G Proteins Gα i1/3 Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

Abstract

ABSTRACT Pertussis toxin (PTX) is an AB5-type exotoxin produced by the bacterium Bordetella pertussis , the causative agent of whooping cough. In vivo intoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H 1 receptor ( Hrh1 /H 1 R) as the gene in mice that controls differential susceptibility to B. pertussis PTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F 1 hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gα i/o G-protein subunits, we demonstrate that Gα i1 and Gα i3 are the critical in vivo targets of ADP-ribosylation underlying VAAS elicited by PTX exposure.