Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina

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dc.contributor.advisorHoving, Jennifer Claire
dc.contributor.advisorMarakalala, Mohlopheni J
dc.contributor.authorMthembu, Nontobeko F
dc.date.accessioned2020-09-25T15:47:07Z
dc.date.available2020-09-25T15:47:07Z
dc.date.issued2020
dc.date.updated2020-09-25T15:45:57Z
dc.description.abstractPneumocystis jirovecii causes fungal pneumonia in immunocompromised patients and can be fatal if left untreated. The global mortality rate is estimated to be over 200 000 in AIDS patients. In non-AIDS patients there is an estimated mortality rate of 50 000 cases. This rate is increasing in developed countries, attributed to an increase in disorders which require immunotherapy. These include hematologic malignancies, organ transplant, inflammatory disorders and pre-existing lung disease. Immediate immunity is initiated by receptors that recognize pathogen associated molecular patterns on the surface of pathogenic fungi. Specifically, C-type lectin receptors (CLRs) have been shown to be the principal initiators of innate immune response during fungal infection. Limited studies have focused on the role of CLRs in Pneumocystis infection. Dectin1and Mincle have been shown to recognise Pneumocystis surface antigens with Dectin-1 recognizing β-glucans on the Pneumocystis cell wall leading to an effective immune response. However, the role of a newly described CLR, the Dendritic Cell Immunoactivating Receptor (DCAR) remains undefined. For this reason, we investigated the potential role of this receptor in a mouse model of Pneumocystis murina infection. Wild type and DCAR-deficient C57BL/6 mice were infected with P. murina organisms via intratracheal instillation. Fungal burden was measured in the lung using quantitative Polymerase Chain Reaction. DCAR-deficient mice had a significantly reduced burden compared to wild type mice at Day 7 and 14 post-infection. To identify the immune components involved in pathogen clearance in these mice we measured cellular recruitment and cytokine production at both early (48 hours) and late (7, 14 and 21 days) time points. Flow cytometry analysis showed an increase in alveolar macrophage, dendritic cells, inflammatory monocytes, eosinophils and T cell recruitment to the lung. While ELISA showed increased levels of IL-1β and IFN-γ at 48 hours, and later on in infection IL-1β and IL-12p40 levels were also elevated. Histology analysis determined the localization of the recruited cells, and v interestingly showed an increase in mucus production at day 21 in DCARdeficient mice. In conclusion, we have identified DCAR deficiency as a potential driver of protective immunity in mice during P. murina infection. This may be associated with increased levels of IL-1β in DCAR-deficient mice. Furthermore, DCAR may also be important in adaptive inflammatory response regulation, as DCAR-deficient mice have increased cellular recruitment and mucus production later in infection. The mechanism by which the deletion of this receptor affords these mice the ability to efficiently clear P. murina remains to be determined.
dc.identifier.apacitationMthembu, N. F. (2020). <i>Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina</i>. (). ,Faculty of Health Sciences ,Department of Clinical Laboratory Sciences. Retrieved from http://hdl.handle.net/11427/32291en_ZA
dc.identifier.chicagocitationMthembu, Nontobeko F. <i>"Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina."</i> ., ,Faculty of Health Sciences ,Department of Clinical Laboratory Sciences, 2020. http://hdl.handle.net/11427/32291en_ZA
dc.identifier.citationMthembu, N.F. 2020. Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina. . ,Faculty of Health Sciences ,Department of Clinical Laboratory Sciences. http://hdl.handle.net/11427/32291en_ZA
dc.identifier.ris TY - Master Thesis AU - Mthembu, Nontobeko F AB - Pneumocystis jirovecii causes fungal pneumonia in immunocompromised patients and can be fatal if left untreated. The global mortality rate is estimated to be over 200 000 in AIDS patients. In non-AIDS patients there is an estimated mortality rate of 50 000 cases. This rate is increasing in developed countries, attributed to an increase in disorders which require immunotherapy. These include hematologic malignancies, organ transplant, inflammatory disorders and pre-existing lung disease. Immediate immunity is initiated by receptors that recognize pathogen associated molecular patterns on the surface of pathogenic fungi. Specifically, C-type lectin receptors (CLRs) have been shown to be the principal initiators of innate immune response during fungal infection. Limited studies have focused on the role of CLRs in Pneumocystis infection. Dectin1and Mincle have been shown to recognise Pneumocystis surface antigens with Dectin-1 recognizing β-glucans on the Pneumocystis cell wall leading to an effective immune response. However, the role of a newly described CLR, the Dendritic Cell Immunoactivating Receptor (DCAR) remains undefined. For this reason, we investigated the potential role of this receptor in a mouse model of Pneumocystis murina infection. Wild type and DCAR-deficient C57BL/6 mice were infected with P. murina organisms via intratracheal instillation. Fungal burden was measured in the lung using quantitative Polymerase Chain Reaction. DCAR-deficient mice had a significantly reduced burden compared to wild type mice at Day 7 and 14 post-infection. To identify the immune components involved in pathogen clearance in these mice we measured cellular recruitment and cytokine production at both early (48 hours) and late (7, 14 and 21 days) time points. Flow cytometry analysis showed an increase in alveolar macrophage, dendritic cells, inflammatory monocytes, eosinophils and T cell recruitment to the lung. While ELISA showed increased levels of IL-1β and IFN-γ at 48 hours, and later on in infection IL-1β and IL-12p40 levels were also elevated. Histology analysis determined the localization of the recruited cells, and v interestingly showed an increase in mucus production at day 21 in DCARdeficient mice. In conclusion, we have identified DCAR deficiency as a potential driver of protective immunity in mice during P. murina infection. This may be associated with increased levels of IL-1β in DCAR-deficient mice. Furthermore, DCAR may also be important in adaptive inflammatory response regulation, as DCAR-deficient mice have increased cellular recruitment and mucus production later in infection. The mechanism by which the deletion of this receptor affords these mice the ability to efficiently clear P. murina remains to be determined. DA - 2020_ DB - OpenUCT DP - University of Cape Town KW - Pneumocystis murina KW - C-type lectin receptor KW - Dendritic Cell KW - Immunoactivating Receptor LK - https://open.uct.ac.za PY - 2020 T1 - Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina TI - Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina UR - http://hdl.handle.net/11427/32291 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/32291
dc.identifier.vancouvercitationMthembu NF. Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina. []. ,Faculty of Health Sciences ,Department of Clinical Laboratory Sciences, 2020 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/32291en_ZA
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Clinical Laboratory Sciences
dc.publisher.facultyFaculty of Health Sciences
dc.subjectPneumocystis murina
dc.subjectC-type lectin receptor
dc.subjectDendritic Cell
dc.subjectImmunoactivating Receptor
dc.titleInvestigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationlevelMSc
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