Shared Characteristics Between Mycobacterium tuberculosis and Fungi Contribute to Virulence

Sam Willcocks; Brendan W Wren

Disclosures

Future Microbiol. 2014;9(5):657-668. 

In This Article

Pathophysiology

A defining feature of tuberculosis, the granuloma, may be induced by a range of fungal or protozoan infectious agents, but few bacteria demonstrate this capability. Those that do possess orthologous characteristics to M. tuberculosis: Nocardia spp. express nocardomycolic acids that are similar to TDM and the bacterium Burkholderia pseudomallei has a thick cell wall, albeit one comprised predominantly of carbohydrates rather than lipids. Some fungi cause infection that present so clinically similar to tuberculosis that diagnosis is often mistaken. Blastomycosis can result in a chronic pulmonary illness complete with night sweats, low-grade fever, weight loss and productive cough. Purified TDM is able to form a nascent granuloma even in the absence of live bacteria.[65] Although there is no TDM present in the fungal cell wall, its receptor, Mincle, recognizes an unidentified glycolipid on Malassezia spp., a fungus that can cause granulomatous skin infections.[66] This glycolipid must therefore share a similar structure to TDM, and may be an example of molecular mimicry.

M. tuberculosis shares the vulnerability of fungi such as Histoplasma sp. to Th1-dominated granuloma, with high IFN-γ and TNF-α titers successfully containing the infection.[67] The most virulent clinical strains of M. tuberculosis fail to induce a containing granuloma and spread rapidly, which has been associated with a Th2 immune bias. This is similar to the disease spectrum exhibited by M. leprae, with tuberculoid leprosy inducing well-defined granuloma, with fewer bacilli and a Th1 bias, whereas lepromatous leprosy is associated with multiple diffuse lesions, greater numbers of bacilli, and a Th2 bias.[68] One way that virulent mycobacteria may achieve this is by promotion of Treg activity, which is associated with failure of the granuloma and disease progression.[69] Subversion of Treg function is also a proposed mechanism by which Aspergilus sp. directs the Th response towards Th2 to enable fungal persistence.[70] Patients with chronic disseminated candidiasis similarly show a skew towards Th2, with high serum IL-10 and large granuloma that fail to contain the infection.[71,72]

Like M. tuberculosis, infection with C. albicans is able to manifest as either localized subclinical infection or, in an immunocompromised host, potentially lethal systemic infection of virtually any tissue. In C. albicans, the progression of one type of infection to another is accompanied by gene regulation events that alter morphology, evoking changes in antigenicity and drug resistance;[73] this phase switching in C. albicans from elongated to round cells is believed to support survival in the host.[74] Investigation of drug-resistant strains, extensively drug-resistant (XDR) tuberculosis and extremely drug-resistant (XXDR) tuberculosis, has similarly revealed distinctive differences in cell morphology, namely the shift towards the production of small round bacilli closely resembling spores instead of the usual larger rod shape. This is also analogous to the change from elongated hyphal growth in the environment to a yeast form inside the host, a seen in fungi such as the Coccidiodes spp..[74] Although this requires further study, altered morphology in M. tuberculosis may correlate with a drug-resistant phenotype as it does in some fungal species.

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