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In Vitro Assay of Plasmodium-Infected Red Blood Cell Killing by Cytotoxic Lymphocytes
Published on: August 17, 2022
Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive
Christopher L Harding1, Nicolas F Villarino2, Elena Valente3
1Department of Microbiology and Immunology, University of Louisville, Louisville, KY, United States.
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.
Insights
Malaria infection weakens the immune system, increasing susceptibility to bacterial infections like Listeria and Streptococcus pneumoniae. This impairment is linked to parasite factors affecting innate immunity, not just known mechanisms.
Area of Science:
- Immunology
- Infectious Diseases
- Parasitology
Background:
- Malaria (Plasmodium infection) is known to increase susceptibility to invasive bacterial infections, particularly non-Typhoid Salmonella (NTS).
- Existing research suggests NTS susceptibility is mediated by heme-oxygenase I (HO-I) and IL-10, but it's unclear if these mechanisms apply to other bacteria.
Purpose of the Study:
- To investigate if Plasmodium yoelii (Py) infection impairs host immunity to other bacteria, such as Listeria monocytogenes (Lm) and Streptococcus pneumoniae (Sp).
- To elucidate the mechanisms underlying Py-induced susceptibility to bacterial co-infections, exploring the roles of HO-I, IL-10, and parasite-derived factors.
Main Methods:
- Mice infected with Plasmodium yoelii (Py) were challenged with Listeria monocytogenes (Lm) and Streptococcus pneumoniae (Sp).
- Immune responses, including bacterial clearance, survival rates, phagocyte function, reactive oxygen species (ROS) production, and serum components, were analyzed.
- Naïve mice were treated with Plasmodium-derived hemozoin (Hz) to assess its direct impact on bacterial clearance.
Main Results:
- Py-infected mice showed impaired clearance of Lm and increased susceptibility to Sp bacteremia, persisting for up to two months post-infection.
- Impaired immunity to Sp was independent of HO-I but dependent on Py-induced IL-10.
- Neutrophils from Py-infected mice exhibited reduced ROS production, and a serum defect also contributed to impaired Sp immunity. Plasmodium-derived hemozoin directly suppressed antibacterial immunity.
Conclusions:
- Plasmodium infection broadly impairs host innate immunity against diverse bacterial pathogens, including Streptococcus pneumoniae.
- Multiple mechanisms contribute to this suppression, involving impaired phagocyte function, reduced ROS production, and serum defects.
- Plasmodium-derived hemozoin, containing bound bioactive molecules, is a key factor directly contributing to malaria-induced suppression of antibacterial innate immunity.
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