst function in clearing infections, and thus allows multiplication of co-infecting Salmonella in neutrophils (Cunnington et al, 2012;Harding et al, 2020). Activation of TLR9 also results in the production of pro-inflammatory cytokines, certain chemokines, and causes up-regulation of costimulatory molecules (Coban et al, 2005).…”