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

Abstract

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.

Cryptococcus: History, Epidemiology and Immune Evasion

“…Titan cells have been found in both C. neoformans and C. gattii [185,186]. These yeasts have a size greater than 20 µm in cell body diameter and have a greater-than-normal capsular thickening, which gives the yeast greater external coverage with its structural virulence factors [187,188]. A characteristic that the fungus has during infection is the tropism for the central nervous system [189], and associated with this, the titanization of the yeast is a morphological modification that is linked to favoring the spread to this region of the organism; however, C. gattii is less likely to disseminate to the CNS as compared to C. neoformans, and C. gattii is more likely to present as pneumonia [171,190].…”

“…This profile is associated with less control in fungal dissemination and less oxidative capacity to eliminate yeast intracellularly [214]. In addition, the result of a Th2-induced lymphocyte profile is also associated with reduced infection control [187,215]. In this sense, an immunological alteration caused by the opportunistic infection of Cryptococcus spp.…”

“…Specifically, natural IgM produced by B-1 lymphocytes appears to mediate antifungal immunity in the early stages of infection caused by C. neoformans [244,245]. However, not only the production of natural IgM seems to be related to the reduction in the predisposition to the formation of titan yeasts, but the population of B-1 lymphocytes seems to limit this phenotype that is associated with the worsening of the C. gattii and C. neoformans infection [187,190,246]. This demonstrates the importance that the B lymphocyte population as a whole seems to have in anticryptococcal immunity, especially when it is associated with the clinical description of a higher incidence of C. neoformans cryptococcosis in human individuals who have compromised B lymphocyte populations [247,248].…”

The Sweet Side of Fungal Infections: Structural Glycan Diversity and Its Importance for Pathogenic Adaptation

“…Historically, the pathogenic species of the genus Cryptococcus, Crytococcus neoformans and Cryptococcus gattii were fungi known to chronically establish a silent infection with difficult diagnosis in the early stages of disease progression [3]. This is mainly complicated by the low spectrum of effective antifungal drugs for the most serious infections [4], especially when associated with the spread of the pathogenic microorganism to critical host tissues such as the central nervous system where it can lead to severe fungal meningoencephalitis [5,6]. In particular, there are indications that the dynamics of infections caused by Cryptococcus spp.…”

“…These polysaccharides, mostly found in the cell wall, play an important structural role, and many are conserved among different species of fungi [47]. One of the main components present in the fungal cell wall is the β-glycans, with the β-(1,3)glycan being the most abundant in C. albicans species and β- (1,6)-glycan in C. neoformans species [48,49]. These components provide structural stability to the fungal cell and a way of interacting with host cells.…”