Date on Master's Thesis/Doctoral Dissertation

12-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Schmidt, Nathan

Committee Member

Kosiewicz, Michele

Committee Member

Egilmez, Nejat

Committee Member

Sokoloski, Kevin

Committee Member

Watson, Cory

Author's Keywords

malaria; microbiota; germinal center; plasmodium

Abstract

Plasmodium infection leads to over 200 million cases of malaria and 400,000 deaths worldwide each year. These deaths are largely in children under the age of five and pregnant women [1]. Caused by transmission of Plasmodium parasites by the female Anopheles mosquito, malaria poses a risk for over 40 percent of the world’s population [1]. Despite worldwide efforts to eradicate malaria leading to a decrease in malaria-associated mortalities in the early 2000s [2], growing resistance to the available antimalarials and the lack of an effective, long-lasting vaccine has caused this decrease to plateau in recent years [1, 3-6]. Furthermore, malaria has a global economic burden reaching billions of dollars owing to clinical costs, distributing antimalarials or other preventative measures, and loss of productivity while parents care for sick children [7-9]. Together, this points to a need for a more thorough understanding of the host immune response to malaria in efforts to identify novel, affordable treatment options. Our lab has previously shown that C57BL/6 mice purchased from different venders exhibit profound differences in parasite burden when infected with Plasmodium. Through the colonization of germ-free mice with the cecal contents from mice with differential susceptibility to Plasmodium, it was shown that these differences in parasite burden are driven by variations in the composition of the gut microbiota [10]. Additionally, recent evidence pointing to a role of the gut microbiota in both the susceptibility to malaria and the induction of antibodies against gut bacteria that cross react with Plasmodium has been shown in human infections [11, 12]. While these publications point to a role of the gut microbiota in Plasmodium susceptibility, the influence of the microbiota on the immune response to Plasmodium leading to these differences is not well understood. To better characterize the role of the gut microbiota on the immune response to Plasmodium, the humoral immune response between phenotypically resistant and phenotypically susceptible mice was evaluated. In addition to an increase in the number of germinal center (GC) B cells, plasmablasts, and T follicular helper (Tfh) cells in resistant mice compared to susceptible mice, resistant mice exhibited higherPlasmodium-specific antibody titers that were shown to be specific for a greater number of Plasmodium antigens. These differences in the humoral immune response were shown to be dependent on the gut microbiota through using germ-free mice colonized with either resistant or susceptible cecal contents. Furthermore, these differences in initial susceptibility to Plasmodium infection led to long-term resistance to heterologous-Plasmodium challenge, illustrating that microbiota-induced increased humoral immune response to malaria likely leads to a better long-term immune response. Though the exact mechanism driving these immune differences remains unknown, variances in IFN-g and IL-10 concentrations between resistant and susceptible mice at immune-critical timepoints during infection point to a potential role of differential cytokine production in susceptibility. However, the exact role of these cytokines is difficult to distinguish due to the complexity of the inflammatory response during a Plasmodium infection and the intricacies of time-dependent cytokine interactions. Previous research shows that parasite burden can be decreased through the treatment of mice with antibiotics followed by yogurt [10]. This leads to the exciting prospect of using probiotic administration in young children as a novel and affordable treatment for malaria [13]. In order to further evaluate the role of probiotic treatment on the severity of Plasmodium in a mouse model, mice were treated with a combination of antibiotics, homemade or Dannon brand yogurt, or probiotic strains of Lactobacillus and Bifidobacterium for varying amounts of time. Though antibiotic treatment followed by yogurt consistently showed a decrease in parasite burden, antibiotic treatment alone also caused enough alteration to microbiota composition to influence parasitemia. However, yogurt and probiotic treatment alone in both adult and newborn mice was not adequate to induce changes to infection severity. While these results do not negate the possibility of using probiotics to alter Plasmodium susceptibility in young children, they illustrate the complexity and challenges of gut microbiota modulation as a treatment option for infection or disease. This research provides a better understanding of the gut microbiota in modulating the immune system during a Plasmodium infection and further illustrates the complexities of the interactions between gut microbiota, malaria, and the host response. Whereas additional work needs to be done to identify the mechanisms by which gut microbiota modulate the immune response and to further optimize gut microbiota modulation as a treatment for severe malaria, the data provided through this research offers increased evidence for gut microbiota modulation as a novel treatment to prevent severe Plasmodium infection.

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