Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

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.Cryptococcus neoformans is an opportunistic fungal pathogen which preferentially afflicts immunocompromised persons, particularly those with AIDS or lymphoid malignancies and recipients of immunosuppressive treatments for solid organ transplants (2). The primary site of infection is generally the lungs. While exposure is thought to be common, most immunocompetent persons are able to contain the infection. However, in the absence of effective CD4 ϩ T-cell responses, the organism can disseminate and eventually cross the blood-brain barrier to produce cryptococcal meningitis (18).The inverse correlation between CD4 ϩ T-cell function and the propensity to develop cryptococcosis has prompted investigators to search for antigens which drive the cell-mediated immune response. In this regard, a family of heavily mannosylated proteins, termed mannoproteins (MP), has been identified as immunodominant antigens in mouse models of cryptococcosis and in patients who have recovered from infection (1,16,26). MP possess serine-and threonine-rich C-terminal regions which serve as sites for extensive O-linked mannosylation. Additional mannosylation may be provided via N linkages (17). These areas of O-linked and N-linked mannosylation promote the recognition of MP by host receptors for mannose, in particular, the mannose receptor (MR, CD206) and dendritic cell (DC)-specific intercellular adhesion molecule 3 grabbing nonintegrin (CD209) (17,21). DCs are the main antigenpresenting cells responsible for the uptake, processing, and presentation of MP to CD4 ϩ T cells (21, 22). Blocking receptors for mannose with mannan or deglycosylating MP results in strongly diminished T-cell responses (21,22,32).The MR is a C-type lectin receptor which recognizes terminally mannosylated molecules (24...

Modulation of Toll-Like Receptor 2 (TLR2) and TLR4 Responses byAspergillus fumigatus

“…Despite its reported ability to recognize fungi like Candida albicans, Cryptococcus neoformans, and Pneumocystis, little is known about the role of MR as a PRR for A. fumigatus (3,6,26). This is intriguing given that terminal mannose, fucose, and N-acetylglucosamine are established ligands for MR (35) and such mannose-based moieties are a major component of the Aspergillus cell wall (15).…”

Increased Accumulation of Regulatory Granulocytic Myeloid Cells in Mannose Receptor C Type 1-Deficient Mice Correlates with Protection in a Mouse Model of Neurocysticercosis

“…Our data show that several CLRs, including mannose receptor C type 1 (MRC1), are induced during NCC in CNS cells as well as infiltrating cells (19,20). MRC1 is an endocytic receptor which has been shown to play a crucial role in mediating inflammatory immune responses against pathogens such as Mycobacterium tuberculosis, Cryptococcus neoformans, and Candida albicans (21)(22)(23)(24). It is a 175-kDa type I membrane protein which contains 8 C-type lectin domains (CTLDs), 1 fibronectin type II domain, and 1 cysteine-rich (CR) domain.…”

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

“…MR synergizes with TLR and lectins in immune sensing of C. albicans [45] and regulates proinflammatory cytokine production induced by Mycobacteria through interfering with TLR2-mediated signaling [46]. MR-mediated signaling could be positive [47] or negative [48,49] depending on the structure of stimulus or the site of infection. Signals originated from the cell surface converge into two major intracellular targets, NF-kB and MAPK activation.…”