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Identification of leprosy associated immune signatures

  • Grant: LRI Regular Grant
  • Research priorities: Disability
  • Country: India
  • Project no.: 704.16.57
  • Budget: € 147,676
  • Duration: January 2016 - January 2020
  • Status: Completed
  • Co-funding partners: Turing Foundation

Turing Foundation leprosy

Full project title:
To identify leprosy associated Mycobacterium leprae transcriptomic and human host immune signatures that aid as early signals for determination of type I and type II reactions in leprosy

Project coordination
The Schieffelin Institute of Health-Research and Leprosy Centre (India)

Partners
Leiden University Medical Centre (the Netherlands)

Aim: This study used molecular biology techniques to develop a laboratory test for early diagnosis of type I and type II reactions in leprosy.

Final project summary
Estimation of gene expression profiles using Real time PCR 1Reactions are major cause of nerve damage and ensuing disability in leprosy. Mycobacterium leprae invades the macrophages incirculation and Schwann cells of the peripheral nerve cells eliciting immune responses that often exacerbate as hypersensitivity reactions. Predicting the onset of these reactional episodes may aid in early treatment interventions with anti-inflammatory drugs and prevention of consequent nerve damage. This study focused on identifying gene expression and serological markers that demonstrate an association with type I and type II reactions in leprosy.

Blood and skin biopsy samples were taken from the leprosy patients and genetic material was extracted. Laboratory assays were performed with this material to check the genes that show differences in function between the leprosy cases in reactions and those not in reactions. These genes are chosen and the proteins they encode are used in the development of laboratory test.

In the cross section arm of the study, the researchers conducted in-depth qualitative analysis of the genome of M. leprae and recognised differences in the expression of various genes between type I, type II and cases without any reactions. State-of-the-art whole transcriptome microarraysfrom Agilent Inc. were developed for M. leprae for the first time to study gene expressions across the transcriptome. These arrays are now commercially available for research use.

Additionally, the study explored the variations in human immune gene expressions between the study groups. Along with the gene expressionmarkers, researchers also studied variations in circulatory levels of immune molecules such as cytokines, chemokines and growth factors in the serum extracted from peripheral venous blood and T cell culture supernatant samples. Statistically significant variations in M. leprae specific and human immune gene expressions, and circulatory levels of cytokines were noted.

In the longitudinal arm, circulatory levels of cytokines and antibodies against M. leprae cell wall antigen (PGL-1) were estimated using upconverting phosphor lateral flow assay strips in leprosy cases before, during and after reactions.

Based on the inferences from both the cross sectional and longitudinal arms of the study, the researchers recommend a gene set signature involving genes ML2388 (encodes a possible membrane protein in M. leprae), ML2664 (encodes a secretory protein involved in peptidoglycanbiosynthesis in M. leprae) and CXCL10 (encodes interferon gamma inducible protein-10 in humans) for gene expression and serum levels of CXCL10 and anti-PGL-1 IgM antibodies as serological markers for reactional states in leprosy.

Impact

Das M, David D, Horo I, Van Hooij A, Tió-Coma M, Geluk A and Vedithi SC (2023) Mycobacterium leprae and host immune transcriptomic signatures for reactional states in leprosy. Front. Microbiol. 14:1113318

Reduction of plantar pressure

  • Grant: LRI Regular Grant
  • Budget round: 2015
  • Research priorities: Disability
  • Country: Bangladesh
  • Project no.: 703.15.47
  • Budget: € 23,730
  • Duration: April 2015 - December 2016 
  • Status: Completed

Project coordination
The Leprosy Mission International (Bangladesh)

Partners
American Leprosy Missions (Nepal)

Aim: This study sought to quantify the differences or similarities between MCR commonly sourced in Bangladesh and footwear available in the Bangladesh market. 

Full project title:
Trial for effective plantar pressure reduction

Final project summary:
Although Micro-cellular rubber (MCR) is not available in commercially produced footwear, other comfort-enhancing products have been developed and are readily available in many markets. As MCR has a long and successful history of reducing foot ulcers, it would be ill-advised to recommend replacement materials without evidence of their efficacy. 

This project compared the pressure applied on various parts of the sole of the foot while wearing different types of commercially available footwear with the pressure while wearing traditional MCR footwear. Footwear that was performing comparable to (or better than) MCR footwear was subsequently field-tested by leprosy affected persons who could not feel a 10mg monofilament and by leprosy affected persons with a history of plantar ulcers. Two commercially available models that had similar peak pressure and pressure time interval effect as MCR were identified for men and two models were identified for women. The cross over study was completed in January 2017 and the results indicate that the market footwear that was selected produced similar protection against ulcers. 

Impact

Presentation at International Leprosy Congress, Beijing, 20 September 2016. Comparison of in Shoe Plantar Pressure Using MCR and Market Footwear. Bowers, B., Hossain, D., Singh, S., & Cross, H.

Helminths influences in leprosy

  • Grant: LRI Regular Grant
  • Budget round: 2015
  • Research priorities: Disability
  • Country: Nepal
  • Project no.: 703.15.41
  • Budget: € 200,000
  • Duration: September 2015 - May 2024
  • Status: Completed

Project coordination
The Leprosy Mission Nepal

Aim: This study investigated if worm infection or deworming has any relevance to leprosy clinical care. The research group aimed to detect risks and associations between helminth indicators, leprosy indicators and clinical outcomes including leprosy reaction development, severity and duration.

Full project title:
Helminth Influences in Leprosy: Indicators, Treatment, Reactions and Clinical Outcome

Final project summary:
Leprosy remains a significant public health challenge in many parts of the world, particularly in countries where poverty, inadequate sanitation, and limited access to safe water persist. In fact, approximately 99% of new leprosy cases occur in 23 priority countries that are also highly affected by chronic intestinal worm infections. These overlapping diseases are closely associated with the same underlying social and environmental conditions, including poor sanitation, unsafe drinking water, and limited healthcare access.

Chronic intestinal worm infections can alter the body's immune response, allowing worms to survive for long periods without being cleared by the immune system. While this reduced inflammatory response benefits the worms, it may also affect how the body responds to other infections, including leprosy. Previous studies have suggested that people affected by both leprosy and intestinal worms may carry higher numbers of leprosy bacteria, potentially increasing the risk of severe disease and long-term complications. However, little was known about how routine deworming might influence leprosy outcomes.

To better understand this relationship, researchers conducted a longitudinal study in Nepal involving 441 participants, including 226 newly diagnosed leprosy patients without inflammatory complications, 106 patients experiencing a new inflammatory episode, and 109 healthy household contacts. Participants underwent detailed clinical assessments, neurological examinations, and laboratory investigations to identify both leprosy and intestinal worm infections.

As part of the study, all participants received education on Water, Sanitation and Hygiene (WASH) practices and were offered deworming treatment every six months. Participants were followed for up to two years, allowing researchers to monitor changes in infection status, immune responses, and leprosy outcomes over time.

At enrolment, approximately one-third of all leprosy patients were co-infected with intestinal worms. Analysis revealed that worm infection was strongly associated with more severe manifestations of leprosy at diagnosis. Patients with intestinal worm infections were more likely to present with a greater number of skin lesions, involvement of multiple body regions, higher bacterial loads, and increased nerve-related symptoms. These findings suggest that chronic worm infection may contribute to a form of immune suppression that allows leprosy bacteria to multiply more easily within the body.

Researchers also observed important changes following deworming treatment. Individuals who had previously been infected with worms demonstrated measurable shifts in immune biomarkers, indicating that their immune systems were beginning to respond differently to leprosy bacteria. These findings suggest that removing worm infections may help restore immune function and improve the body's ability to control leprosy infection.

A separate analysis examined the broader population-level impact of regular deworming. The results indicated that communities receiving periodic deworming experienced earlier diagnosis of leprosy and fewer risk factors associated with severe disease. Newly diagnosed patients in these populations tended to have lower bacterial loads and less advanced disease at presentation. Although inflammatory episodes still occurred in some individuals, the overall profile of new leprosy cases appeared less severe.

Importantly, researchers also observed that when deworming activities were discontinued for extended periods, bacterial loads and risk factors for inflammatory complications gradually increased again among newly diagnosed leprosy patients. This finding highlights the potential value of maintaining regular deworming programmes in areas where both intestinal worms and leprosy are common.

The study also provided valuable insight into the living conditions faced by many participants. Nearly half did not have access to an adequate toilet, most had only a secondary-level education or less, and very few households were able to consistently treat or purify their drinking water. Economic hardship was widespread, with nearly half of households surviving on approximately €100 per month or less and many struggling to secure sufficient food. These conditions create an environment where both intestinal worms and leprosy can continue to spread and persist.

While education programmes focused on hygiene and sanitation remain essential, the study highlights the reality that meaningful improvements in water and sanitation infrastructure often require substantial long-term investment. Until such changes are achieved, intestinal worm infections are likely to remain an important public health challenge in many endemic communities.

Against this backdrop, periodic deworming presents a highly affordable and practical intervention. In Nepal, providing two deworming treatments per year costs approximately €2.25 per person, making it a potentially cost-effective strategy for improving population health. The findings from this research suggest that routine deworming may not only reduce the burden of intestinal worm infections but could also contribute to earlier detection of leprosy, lower bacterial loads, reduced risk of severe disease, and potentially reduced transmission within communities.

By demonstrating the important interactions between neglected tropical diseases, this study underscores the value of integrated public health approaches. Combining deworming programmes with leprosy control efforts, health education, and improvements in water, sanitation, and hygiene could provide a powerful strategy for reducing disease burden and improving outcomes for vulnerable populations in endemic regions.

Impact

Hagge, D. A., Parajuli, P., Kunwar, C. B., Rana, D. R., Thapa, R., Neupane, K. D., ... & Napit, I. B. (2017). Opening a can of worms: leprosy reactions and complicit soil-transmitted helminths. EBioMedicine, 23, 119-124.

 

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