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 6

The Cyba transgene reduces the B. cepacia susceptibility of the nmf333 strain.

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The Cyba transgene reduces the B. cepacia susceptibility of the nmf333 s...
(A) The Cyba transgene consists of a CMV immediate-early enhancer, a chicken β-actin promoter, a chimeric intron, the p22phox-encoding Cyba sequence, and an SV40 polyadenylation (polyA) site. (B) Blue colorimetric test for superoxide production in PMA-stimulated neutrophil granulocytes isolated from homozygous nmf333 mice and from Cyba-transgenic homozygous nmf333 [Tg(Cyba)-nmf333] mice. Two neutrophils are visible in each. Nuclei were stained with Safranin O. Original magnification, ×63. Images are representative of n = 38. (C) Quantitative analysis of superoxide production by PMA-activated neutrophil granulocytes isolated from homozygous nmf333 mice, Cyba-transgenic homozygous nmf333, and WT mice. Superoxide production was assessed using the superoxide dismutase–sensitive ferricytochrome c reduction assay. Horizontal lines indicate the mean rate of superoxide production; each circle represents a single mouse (n = 5 to 8 mice). One-way ANOVA, P < 0.0001. post hoc Tukey’s test: *P < 0.05, **P < 0.01. (D) Probability of survival of homozygous nmf333 mice (filled squares; n = 5) and of Cyba-transgenic homozygous nmf333 mice (open triangles; n = 7) after intratracheal inoculation with 104 CFU B. cepacia (log-rank test, P = 0.0004). (E) Typical histological appearance of lung sections prepared from Cyba-transgenic homozygous nmf333 mice 3.5 days after intratracheal inoculation with 104 CFU B. cepacia (n = 3). Left: low-magnification overview. Right: higher-magnification view of peribronchial inflammation in the boxed region. Scale bars: 100 μm.