Special Issue: "Parasitic Infection and Host Immunity": Editorial.

Parasite-host interactions depend on a complex interplay between the metabolism of the parasite, their antigens, and the host immune response system [...].

X-linked immunodeficient (XID) mice exhibit high susceptibility to Cryptococcus gattii infection.

Cryptococcosis is an opportunistic disease caused by the fungus Cryptococcus neoformans and Cryptococcus gattii. It starts as a pulmonary infection that can spread to other organs, such as the brain, leading to the most serious occurrence of the disease, meningoencephalitis. The humoral response has already been described in limiting the progression of cryptococcosis where the B-1 cell seems to be responsible for producing natural IgM antibodies, crucial for combating fungal infections. The role of the B-1 cell in C. neoformans infection has been initially described, however the role of the humoral response of B-1 cells has not yet been evaluated during C. gattii infections. In the present study we tried to unravel this issue using XID mice, a murine model deficient in the Btk protein which compromises the development of B-1 lymphocytes. We use the XID mice compared to BALB/c mice that are sufficient for the B-1 population during C. gattii infection. Our model of chronic lung infection revealed that XID mice, unlike the sufficient group of B-1, had early mortality with significant weight loss, in addition to reduced levels of IgM and IgG specific to GXM isolated from the capsule of C. neoformans. In addition to this, we observed an increased fungal load in the blood and in the brain. We described an increase in the capsular size of C. gattii and the predominant presence of cytokines with a Th2 profile was also observed in these animals. Thus, the present study strongly points to a higher susceptibility of the XID mouse to C. gattii, which suggests that the presence of B-1 cells and anti-GXM antibodies is fundamental during the control of infection by C. gattii.

The role of Toll-like receptor 9 in a murine model of Cryptococcus gattii infection.

Toll-like receptor 9 (TLR9) is crucial to the host immune response against fungi, such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, but its importance in Cryptococcus gattii infection is unknown. Our study aimed to understand the role of TLR9 during the course of experimental C. gattii infection in vivo, considering that the cryptococcal DNA interaction with the receptor could contribute to host immunity even in an extremely susceptible model. We inoculated C57BL/6 (WT) and TLR9 knock-out (TLR9-/-) mice intratracheally with 104 C. gattii yeast cells. TLR9-/- mice had a higher mortality rate compared to WT mice and more yeast cells that had abnormal size, known as titan cells, in the lungs. TLR9-/- mice also had a greater number of CFUs in the spleen and brain than WT mice, in addition to having lower levels of IFN-γ and IL-17 in the lung. With these markers of aggressive cryptococcosis, we can state that TLR9-/- mice are more susceptible to C. gattii, probably due to a mechanism associated with the decrease of a Th1 and Th17-type immune response that promotes the formation of titan cells in the lungs. Therefore, our results indicate the participation of TLR9 in murine resistance to C. gattii infection.

Integrin alphaDbeta2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections.

The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin alphaDbeta2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. alphaDbeta2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of alphaD+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of alphaD conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of alphaD-/- animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of alphaD-/- animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for alphaDbeta2 in systemic infection. These studies identify previously unrecognized and unique activities of alphaDbeta2, and macrophages that express it, in host defense and injury.