Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis

Rohatgi, Soma; Nakouzi, Antonio; Carreño, Leandro J.; Slosar-Cheah, Magdalena; Kuniholm, Mark H.; Wang, Tao; Pappas, Peter G.; Pirofski, Liise Anne

doi:10.1093/ofid/ofx255

Cited by 29 publications

(32 citation statements)

References 15 publications

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“…Consistent with earlier reports, circulating B cells from untreated HIV viremic patients show diffuse B cell activation, deficits in memory B cells, and increased representation of tissue-like memory and plasmablast/plasma cells (24)(25)(26). The impaired B cell responses due to HIV infection are seen to influence B cell responses in cryptococcosis coinfection (27). This underpins the importance of host immune responses in the primary infection (HIV infection) in determining immunological outcomes of secondary or super infections (cryptococcosis coinfection).…”

Section: Discussionsupporting

confidence: 89%

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

et al. 2020

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Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal (n = 31) and noncryptococcal (n = 12) meningitis and in heathy control subjects with neither infection (n = 10). Activation of circulating B cells (CD21low) was significantly higher in the blood of subjects with HIV infection than in that of healthy controls and greater yet in matched CSF B cells (P < 0.001). Among B cell subsets, elevated frequencies of memory and plasmablasts/plasma cells most clearly distinguished the CSF from blood compartments. With cryptococcal meningitis, lower frequencies of expression of the regulatory protein programmed death-1 (PD-1) on plasmablasts/plasma cells in blood (median, 7%) at presentation were associated with significantly decreased 28-day survival (29% [4/14 subjects]), whereas higher PD-1 expression (median, 46%) characterized subjects with higher survival (88% [14/16 subjects]). With HIV infection, B cell differentiation and regulatory markers are discrete elements of the circulating and CSF compartments with clinical implications for cryptococcal disease outcome, potentially due to their effects on the fungus and other local immune cells.

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Section: Discussionsupporting

confidence: 89%

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

et al. 2020

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“…These findings may help explain why C. neoformans in the lungs of C. neoformans-infected IgM-deficient XID mice were markedly larger than those in control mice (28). In humans, cryptococcal disease status is associated with lower levels of IgM memory B cells (which produce IgM) and/or IgM in multiple studies (22,25,26,34). This lends strength to the idea that patient immunoglobulin levels may affect C. neoformans biology in vivo.…”

Section: Discussionmentioning

confidence: 77%

Human IgM Inhibits the Formation of Titan-Like Cells in Cryptococcus neoformans

et al. 2020

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Human studies have shown associations between cryptococcal meningitis and reduced IgM memory B cell levels, and studies in IgM- and/or B cell-deficient mice have demonstrated increased Cryptococcus neoformans dissemination from lungs to brain. Since immunoglobulins are part of the immune milieu that C. neoformans confronts in a human host, and its ability to form titan cells is an important virulence mechanism, we determined the effect of human immunoglobulins on C. neoformans titan cell formation in vitro. (i) Fluorescence microscopy showed normal human IgG and IgM bind C. neoformans. (ii) C. neoformans grown in titan cell-inducing medium with IgM, not IgG, inhibited titan-like cell formation. (iii) Absorption of IgM with laminarin or curdlan (branched and linear 1-3-beta-d-glucans, respectively) decreased this effect. (iv) Transmission electron microscopy revealed that cells grown with IgM had small capsules and unique features not seen with cells grown with IgG. (v) Comparative transcriptional analysis of cell wall, capsule, and stress response genes showed that C. neoformans grown with IgM, not IgG or phosphate-buffered saline (PBS), had decreased expression of chitin synthetase, CHS1, CHS2, and CHS8, and genes encoding cell wall carbohydrate synthetases α-1-3-glucan (AGS1) and β-1,3-glucan (FKS1). IgM also decreased expression of RIM101 and HOG1, genes encoding central regulators of C. neoformans stress response pathways and cell morphogenesis. Our data show human IgM affects C. neoformans morphology in vitro and suggest that the hypothesis that human immunoglobulins may affect C. neoformans virulence in vivo warrants further investigation.

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“…Whole genome sequencing or exome sequencing of the patient could have determined if any of these underlying non-HIV related predisposing factors played a role in the patient’s acquisition of disease but were not performed in this study. Additionally, there is data to suggest that total and memory B-cell levels are lower in HIV-uninfected patients with C. neoformans infections (42). However, only limited flow cytometry measuring T-cell but not B-cell populations was analyzed in the patient.…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus deuterogattii VGIIa infection associated with travel to the Pacific Northwest outbreak region in an anti-GM-CSF autoantibody positive patient in the United States

Clancey

Ciccone

Coelho

et al. 2019

Preprint

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The Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington have been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver three years earlier and Costa Rica four months prior to presentation. Phenotypic evidence shows the fungal mass isolated from the patient's brain is C. gattii. In agreement with the phenotypic results, MLST provides genotypic evidence that assigns the infecting organism within in the C. gattii species complex and belonging to the C. deuterogattii VGIIa clade. Whole genome sequencing revealed >99.99% identity to the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude the patient acquired the C. gattii infection during his travel to region three years prior and the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor a risk factor associated with C. gattii infection.

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Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis

Cited by 29 publications

References 15 publications

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

Human IgM Inhibits the Formation of Titan-Like Cells in Cryptococcus neoformans

Cryptococcus deuterogattii VGIIa infection associated with travel to the Pacific Northwest outbreak region in an anti-GM-CSF autoantibody positive patient in the United States

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