New insights into strengthening immune defence to cure diarrhoeal diseases

At a time when more and more infectious diseases are becoming resistant to antibiotics, a new study from icddr,b researchers working with international collaborators has shown promising insights into prompting the body’s self-defence mechanism to work against and cure infections.

Certain amino acid compounds in the body have the quality of working against infections. This new research by scientists from the Karolinska Institute, Sweden and University of Iceland with collaborators from icddr,b, showed that one such substance known as antimicrobial peptide (AMP) can  be produced in high amount to work against diarrhoeal disease caused by Shigella infection. Shigella-caused diarrhea or shigellosis is one of the major causes of diarrhoea worldwide affecting children in both developed and developing countries.

 

Pathogens' sensitivity to antibiotics shown in culture plate. Photo: Wellcome Images. CC BY-NC-ND 2.0

 

“Part of the research, conducted at icddr,b using an animal model, focused on host-directed therapy which would invoke the body’s own defence mechanism to become stronger to work against infections instead of relying on antibiotics,” says Dr Rubhana Raqib, senior scientist and co-author of the new study published in the prestigious Scientific Report of the Nature Publishing Group.

Antibiotic overuse has led to a massive worldwide increase in antibiotic resistance, posing a serious threat to global public health. Producing new antibiotics is a complex process requiring expensive clinical trials and extensive regulatory approvals. This new host-directed therapy for treating bacterial infections offers a potential way to overcome the growing crisis of antibiotic resistance.

This new study has shown that rabbits infected with the diarrhoeal pathogen Shigella recovered when treated with a chemical compound, which was earlier shown to induce AMP production in cultured cells. The compound has been undergoing trials to treat cancer and now applied in treatment of bacterial infections in this study.

 

Microscopic view of Shigella pathogens, responsible for dysentery. Photo: AJC1. CC BY-SA 2.0

 

“This medication can induce an AMP named LL-37 to be released in copious amounts from intestinal tissue and eliminate the Shigella pathogens from the body which causes dysentery,” says Dr Protim Sarker, an assistant scientist and the principal investigator of research conducted at icddr,b.

Using a drug specified for one disease to treat another disease is known as drug re-purposing. This is a growing worldwide phenomenon.  This research has shown how a drug developed for cancer could potentially be used to trigger innate immune response in the body and defeat bacterial infections”, says Dr Raqib.

Professor Birgitta Agerberth of Karolinska Institute, and Professor Guðmundur Hrafn Guðmundsson of University of Iceland, key investigators in this study, earlier discovered LL-37 AMP in the mid-1990s and earlier conducted research [1  2] on the antimicrobial properties of the LL-37 AMP.

A subsequent study in 2001 by icddr,b scientist Dr Dilara Islam showed that Shigella infection reduces the amount of LL-37 in the human body. This suggests that this specific AMP is an important component of the natural host response to bacterial infections, but pathogens like Shigella have evolved mechanisms to suppress this innate immune response.

In a series of studies led by Dr Raqib intriguingly showed that treatment with butyrate – a compound generally produced after eating fibrous food like green bananas – increased LL-37 in both animal and human body and decrease the severity of inflammation from Shigella-caused dysentery.

 

Butyrate from green bananas can reduce dysentery from Shigella. Photo: ChristinaEatsBrains. CC BY-NC-ND 2.0

 

More recently in 2010 a review co-authored by Dr Raqib discusses the idea that AMPs can be induced by compounds like butyrate, phenylbutyrate and vitamin D, and that host-directed therapies have successfully worked against shigellosis and tuberculosis.

These latest findings highlight the growing significance of novel host-directed therapies against infectious diseases in an age of antibiotic resistance. By leveraging our improved knowledge of immune cell biology, scientists can bridge basic research and clinical practice to discover completely new classes of antimicrobial drugs.

Muhammad Nabil

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