Cryptococcus gattii Species Complex as an Opportunistic Pathogen: Underlying Medical Conditions Associated with the Infection

Abstract

The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.

Keywords: Cryptococcus gattii species complex; anti-GM-CSF autoantibodies; molecular epidemiology; opportunistic pathogen; underlying medical conditions.

FIG 1

The global distribution of 135 C. gattii infection cases. (A) Number of C. gattii infection cases in five continents. The immune status of patients determined at the time of diagnosis for cryptococcosis and the molecular types of C. gattii isolates in Africa (B), America (C), Asia (D), Australia (E), and Europe (F). The inner ring shows the immune status of C. gattii-infected patients at the time of diagnosis, and the outer ring shows the molecular types of C. gattii isolates.

FIG 2

Molecular types of isolates obtained from patients. (A) Molecular types of total 135 clinical isolates. (B) Molecular types of 32 isolates from patients whose plasma was tested for the presence of functional GM-CSF autoantibodies. (C) Molecular types of 20 isolates from patients with anti-GM-CSF autoantibodies.

FIG 3

Molecular types of the total 133 isolates obtained from patients considered to be immunocompetent or immunosuppressed at the time of diagnosis for cryptococcosis.

FIG 4

Plasma samples from C. gattii patients tested for the presence of GM-CSF antibodies. (A) The immune status of 32 patients determined prior to (1) and after (2) the plasma test for the presence of GM-CSF autoantibody. (B) The functionality test of anti-GM-CSF autoantibody. Peripheral blood mononuclear cells (PBMCs) were incubated with 10% plasma from healthy volunteers (control) or GM-CSF antibody-positive patients. Cells were then unstimulated or stimulated with 1 ng/ml or 10 ng/ml GM-CSF. pSTAT5 production in PBMCs was analyzed by flow cytometry. Plasma from two patients, R104 and DW-1, tested for the presence of functional GM-CSF antibody are shown as examples.