A need for null models in understanding disease transmission: the example of Mycobacterium ulcerans (Buruli ulcer disease)

Abstract

Understanding the interactions of ecosystems, humans and pathogens is important for disease risk estimation. This is particularly true for neglected and newly emerging diseases where modes and efficiencies of transmission leading to epidemics are not well understood. Using a model for other emerging diseases, the neglected tropical skin disease Buruli ulcer (BU), we systematically review the literature on transmission of the etiologic agent, Mycobacterium ulcerans (MU), within a One Health/EcoHealth framework and against Hill's nine criteria and Koch's postulates for making strong inference in disease systems. Using this strong inference approach, we advocate a null hypothesis for MU transmission and other understudied disease systems. The null should be tested against alternative vector or host roles in pathogen transmission to better inform disease management. We propose a re-evaluation of what is necessary to identify and confirm hosts, reservoirs and vectors associated with environmental pathogen replication, dispersal and transmission; critically review alternative environmental sources of MU that may be important for transmission, including invertebrate and vertebrate species, plants and biofilms on aquatic substrates; and conclude with placing BU within the context of other neglected and emerging infectious diseases with intricate ecological relationships that lead to disease in humans, wildlife and domestic animals.

Keywords: Buruli ulcer; emerging disease; environmental pathogens; mycobacteria; neglected disease; vector competency.

Figure 1.

Number of studies investigating the ecology of Buruli ulcer (BU) and/or Mycobacterium ulcerans (MU) by year of publication. A literature search of the electronic database Scopus (1788–present) was performed on 1 November 2020 to identify articles, letters, notes and short surveys published up to November 2020. No language constrains were applied. Titles, abstracts and keywords of documents were searched using the Advanced Search interface and the following search terms: (TITLE-ABS-KEY (‘Buruli ulcer’) or TITLE-ABS-KEY (‘Mycobacterium ulcerans’)) and (TITLE-ABS-KEY (ecology) or TITLE-ABSKEY (environment*)). In addition to the database search, the references of identified articles were reviewed for relevance. The resulting literature database was reviewed for duplicates. Studies were selected if they met the following criteria: (1) reported original research content, (2) were not obvious clinical studies related to disease treatment or associated research, or country or regional focused reporting of cases, (3) were not obvious studies of pharmaceutical relevance and (4) focused on the environment and/or ecology or evolution of BU/MU. A total of 281 citation titles were screened for relevance. Where titles and abstracts were considered inconclusive, the full text was retrieved to determine if inclusion criteria were met. After this secondary review, the database comprised 153 citations investigating the ecology or evolution of BU and/or MU.

Figure 2.

Sequence of steps essential for a female mosquito to biologically transmit a virus. (1) female mosquito imbibes the virus from an infective host, (2) once infected inside the midgut, the virus overcomes the midgut infection barrier by replicating inside the midgut epithelial cells (MEC), (3) escaping the MEC, the virus enters the mosquito hemolymph—overcoming the midgut escape barrier developing into an infection, (4) the virus infects and replicates in all peripheral tissues and organs, (5) the penultimate step is to infect the salivary glands overcoming the salivary gland infection barrier and (6) finally shedding into the acinar cells and becoming present in the saliva for inoculation into a host during the next blood feeding. (Modified from Azar and Weaver 2019).