Shared Characteristics Between M. tuberculosis and Fungi

Abstract and Introduction

Abstract

Mycobacterium tuberculosis, an etiologic agent of tuberculosis, exacts a heavy toll in terms of human morbidity and mortality. Although an ancient disease, new strains are emerging as human population density increases. The emergent virulent strains appear adept at steering the host immune response from a protective Th1 type response towards a Th2 bias, a feature shared with some pathogenic fungi. Other common characteristics include infection site, metabolic features, the composition and display of cell surface molecules, the range of innate immune receptors engaged during infection, and the ability to form granulomas. Literature from these two distinct fields of research are reviewed to propose that the emergent virulent strains of M. tuberculosis are in the process of convergent evolution with pathogenic fungi, and are increasing the prominence of conserved traits from environmental phylogenetic ancestors that facilitate their evasion of host defenses and dissemination.

Introduction

The etymology of 'mycobacterium' reflects early observations that the growth characteristics and morphology of the bacterium resemble that of fungi. Recent investigations have revealed this likeness extends to multiple characteristics, particularly relating to pathogenesis. Members of the mycobacterium complex, that is, bacteria of the genus Mycobacterium that can cause disease in humans, have long been considered a peculiarity among bacteria, neither Gram positive nor Gram negative, and very slow growing. Their distinctive lipid-rich cell wall structure has set them apart from most bacteria, and for pathogenic mycobacteria such as M. tuberculosis it is key for its growth, viability and virulence characteristics.

Although M. tuberculosis has a highly conserved genome,^[1] new strains are emerging, generating diversity in virulence and clinical outcome.^[2–4] Recent advances in gene sequencing technology have enabled, for the first time, large-scale comparisons to be made between the genomes of M. tuberculosis from diverse origins, and have revealed important insights into the phylogeny and global spread of this pathogen. The major genetic lineages of M. tuberculosis occupy different geographical regions and have evolved varying degrees of virulence.^[5–7] Thousands of single-nucleotide polymorphisms (SNPs) have been identified among clinical isolates, some of which have been linked with important phenotypes such as resistance to antibiotics.^[8–11] Differences have also been identified among mycobacterial cell wall glycolipids^[12–14] and secreted proteins such as those of the PE/PPE family.^[15] This information has contributed to the emergence of a broader concept: a working hypothesis that the more virulent strains, especially outbreak strains of M. tuberculosis, are hypo-inflammatory for a Th1-type immune response.^[6,16–18]

Furthermore, the evolutionarily new strains appear to be disseminating more rapidly than their ancient counterparts. A similar distinction in mycobacterial virulence has been known of for some time at the species level; for example, the cell wall component lipomannan (LM) differs in its ability to induce TNF-α, depending on whether it is derived from M. tuberculosis or Mycobacterium smegmatis.^[19] If indeed there is a causative link between more virulent strains and the lack of a protective response by the host, some of the features that may facilitate this bear comparison with shared features in pathogenic fungi. In this article we shall consider some of the striking similarities between M. tuberculosis virulence factors and their fungal counterparts. In some of the examples provided it may be that other bacteria also share the related characteristic with fungi, particularly in species closely related to mycobacteria, but no other pathogenic species collectively demonstrates such a remarkable degree of similarity with fungi, of which all of those features enhance the virulence of the single most successful bacterial pathogen in human history.

Executive Summary

Background

While likeness between Mycobacterium tuberculosis and fungi has been reported, it is only recently that we have been able to monitor the evolution of M. tuberculosis, which has revealed that the more virulent strains elicit a different type of immune response compared with less virulent strains.
Given the rise of multidrug-resistant strains and the scarcity of new antimycobacterial drugs and vaccines, novel ways to counteract our old adversary are as relevant as they have ever been. The examples brought together in this article seek to highlight how nature may select similar pathogenic features in M. tuberculosis to those found in pathogenic fungi. The study of mycobacteriology may be relevant to mycology, and vice versa.

Cell wall components

Like fungi, but unlike most bacteria, mycobacteria are able to synthesize trehalose and inositol. Trehalose is a key component of the cell wall molecule, trehalose dimycolate, modification of which has been described to influence virulence.
Similarly, mycobacteria utilize mannose to decorate glycolipids such as lipoarabinomannan and phosphatidyl innositol mannoside, cell wall components that affect virulence. Mannose is a key sugar in the structural components of the cell structure in most fungi.

The immune response

Strains of M. tuberculosis that are able to divert the immune response from a protective Th1 response towards a Th2-dominated response are more virulent. Successful fungi have developed comparable strategies to affect the same phenomenon. These include the masking of Toll-like receptor (TLR) ligands and the expression of C-type lectin receptor ligands.

Pathophysiology

Granuloma in the lung may be caused by a myriad of agents, including noninfectious diseases. However, few species of bacteria cause this distinctive cellular feature, while it is relatively common in pathogenic fungi.
Granuloma may be considered mutually beneficial for host and pathogen as it constrains the pathogen, while providing a microenvironment for replication of the invading organism. Both mycobacteria and fungi may either be contained or disseminate depending on the immune state of the host to maintain a protective granuloma, which may itself be influenced by virulence factors.

Genetic perspectives

Genetic divergence from ancient lineages may be facilitated by fungal characteristics.
A Th2 phenotype may accelerate genetic diversity by virtue of avoiding expression of conserved T-cell epitopes.
M. tuberculosis has retained fungal traits from phylogenetic ancestors that benefit its virulence in humans.
M. tuberculosis shares genetic features with fungi, including eukaryotic genes, megasatellites responsible for antigenic variation, and the conservation of cutinase-like domains.

Metabolic similarities

M. tuberculosis and some fungal species utilize the glyoxylate and methylcitrate cycles as alternative means of metabolism that is not common among other bacteria.
Antifungal agents that target key metabolic enzymes are also effective against M. tuberculosis.

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