Capsular polysaccharide A (PSA) protect against fatal neuroinflammation

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01AMSSHJ - Coloured axial computed tomography (CT) scan of an adult's brain, showing encephalitis in the right temporal caused by an infection with herpes virus (encephalitis herpetica, in yellow). Encephalitis results in the inflammation of the encephalon.

The existence of certain microorganisms in your gut may bolster the immune system’s ability to fend off a herpes viral attack that can cause fatal brain inflammation, reports a new City of Hope-led study.

Researchers say the findings are the first to suggest that an envelope molecule from a bacterium called Bacteroides fragilis (B. fragilis) might be useful against viral inflammatory diseases. Called capsular polysaccharide A (PSA), the envelope molecule appears to promote protective, anti-inflammatory responses during a viral infection, said Ramakrishna Chandran, Ph.D., and Edouard Cantin, Ph.D., authors of the study and virology and immunology experts at City of Hope.


The Bacteroides fragilis group comprises the most important anaerobic pathogens in human infections.

These pathogens are often associated with polymicrobial infections such as intra-abdominal, obstetric-gynecologic, diabetic foot, and skin and skin structure infections.

The virulence of these pathogens contributes to the spread of the infection, abscess formation, and the production of an antiphagocytic polysaccharide capsule (6).

Documented increases in antimicrobial resistance to β-lactams and clindamycin have been reported (528).

β-Lactam resistance is mediated predominantly by production of β-lactamase enzymes among both gram-negative and -positive bacilli, as well as Acidaminococcus (61422).

The incidence of β-lactamase production among the B. fragilis group has been reported to be ≥95% of isolates (6).

These enzymes have been characterized primarily as cephalosporinases; however, penicillinases and carbapenemases have also been reported (8171822232730).

Anaerobic bacteremia is an infrequent infection; however, it can result in a high mortality rate.

Two previous studies (910) of Bacteroides bacteremia determined that the mortality rate varied according to the species isolated. Bacteremia due to B. fragilis had associated mortality rates of 24 and 31%, respectively, whereas the mortality rate for B. distasonis was 50% and that for B. thetaiotaomicron was as high as 100%.

More recently Redondo et al. (25) compared a group of patients with B. fragilis group bacteremia to a demographically matched-pair group of patients without bacteremia.

The mortality rate was significantly higher in the bacteremic group (28% versus 8.7%, P = 0.002) and had a mortality risk ratio of 4.9.

Moreover, patients with bacteremia remained in the hospital 16 days longer.

These authors also reported that the most common source of bacteremia was associated with bowel surgery or disease.

Risultati immagini per Bacteroides fragilis

Montravers et al. (19) studied 100 patients who developed postoperative peritonitis due to aerobes and anaerobes and compared their clinical outcome to the appropriateness of their antimicrobial therapy based on in vitro susceptibility data.

Patients who were infected with resistant isolates had a significantly higher mortality rate than those infected with susceptible isolates (45% versus 16%, P < 0.05).

These authors concluded that the choice of initial empirical therapy directly affected the clinical outcome and that the subsequent change of antibiotic therapy based on

culture results did not affect clinical outcome when the initial therapy was judged as inadequate.

In a similar study recently reported by Nguyen et al. (21), a multicenter, observational study of 128 patients with Bacteriodes bacteremia compared the clinical outcome of these patients with the in vitro susceptibility of their blood isolates.

The mortality rate of patients who received appropriate therapy (susceptible in vitro) was 16% compared to patients who received inappropriate therapy (resistant in vitro), whose mortality rate was 45% (P = 0.04).

Microbiological persistence was higher with inactive versus active therapy (42% versus 12%, P = 0.06). That study concluded that in vitro susceptibility results reliably predicted the clinical outcome of the patients with a specificity of 97% and positive predictive value of 82%.

We report here the results of a retrospective analysis of in vitro susceptibility of B. fragilis group blood isolates as a subset of >3,600 isolates tested from 1987 to 1999.


“This mouse study shows that B. fragilis PSA can temper the immune system so that infection does not result in an uncontrolled, potentially fatal inflammatory response in the brain,” Cantin said.

“Although herpes simplex encephalitis is a rare brain inflammation disorder, the lessons we learned here might, with more research, be applicable to other viral infections such as other herpesviruses, influenza virus, West Nile virus and maybe even viral respiratory diseases – conditions where inflammation begins to jeopardize the health of your body and brain function.”

Herpes simplex encephalitis affects about 2,000 people in the United States each year and has a high mortality rate if symptoms are not recognized and patients aren’t treated promptly; survivors usually have serious neurological conditions.

About 70% of untreated individuals die, according to multiple scientific reports.

The study, published in Nature Communications on May 14, found that B. fragilis‘ bacterial envelope, PSA, brings forth regulatory T and B cells that suppress the immune system from overproducing harmful inflammatory responses triggered by herpes simplex virus infection.

In other words, PSA reduced brainstem inflammation by promoting the appearance of IL-10 secreting regulatory T and B cells.

IL-10 is a strong anti-inflammatory cytokine which creates a protective, anti-inflammatory response that prevents encephalitis.


Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis.

Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases.

Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response.


“It’s possible that consumption of certain prebiotics, probiotics or synbiotics may enhance your body’s natural ability to suppress inflammatory diseases,” Chandran said.

“Our study provides an exciting proof of principle that needs further research validation, but it seems reasonable that what you decide to eat may affect your overall health and ability to fight off disease.”

Chandran, Cantin and their colleagues found that mice pretreated with the candidate probiotic, B. fragilis or PSA, survived a lethal herpes simplex virus infection, whereas mice pretreated with a placebo did not survive despite the fact that both groups were given Acyclovir, an antiviral that is the standard of care for herpes simplex virus encephalitis.

The finding suggests that the probiotic-derived PSA optimizes the immune system to fight against viruses, especially those that induce damaging inflammation.

Risultati immagini per Herpes simplex encephalitis

Herpes simplex encephalitis

Herpes simplex encephalitis affects about 2,000 people in the United States each year and has a high mortality rate if symptoms are not recognized and patients aren’t treated promptly; survivors usually have serious neurological conditions.

About 70% of untreated individuals die, according to multiple scientific reports.

The researchers reported on the important role B cells play in extinguishing inflammation.

B cells are a type of white blood cell that secretes antibodies. When the scientists depleted mice of their B cells prior to PSA treatment, the mice lost their ability to marshal regulatory T cells and to secrete the anti-inflammatory cytokine IL-10.

The researchers showed that B cells bound PSA, and this was crucial for the induction of protective regulatory T cells, which secrete the anti-inflammatory cytokine IL-10. Thus, eliminating B cells rendered the immune system weaponless in the fight against fatal herpes simplex virus brain inflammation.

Sarkis Mazmanian, Ph.D., from the California Institute of Technology also contributed to this research, which was supported by the Caltech and City of Hope Biomedical Research Initiative and the City of Hope Shared Resources Pilot Program.

Source:
City of Hope
Media Contacts: 
Zen Vuong – City of Hope
Image Source:
The image is in the public domain.

Original Research: Open access
Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis”. Chandran Ramakrishna, Maciej Kujawski, Hiutung Chu, Lin Li, Sarkis K. Mazmanian & Edouard M. Cantin .
Nature Communications. doi:10.1038/s41467-019-09884-6

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