Abstract
Few live attenuated vaccines protect against multiple serotypes of bacterial pathogen because host serotype-specific immune responses are limited to the serotype present in the vaccine strain. Here, immunization with a mutant of Shigella flexneri 2a protected guinea pigs against subsequent infection by S. dysenteriae type 1 and S. sonnei strains. This deletion mutant lacked the RNA-binding protein Hfq leading to increased expression of the type III secretion system via loss of regulation, resulting in attenuation of cell viability through repression of stress response sigma factors. Such increased antigen production and simultaneous attenuation were expected to elicit protective immunity against Shigella strains of heterologous serotypes. Thus, the vaccine potential of this mutant was tested in two guinea pig models of shigellosis. Animals vaccinated in the left eye showed fewer symptoms upon subsequent challenge via the right eye, and even survived subsequent intestinal challenge. In addition, oral vaccination effectively induced production of immunoglobulins without severe side effects, again protecting all animals against subsequent intestinal challenge with S. dysenteriae type 1 or S. sonnei strains. Antibodies against common virulence proteins and the O-antigen of S. flexneri 2a were detected by immunofluorescence microscopy. Reaction of antibodies with various strains, including enteroinvasive Escherichia coli, suggested that common virulence proteins induced protective immunity against a range of serotypes. Therefore, vaccination is expected to cover not only the most prevalent serotypes of S. sonnei and S. flexneri 2a, but also various Shigella strains, including S. dysenteriae type 1, which produces Shiga toxin.
Highlights
A Global Enteric Multicenter study indicated that S. flexneri (65.9%), serotype 2a (20.2%), and S. sonnei (23.7%) are the most prevalent strains isolated from patients aged
Consistent with our previous studies [27,28,29], we found that a mutant of S. flexneri 2a harboring a deletion of the hfq gene (Δhfq: MF4835) expressed InvE and a T3SS effector (IpaB) at the repressive temperature of 30 ̊C (S1A Fig)
When 1.0×109 cfu of bacteria were injected into colon loop segments in vivo, the mutant caused less severe symptoms (Fig 1A, a and 1B); a high invasion rate was observed at the early stage (6 hr) (Fig 1D, white bars)
Summary
Vaccines against shigellosis are being developed [3, 4]. Shigella strains comprise four subspecies: S. dysenteriae, S. flexneri, S. sonnei, and S. boydii. These are further divided into 50 distinct serotypes [1, 3] according to the immunogenicity of capsular lipopolysaccharide O-antigens. S. sonnei is the most prevalent strain in industrialized countries [1]; imported epidemics of Sd1 with HUS have been reported [6]. A Global Enteric Multicenter study indicated that S. flexneri (65.9%), serotype 2a (20.2%), and S. sonnei (23.7%) are the most prevalent strains isolated from patients aged
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