Salmonella Typhimurium Infection Leads to Colonization of the Mouse Brain and Is Not Completely Cured With Antibiotics

Abstract

Salmonella systemic infections claim thousands of lives worldwide even today. Certain cases lead to an infection in the brain culminating in meningitis and associated neurological abnormalities. Multiple reports have indicated neurological manifestations in patients suffering from typhoid fever during the course of infection and afterwards. While the meanderings of Salmonella systemic infections are fairly well studied, the flow of events in the brain is very poorly understood. We investigated the colonization of various brain parts by Salmonella in mice. It was observed that the bacterium is frequently able to invade various brain parts in mice. Selected mutants namely deletion mutants of key proteins encoded by the Salmonella pathogenicity islands (SPIs) 1 and 2 and ompA gene were also used to decipher the roles of specific genes in establishing an infection in the brain. Our results suggest roles for the Salmonella pathogenicity island (SPI) 1 and outer membrane protein A gene in enabling blood-brain barrier penetration by the pathogen. We further investigated behavioral abnormalities in infected mice and used an antibiotic treatment regime in an attempt to reverse the same. Results show some mice still display behavioral abnormalities and a high bacterial burden in brain despite clearance from spleen and liver. Overall, our study provides novel insights into S. Typhimurium's capacity to invade the mouse brain and the effectiveness of antibiotic treatment on behavioral manifestations due to infection. These observations could have important implications in understanding reported neurological manifestations in typhoid patients.

Salmonella Strain Specificity Determines Post-typhoid Central Nervous System Complications: Intervention by Lactiplantibacillus plantarum at Gut-Brain Axis

“…They excluded the role of previously documented Salmonella pathogenicity island 1 (SPI-1) locus (otherwise implicated in epithelial cell invasion) and suggested the possibility of yet another novel unexplored mechanism which might be responsible for hBMEC invasion (van Sorge et al, 2011). Another recent study, using the same Salmonella strain, has highlighted the role of SPI-1 and outer membrane protein A gene, aiding in host brain invasion (Chaudhuri et al, 2018). However, the exact mechanism still remains to be deciphered.…”

“…Typhoid associated neurological complications are associated with a very high mortality rate. Additional complications such as emerging antimicrobial resistance and the inability of antibiotics in treating such infections (Chaudhuri et al, 2018), suggest the use of probiotics as the most suitable recourse. Mounting evidence has highlighted the role of probiotics in influencing the gut-brain axis by modulating the gut microbiota composition (Rogers et al, 2016).…”

“…Similarly, increase in AChE at the neuromuscular junction might have contributed to a decrease in acetylcholine concentration, thereby making it fall below the threshold potential required for nerve transmission, resulting in cognitive decline and muscle fatigue. Since AChE is also considered to be an initiator in oxidative stress and plays a role in memory dysfunction, learning/memory loss associated with Salmonella infection of the brain, as documented by Chaudhuri et al (2018), could also be due to this facet. The effect of these molecules might be mediated via the vagal nerve activation or modulation of the enteric nervous system by them (Bercik et al, 2011;Bravo et al, 2011).…”

“…The present study, thus, elaborates on typhoid induced brain infection using Salmonella Typhimurium (known to cause typhoid like disease in murine model) which has been employed as a model for mimicking neurological complications occurring due to typhoid fever in humans (Wickham et al, 2007;Chaudhuri et al, 2018). To the best of our knowledge, this is the first report to explore whether the disseminative ability of Salmonella from gut to brain is strain specific or not.…”

“…Low index of suspicion, resulting in inability to provide prompt medication by the clinicians, has contributed to adverse outcome in patients (Samal et al, 2009). More importantly, inability of the existing antibiotics in treating such complications along with the emergence and spread of multi-drug resistant Salmonella, including colistin resistant (Rule et al, 2019) and extensively drug resistant strains (Khurshid et al, 2019), has worsened the situation, resulting in a serious dearth of effective antimicrobials in the treatment arsenal for this pathogen (Chaudhuri et al, 2018). Therefore, to combat such infections, efforts are being directed by the scientific community toward exploring various biocompatible strategies to which the organisms are not likely to acquire resistance.…”