X-Linked Immunodeficient Mice Exhibit Enhanced Susceptibility to Cryptococcus neoformans Infection

Abstract

Bruton’s tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance to Cryptococcus neoformans infection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6 weeks after infection with C. neoformans strain 52D (CN52D); however, consistent with the propensity for greater virulence of C. neoformans strain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3 weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total and C. neoformans-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellular C. neoformans cells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6 weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancing C. neoformans phagocytosis and restricting C. neoformans enlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs.

The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1–Sphingosine 1-Phosphate Pathway

“…(i) The increase in MCP-1 levels in both studies was time dependent; thus, it is possible that the mice infected with the wild-type strain did not survive long enough to demonstrate a spike in MCP-1 (the mice died in an average of 21 days, with the latest measurement being performed at 16 days postinfection). (ii) The strain used in the study of Huffnagle et al (33), strain 52D, is less virulent than the strain used in the current study, strain H99 (43). It is possible that a stronger immune response is elicited against less virulent cryptococcal strains, and this notion is consistent with our observations that MCP-1 levels were significantly increased in response to the attenuated C. neoformans ⌬gcs1 strain but not in response to the wild type.…”

Immunity against fungi

“…For example, natural fungal polysaccharide-targeting IgM antibodies enhance DC-mediated recognition of fungal antigen, the development of Th2 and Th17 responses, and B cell isotype class-switch recombination during murine pneumocystosis (108). In a model of X-linked agammaglobulinemia, pulmonary and CNS cryptococcal disease progressed rapidly, in part due to IgM-dependent defects in macrophage phagocytosis (109). Although there is significant support for the concept that antibody-dependent opsonization and complement activation enhance fungal clearance in animal models (107), loss of antibody-mediated immunity is generally compensated by alternate effector systems, such as myeloid and CD4 + T cell-mediated immunity.…”

Adaptive Immunity to Fungi

“…However, the advent of monoclonal antibody technology made it possible to identify the protective effects of immunoglobulins against fungi. Since then, the impact of immunoglobulins and B cells secreting them has been well scrutinized in C. neoformans (Aguirre and Johnson 1997;Rivera et al 2005;Szymczak et al 2013), C. albicans (Wahab et al 1995;Matthews and Burnie 2001;Saville et al 2008), H. capsulatum (Nosanchuk et al 2003), and Pneumocystis sp. infections (Rapaka et al 2010) (Fig.…”