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Humanized Mouse Model to Study Bacterial Infections Targeting the Microvasculature
Published on: April 1, 2014
Role of the mannose receptor in a murine model of Cryptococcus neoformans infection
Jennifer M Dan1, Ryan M Kelly, Chrono K Lee
1Department of Microbiology and Immunology Training Program, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Abstract:
Cryptococcus neoformans is an encapsulated fungal pathogen with a predilection to infect persons with suppressed T-cell function. Cryptococcal mannoproteins (MP) are highly mannosylated antigens which elicit T-cell responses in infected mice and in convalescent patients. Key to the immunogenicity of MP is its capacity to bind to the conserved mannose receptor (MR), CD206, on dendritic cells (DCs). To test the role of the MR in the immune response to C. neoformans, wild-type and MR knockout (MR KO) mice were compared by using in vivo and ex vivo models of cryptococcosis. Following a pulmonary challenge with C. neoformans, MR KO mice died significantly faster than wild-type mice and had higher lung fungal burdens after 4 weeks of infection. Uptake of MP was similar when DCs obtained from wild-type and MR KO mice were compared. Additionally, MP did not upregulate the maturation markers major histocompatibility complex class II, CD86, and CD40 in either wild-type or MR KO DCs. However, MP stimulated lymphoproliferation in CD4(+) T cells obtained from the peripheral lymph nodes of infected wild-type but not MR KO mice. These studies demonstrate a nonredundant role for the MR in the development of CD4(+) T-cell responses to MP and protection from C. neoformans.
Insights
The mannose receptor (MR) is crucial for CD4(+) T-cell responses against Cryptococcus neoformans. Blocking MR impairs T-cell immunity and increases fungal burden, highlighting MR
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcus neoformans is a fungal pathogen that primarily affects individuals with compromised T-cell immunity.
- Cryptococcal mannoproteins (MP) are key antigens that stimulate T-cell responses.
- The mannose receptor (MR), also known as CD206, on dendritic cells (DCs) is critical for MP immunogenicity.
Purpose of the Study:
- To investigate the role of the mannose receptor (MR) in the immune response to Cryptococcus neoformans.
- To compare the susceptibility and immune responses of wild-type and MR knockout (MR KO) mice to C. neoformans infection.
Main Methods:
- Pulmonary challenge model using C. neoformans in wild-type and MR KO mice.
- Ex vivo analysis of dendritic cell (DC) uptake of mannoproteins (MP).
- Assessment of DC maturation markers (MHC class II, CD86, CD40) and CD4(+) T-cell lymphoproliferation.
Main Results:
- MR KO mice exhibited increased mortality and higher fungal burdens in the lungs compared to wild-type mice.
- Mannoprotein uptake by DCs was comparable between wild-type and MR KO mice.
- MP did not induce maturation in DCs from either genotype, but stimulated CD4(+) T-cell proliferation in wild-type mice, but not MR KO mice.
Conclusions:
- The mannose receptor (MR) plays a nonredundant role in developing CD4(+) T-cell responses to cryptococcal mannoproteins (MP).
- MR is essential for protective immunity against C. neoformans infection.
