Study suggests mosquitoes as potential vectors for Buruli ulcers in Australia

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Aug 15 2024

In a recent study published in the journal Emerging Infectious Diseases, researchers used five years of notification data to verify the hypothesis that mosquitoes may serve as transmission vectors of Mycobacterium ulcerans, the causative agent of Buruli ulcers. Previous research has suggested mosquitoes as the disease's vectors, but short-term datasets and a lack of accounting for the incubation period have made these findings less conclusive.

The present study assessed seasonality in Alphavirus infections and Buruli ulcer occurrences in Victoria, Australia, while adjusting for the latter's incubation period. Although the results strongly suggest that native possums act as the environmental reservoir for the M. ulcerans, with mosquitoes as their vectors across both human and possum hosts, the researchers cautioned that further studies are required to confirm this transmission pathway definitively.

Dispatch: Mosquitoes as Vectors of Mycobacterium ulcerans Based on Analysis of Notifications of Alphavirus Infection and Buruli Ulcer, Victoria, Australia. Image Credit: Kateryna Kon / Shutterstock

Background

Buruli ulcers are chronic, necrotizing infections caused by the bacterium M. ulcerans, a close relative of leprosy and tuberculosis bacteria. It is commonly found in tropical areas such as Australia, West Africa, and Japan and are characterized by painless ulcers on the skin of the arms and legs. If left untreated, the disease can affect soft tissue and even bone, leading to permanent disability and disfigurement.

Victoria, a state in the southeastern part of Australia, has been witnessing an alarming surge in the incidence and prevalence of Buruli ulcer cases. More than 240 patients were reported in 2023, a jump of more than 176% compared to 2020 (n = 135). Unfortunately, despite almost two decades of research, the vector transmitting M. ulcerans remains unconfirmed.

A report published in 2007 suggested mosquitoes as the transmission agent, but follow-up studies in 2009 and 2021 produced conflicting results. Separate research identified native possums as environmental reservoirs for the pathogen, with M. ulcerans frequently detected in the excreta of these animals. However, the fact that possums themselves were susceptible to symptomatic infections and the low proximity between possums and humans suggests the presence of a third organism (potentially mosquitoes) that transmits the pathogen between possums and humans and between possums themselves.

Two common areas for improvement of these studies included relying on linear statistical methods and failing to account for the incubation period of M. ulcerans. Overcoming these shortcomings and identifying the vector for Buruli ulcer transmission would allow policymakers and clinicians the information required to better prepare for outbreaks and increase screening during high-risk periods, thereby preventing or treating infections before permanent disfigurement or disability occurs.

About the study

The present study hypothesized that a nonlinear statistical approach comparing Alphavirus infections (confirmed to be transmitted by mosquitoes) versus Buruli ulcer incidence on a monthly (rather than yearly) basis would help elucidate if seasonal fluctuations in mosquito densities were associated with spikes in the transmission of one of both diseases. Furthermore, the present study accounts for the incubation period of M. ulcerans within its analysis framework, a critical omission in previous literature.

Data for the study was obtained from the Department of Health in Victoria, Australia, between 2017 and 2022. Data collection was comprised of all cases of Buruli ulcer and Alphavirus infections. Previous research has estimated Buruli ulcer incubation periods to be between 4.5 and 5 months. So, transmission was assumed to have occurred between 4 and 5 months before diagnosis/notification in the Department of Health dataset. Similarly, Alphavirus transmission was considered to have happened 1 month before diagnosis/notification.

Statistical evaluation included observer-independent signal processing methodologies to investigate confirmation bias and cross-correlation to evaluate notification distribution relationships.

Study findings

The period (6 years) under investigation identified 1,761 confirmed Buruli ulcer cases and 3,839 confirmed Alphavirus infections. Initial statistical evaluations (without incubation period accounting time shifts) demonstrated an antiphase relationship between the occurrences of the two diseases. Since parallel research has revealed that M. ulcerans reservoirs in native possum populations remain stable throughout the year, the seasonal nature of these results excludes direct transmission between possums and humans and supports the hypothesis of a third vector responsible for Buruli ulcer disease transmission.

The correlate function (NumPy Python library) was subsequently used to identify the optimal time-shift factor between Alphavirus infections and Buruli ulcer cases. Results revealed that the time shift was ~5 months, corresponding to the a priori known M. ulcerans incubation period. Furthermore, after accounting for the diseases' respective incubation times, the time of infection for both diseases reached their respective maximum in December-May and minimums during June-November, both of which correspond to the seasonal fluctuations in mosquito populations.

These findings, while compelling, suggest that mosquitoes are likely transmission vectors for Alphavirus and Buruli ulcer infections; however, the researchers emphasize the need for further research to establish this link conclusively.

"We have attempted to investigate alternative models of transmission that would explain the anatomic distribution of Buruli ulcer lesions we observed in Victoria, including variation in human skin temperature, and the hypothesis that outdoor exposure in Buruli ulcer–endemic areas leads to skin contamination with M. ulcerans. Results from none of those studies supported an alternative model."

Conclusions

The present study provides strong evidence supporting mosquitoes as the transmission vectors of Buruli ulcer infections and highlights December-May (summer and autumn) as the highest-risk period. These findings provide public healthcare policymakers and clinicians with the knowledge required to implement mosquito eradication programs and M. ulcerans screening, thereby minimizing this dreadful disease's pathogenic potential.