Date on Master's Thesis/Doctoral Dissertation

8-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Schmidt, Nathan

Committee Co-Chair (if applicable)

Alard, Pascale

Committee Member

Alard, Pascale

Committee Member

Li, Bing

Committee Member

Lawrenz, Matthew

Committee Member

Uriarte, Silvia

Author's Keywords

Plasmodium; malaria; immunosuppression; co-infection; bacteria; innate immunity; pneumococcus

Abstract

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of 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 resolution of Py infection that was independent of HO-I and IL-10. Py-infected mice were also susceptible to Streptococcus pneumoniae (Sp) bacteremia, a common malaria-bacteria coinfection, 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 (Hz) 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. IMPORTANCE Our findings provide evidence that there are multiple factors involved in Plasmodium-induced suppression of antibacterial innate immunity. Given the increased mortality rate associated with malaria and invasive bacterial coinfections, these results may provide insight into new approaches to treat those individuals. Finally, this report provides the first description, to our knowledge, of a murine model system of Plasmodium and S. pneumoniae coinfection. In this model, Plasmodium infections impair host immunity to S. pneumoniae, which resulted in increased mortality. As S. pneumoniae is one of the most common bacteria identified in individuals with invasive bacterial infections during malaria, this model has the potential to provide further knowledge into the dynamics of this coinfection and identify approaches to treat this coinfection.

Download

Share

COinS