Investigating the mechanisms underlying antibody-mediated effector functions in malaria and Multisystem Inflammatory Syndrome in Children (MIS-C)

Loading...
Thumbnail Image

Persistent link to this item

Statistics
View Statistics

Journal Title

Journal ISSN

Volume Title

Title

Investigating the mechanisms underlying antibody-mediated effector functions in malaria and Multisystem Inflammatory Syndrome in Children (MIS-C)

Alternative title

Published Date

2024-06

Publisher

Type

Thesis or Dissertation

Abstract

Antibodies have multiple functions within the body to provide host protection, including interacting with Fc receptors on innate immune cells to destroy pathogens or cells infected by pathogens. We studied antibody-mediated cellular responses in the context of two infections: malaria, a parasitic infection, and SARS-CoV-2, a viral infection. Plasmodium falciparum (P.f) is the main cause of malaria worldwide and is major cause of morbidity and mortality. Deaths occur because of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malaria vaccine. Natural killer (NK) cells inhibit the growth in the blood through interacting with antibodies via antibody dependent cellular cytotoxicity (ADCC). A subset of NK cells in malaria, known as adaptive NK cells, lack the FcR chain and have enhanced ADCC. However, it is unclear if the lack of FcRchain is the reason for increased functionality or if it only serves as a marker. Using CRIPSR/Cas9, we found that ablating the FcR chain did not enhance ADCC. Using cohort of subjects from a malaria clinical study in Mali, we then searched for other alterations in malaria NK cells that could explain the enhanced functionality. We found that the expression of Sigelc-7, an inhibitory receptor, is decreased on NK cells from individuals with malaria and that decreased expression of Siglec-7 correlates with increased ADCC. These data provide evidence that the host may increase the number of Siglec-7 negative NK cells to aide in the clearance of infected RBCs through ADCC. I then investigated antibody-mediated effector functions in Multisystem Inflammatory Syndrome in Children (MIS-C), a rare and severe complication of SARS-CoV-2 infection that is characterized by multi-organ involvement and substantial inflammation. Little is known about antibody-mediated cellular responses in MIS-C. We show that monocytes in MIS-C were hyperfunctional while NK cells were hypofunctional for antibody-dependent cellular destruction and cytokine production. We also show multiple ways leading to decreased cytotoxicity for NK cells, including phenotypic exhaustion of NK cells and cytokine-induced associations. Together, our results reveal unique dysregulation in antibody-mediated responses in MIS-C that contribute to the immune pathology of this disease and may be amenable to immunomodulation. Overall, this thesis provides insight into the mechanisms underlying antibody-mediated cellular functions in malaria and MIS-C that can be utilized in developing therapeutics and vaccine targets for these diseases .

Description

University of Minnesota Ph.D. dissertation. June 2024. Major: Microbiology, Immunology and Cancer Biology. Advisor: Geoffrey Hart. 1 computer file (PDF); x, 151 pages.

Related to

Replaces

License

Collections

Series/Report Number

Funding information

Isbn identifier

Doi identifier

Previously Published Citation

Other identifiers

Suggested citation

Dick , Jenna. (2024). Investigating the mechanisms underlying antibody-mediated effector functions in malaria and Multisystem Inflammatory Syndrome in Children (MIS-C). Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/265121.

Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.