Natural killer T (NKT) cells recognize glycolipid antigens presented by CD1d. These cells express an evolutionarily conserved, invariant T cell receptor (TCR), but the forces driving TCR conservation have remained uncertain. Here we show that NKT cells recognize diacylglycerol-containing glycolipids from Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, and group B Streptococcus, which causes neonatal sepsis and meningitis. Furthermore, CD1d-dependent responses by NKT cells are required for activation and host protection. The glycolipid response was dependent on vaccenic acid, which is found at a low level in mammalian cells. Our results show how microbial lipids position the sugar for recognition by the invariant TCR, and most important, they extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.

h Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (⌬cap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When ⌬cap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Inhalation of the airborne fungal pathogens Cryptococcus neoformans and Cryptococcus gattii causes life-threatening infectious diseases despite treatment with antifungal drugs. These two species are genetically close, although they have some distinct features. C. neoformans typically causes fatal infections, such as meningitis, in immunocompromised hosts, whereas C. gattii causes similar infections in immunocompetent hosts. Although cryptococcosis caused by C. gattii is endemic in tropical areas, such as Australia and Papua New Guinea, outbreaks of C. gattii, including fatalities among healthy individuals, were reported on Vancouver Island and surrounding areas beginning in 1999 (1, 2). In response to this, the Centers for Disease Control and Prevention (CDC) of the United States and British Columbia organized a public health working group to promote awareness of this outbreak (3-5).Using mouse pulmonary infection models, two groups independently showed that C. gattii strain R265, which was clinically isolated during the Canadian outbreak, was more virulent than C. neoformans strain H99, which is frequently studied (6, 7). Although the mechanisms for its hypervirulence remain unknown, there is evidence that C. gattii induces a less severe inflammatory response than that induced by C. neoformans infection. Histological and flow cytometry analyses showed reduced migration of inflammatory cells into the lungs of mice infected with R265 compared with those infected with H99 (7-9). Additionally, a smaller amount of inflammatory cytokines was found in the lungs of mice infected with C. gattii (9) and in the cerebrospinal fluid of humans infected with C. gattii (10,11). These findings suggest that C. gattii has a superior ability to suppress or evade the inflammatory response.Previous studies indicated that one of the capsular components of C. gattii may have been involved in immune avoidance or immune suppression and was required for the complete virulence of...

We investigated the inhibitory effect of human immunoglobulin (h-Ig) on the development of coronary arteritis in a murine model of vasculitis induced with a Candida albicans water-soluble fraction (CAWS). CAWS was intraperitoneally injected to C57BL/6 mice for 5 days. Then h-Ig was administered according to various schedules. The animals were sacrificed in week 5, and the status of vasculitis in the coronary arteries and the aortic root was investigated histologically. The groups in which h-Ig was administered for 5 days from day 3 and from day 5 of the experiment showed a significant reduction in the incidence of panvasculitis. In addition, the scope and severity of the inflammation of the aortic root and the coronary arteries were reduced in both groups. In the group administered h-Ig for 5 days from day 1 and the group administered a high dose of h-Ig once on day 1 or day 3, no suppression of development of vasculitis was observed. The h-Ig acted by suppressing the generation and progression of vasculitis in this CAWS-induced murine vasculitis model.

Mannans are mannose polymers attached to cell wall proteins in all Candida species, including the pathogenic fungus Candida albicans. Mannans are sensed by pattern recognition receptors expressed on innate immune cells. However, the detailed structural patterns affecting immune sensing are not fully understood because mannans have a complex structure that includes α- and β-mannosyl linkages. In this study, we focused on the β-1,2-mannosides of N-linked mannan in C. albicans because this moiety is not present in the non-pathogenic yeast Saccharomyces cerevisiae. To investigate the impact of β-1,2-mannosides on immune sensing, we constructed a C. albicans ∆mnn4/∆bmt1 double deletant. Thin-layer chromatography and nuclear magnetic resonance analyses revealed that the deletant lacked β-1,2-mannosides in N-linked mannan. Mannans lacking the β-1,2-mannosides induced the production of higher levels of inflammatory cytokines, including IL-6, IL-12p40 and TNF-α, in mice dendritic cells compared to wild-type mannan. Our data show that β-1,2-mannosides in N-linked mannan reduce the production of inflammatory cytokines by dendritic cells.

Our results indicate that coinfecting commensal bacteria exacerbate C. albicans infection through IFN-γ produced, in part, by iNKT cells.