Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll-like receptor 4 antagonist.
Shigella dysenteriae causes the most severe of all infectious diarrhoeas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non-absorbable polypropyletherimine dendrimer glucosamine that is a Toll-like receptor-4 (TLR4) antagonist. Antibiotics were not given for this life-threatening infection. Six days later, the clinical score for diarrhoea, mucus and blood was 54% lower, colon interleukin-8 and interleukin-6 were both 77% lower, and colon neutrophil infiltration was 75% less. Strikingly, vasculitis did not occur and tissue fibrin thrombi were reduced by 67%. There was no clinical toxicity or adverse effect of dendrimer glucosamine on systemic immunity. This is the first report in non-human primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR4 antagonist can enable controlled resolution of the infection-related-inflammatory response and can also prevent neutrophil-mediated gut wall necrosis in severe infectious diarrhoeas.
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Dilara
D
Islam
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Eric
E
Lombardini
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Nattaya
N
Ruamsap
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Rawiwan
R
Imerbsin
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Patchariya
P
Khantapura
Department of Medicine, Imperial College London at Hammersmith Campus, London, UK.|Department of Infectious Diseases, Imperial College London at Hammersmith Campus, London, UK.|Department of Immunity, Imperial College London at Hammersmith Campus, London, UK.
Ian
I
Teo
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Pimmnapar
P
Neesanant
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Siriphan
S
Gonwong
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Kosol
K
Yongvanitchit
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Brett E
BE
Swierczewski
Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Carl J
CJ
Mason
Department of Medicine, Imperial College London at Hammersmith Campus, London, UK.|Department of Infectious Diseases, Imperial College London at Hammersmith Campus, London, UK.|Department of Immunity, Imperial College London at Hammersmith Campus, London, UK.|Department of Pathology, Imperial College London at Hammersmith Campus, London, UK.|Department of Chemistry, Imperial College London at Hammersmith Campus, London, UK.
Sunil
S
Shaunak
D000284:Administration, Oral; D000818:Animals; D000930:Antidiarrheals / Q000008:administration & dosage*; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D050091:Dendrimers / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005260:Female; D005944:Glucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D054884:Host-Pathogen Interactions; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008253:Macaca mulatta; D008297:Male; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D012720:Severity of Illness Index; D012762:Shigella dysenteriae / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
D000930:Antidiarrheals; D016207:Cytokines; D050091:Dendrimers; D051197:Toll-Like Receptor 4; C000607946:polypropyletherimine dendrimer glucosamine; D005944:Glucosamine
Toll-like receptor-4; bacterial diarrhoea; cytokines; inflammation