Cryptococcosis is a disease caused by the pathogenic fungi Cryptococcus neoformans and Cryptococcus gattii, both environmental fungi that cause severe pneumonia and may even lead to cryptococcal meningoencephalitis. Although C. neoformans affects more fragile individuals, such as immunocompromised hosts through opportunistic infections, C. gattii causes a serious indiscriminate primary infection in immunocompetent individuals. Typically seen in tropical and subtropical environments, C. gattii has increased its endemic area over recent years, largely due to climatic factors that favor contagion in warmer climates. It is important to point out that not only C. gattii, but the Cryptococcus species complex produces a polysaccharidic capsule with immunomodulatory properties, enabling the pathogenic species of Cryptococccus to subvert the host immune response during the establishment of cryptococcosis, facilitating its dissemination in the infected organism. C. gattii causes a more severe and difficult-to-treat infection, with few antifungals eliciting an effective response during chronic treatment. Much of the immunopathology of this cryptococcosis is still poorly understood, with most studies focusing on cryptococcosis caused by the species C. neoformans. C. gattii became more important in the epidemiological scenario with the outbreaks in the Pacific Northwest of the United States, which resulted in phylogenetic studies of the virulent variant responsible for the severe infection in the region. Since then, the study of cryptococcosis caused by C. gattii has helped researchers understand the immunopathological aspects of different variants of this pathogen.

Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm. In this study, we report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines. Our results show abnormal cytokine levels upon T-cell stimulation, in a nonpolarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28⁻CD57⁺ cells. Of note, we demonstrated for the first time an increased frequency of CD3⁺CD4⁺CD28⁻CD57⁺ T cells with expression of programmed death 1, one of the hallmarks of T-cell exhaustion. These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4⁺ T-cell compartment, and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events.

Cryptococcus neoformans is a lethal fungus that primarily affects the respiratory system and the central nervous system. One of the main virulence factors is the capsule, constituted by the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomanogalactan (GXMGal). Polysaccharides are immunomodulators. One of the target cell populations for modulation are macrophages, which are part of the first line of defense and important for innate and adaptive immunity. It has been reported that macrophages can be modulated to act as a “Trojan horse,” taking phagocytosed yeasts to strategic sites or having their machinery activation compromised. The scarcity of information on canine cryptococcosis led us to assess whether the purified capsular polysaccharides from C. neoformans would be able to modulate the microbicidal action of macrophages. In the present study, we observed that the capsular polysaccharides, GXM, GXMGal, or capsule total did not induce apoptosis in the DH82 macrophage cell line. However, it was possible to demonstrate that the phagocytic activity was decreased after treatment with polysaccharides. In addition, recovered yeasts from macrophages treated with polysaccharides after phagocytosis could be cultured, showing that their viability was not altered. The polysaccharides led to a reduction in ROS production and the mRNA expression of IL-12 and IL-6. We observed that GXMGal inhibits MHC class II expression and GXM reduces ERK phosphorylation. In contrast, GXMGal and GXM were able to increase the PPAR-γ expression. Furthermore, our data suggest that capsular polysaccharides can reduce the microbicidal activity of canine macrophages DH82.

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 gattii is a saprophytic basidiomycete that grows in the environment and can cause systemic cryptococcosis. Ocular cryptococcosis causes blindness and is commonly associated with central nervous system infection. Toll-like receptor 9 (TLR9) can control cryptococcosis and other mycoses. Here, using C57BL/6 TLR9 knockout mice (TLR9−/−), we evaluated the role of TLR9 signaling in ocular involvement during systemic C. gattii infection. We observed ocular impairment and found a high fungal burden in the retina, vitreous humor, and optic nerve of TLR9−/− mice 3 weeks after infection. Capsular polysaccharide glucuronoxylomannan deposition, astrogliosis, and morphological alterations in retina led to progressive blindness of TLR9−/− mice. The phenomenon observed in our work had not been explored previously in a murine model. These results contribute to the understanding of the role of TLR9 during ocular cryptococcosis. Therapies using TLR9 agonists may be important for the treatment of ocular cryptococcosis.

Fungal infections are the most common secondary infections in debilitated individuals in a state of chronic disease or immunosuppression. Despite this, most fungal infections are neglected, mainly due to the lower frequency of their more severe clinical forms in immunocompetent individuals with a healthy background. However, over the past few years, several cases of severe fungal infections in healthy individuals have provoked a change in the epidemiological dynamics of fungal infections around the world, both due to recurrent outbreaks in previously infrequent regions and the greater emergence of more pathogenic fungal variants affecting healthy individuals, such as in the Cryptococcus genus. Therefore, before the arrival of a scenario of prevalent severe fungal infections, it is necessary to assess more carefully what are the real reasons for the increased incidence of fungal infection globally. What are the factors that are currently contributing to this new possible epidemiological dynamic? Could these be of a structural nature? Herein, we propose a discussion based on the importance of the virulence factors of glycoconjugate composition in the adaptation of pathogenic fungal species into the current scenario of increasing severity of these infections.