Pathophysiology of Citrobacter diversus neonatal meningitis: comparative studies in an infant mouse model

Abstract

Citrobacter diversus is a cause of devastating neonatal meningitis, with illness characterized by formation of multiple brain abscesses. We developed an infant mouse intracranial inoculation model to evaluate the pathophysiology of C. diversus neonatal infections. Eighteen of 26 strains inoculated intracranially at a dose of ca. 3.3 x 103 CFU caused >50% mortality in 2-day-old mice. No correlation was seen between the epidemiologic characteristics of a strain and its rate of mortality. When seven C. diversus isolates (four isolates from patients with meningitis, three from non-central nervous system [CNS] sites) were further evaluated, mortality was significantly correlated with bacteremia. The initial lesion in the CNS was a suppurative ventriculitis beginning 1 to 2 days postinoculation. Subsequent ventriculomegaly was associated with ventriculitis and periventricular abscessation. Brain lesions were seen with all strains, although strains of low virulence (as measured by having no bacteremia and low mortality) caused less-severe damage. An age-related susceptibility to C. diversus brain lesions was demonstrated, with 5-day-old mice showing a significant reduction in, and 8-day-old mice being apparently resistant to, infection and CNS damage. Our data indicate that C. diversus has a propensity to cause abscess formation in the neonatal mouse brain, with characteristic pathologic findings; however, the factors that determine whether a strain will cause meningitis in a human infant remain to be identified.

Comparative Genomic Analysis of Citrobacter and Key Genes Essential for the Pathogenicity of Citrobacter koseri

“…Previously research made use of infant mouse models to study the pathogenicity of C. koseri (Soriano et al, 1991). Some in vitro studies have shown that C. koseri is able to invade and replicate inside human U937 macrophages and human brain microvascular endothelial cells (Badger et al, 1999; Townsend et al, 2003).…”

“…To test our hypothesis, we generated a mutant strain that lacks all HPI clusters (ΔHPI:chlR) in C. koseri TBCP-5362. As previously described, two animal models were used in our study: 2-day-old SD rats and 18-day-old BALB/c mice (Soriano et al, 1991; Liu et al, 2019). Three groups of each animal model were inoculated with wild-type or ΔHPI mutants of C. koseri TBCP-5362 (∼5 × 10 5 colony forming units (CFUs) for 2-day-old SD rats and ∼1 × 10 7 CFUs for 18-day-old BALB/c mice).…”

Second Trimester Fetal Loss Due to Citrobacter koseri Infection: A Rare Cause of Preterm Premature Rupture of Membranes (PPROM)

“…Abscesses from C. koseri typically lack a fibrous capsule. Moreover, the bacteria invade meninges and ependyma, with subsequent parenchymal disruption and hydrocephalus [ 35 , 36 ].…”

Myocarditis in Sibling Boxer Puppies Associated withCitrobacter koseriInfection

“…C. koseri is an occasional inhabitant of human and animal intestines and of soil, water, sewage, and food 4. Although disease caused by this organism has not previously been reported in domestic animals, the bacteremia, meningitis, and multifocal brain abscessation described in humans has been experimentally reproduced in a murine model 14. Although it is not clear why C. koseri infection became established in these two puppies, immune naivety or intercurrent immunosuppression may have been contributory factors.…”