Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice
Yoko Nakano, Chantal M. Longo-Guess, David E. Bergstrom, William M. Nauseef, Sherri M. Jones, Botond Bánfi
Yoko Nakano, Chantal M. Longo-Guess, David E. Bergstrom, William M. Nauseef, Sherri M. Jones, Botond Bánfi
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Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

Abstract

In humans, hereditary inactivation of either p22phox or gp91phox leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22phox and gp91phox proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22phox deficiency. Characterization of nmf333 mice revealed that deletion of p22phox inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22phox-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22phox represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22phox expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.

Authors

Yoko Nakano, Chantal M. Longo-Guess, David E. Bergstrom, William M. Nauseef, Sherri M. Jones, Botond Bánfi

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Figure 3

Necrotizing pneumonia in homozygous nmf333 mice following B. cepacia lung infection.

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Necrotizing pneumonia in homozygous nmf333 mice following B. cepacia lun...
(A) Probability of survival after inoculation with various CFU of B. cepacia (104 CFU, filled squares; 105 CFU, filled triangles; 106 CFU, open circles and filled circles) into the tracheas of WT (open circles; n = 8) and nmf333 (filled circles, filled triangles, filled squares; n = 5 or 6) mice. P = 0.0009 between the 106 CFU infected WT and nmf333 groups; log-rank test. (B) Number of B. cepacia recovered from the lung and spleen homogenates of WT and homozygous nmf333 mice 3.5 days after intratracheal inoculation with 104B. cepacia, as evaluated by quantitative culture; bacteria were not detected in lung and spleen homogenates from WT mice. Bars represent mean ± SEM (n = 3). **P = 0.029, *P = 0.043; t tests with 2 degrees of freedom. (C) Histopathological appearance of lung and spleen sections obtained from WT and homozygous nmf333 mice 3.5 days after intratracheal inoculation with 104 CFU B. cepacia. Whereas WT tissue samples had minimal or no inflammation, necrotizing pneumonia and splenitis were apparent in the nmf333 strain. Hematoxylin and eosin staining were used. Scale bars: 100 μm.