The evolutionary pressures that have molded Mycobacterium tuberculosis into an infectious adjuvant

doi:10.1016/j.mib.2012.11.007

Current Opinion in Microbiology

Volume 16, Issue 1, February 2013, Pages 78-84

https://doi.org/10.1016/j.mib.2012.11.007 Get rights and content

Mycobacterium tuberculosis (Mtb) is highly immunogenic and appears to have evolved to preserve its antigenicity. The retention of antigenicity is important to the maintenance of a robust immune response that contributes greatly to the late-stage tissue damage required for transmission and completion of the pathogen's life cycle. Bacterial persistence is achieved through the remodeling of the tissue at site of infection and maintaining the lymphocytes at a distance from the infected macrophages in the granuloma core. The tissue metabolism within the granuloma leads to lipid sequestration that supports bacterial growth. However, growth on host lipids places metabolic stresses on Mtb, which has evolved to incorporate potentially harmful metabolic intermediates into the very cell wall lipids that induce the remodeling of the host tissue response.

Highlights

► Mtb has evolved with mankind for 50 000 years after human migration from Africa. ► Mtb shows minimal genetic mutations linked to the avoidance of antigenicity. ► Mtb is immunogenic, which is critical to the tissue damage required for transmission. ► Mtb avoids the systemic immune response by local modulation of the infection site. ► The strategies employed by Mtb have serious consequences for vaccine development.

Introduction

Mycobacterium tuberculosis (Mtb) is a human-specific pathogen with an impressive penetrance of its host population. In the modern era, infection with Mtb leads to active disease in approximately 5–10% of those individuals during the course of their lifetime. This ability to infect many yet causing active disease in only a few at any given instance has likely contributed to the pathogen's success through co-evolution with its host. The life cycle of the pathogen is shown in Figure 1, which highlights the key points discussed in this article.

Section snippets

Co-evolution of Mtb and mankind

Many publications, even recent ones, describe Mtb as a zoonosis evolving from the bovine pathogen Mycobacterium bovis (Mb) during the development of agriculture around 12 000 years ago [1, 2, 3]. However sequencing of both genomes over 10 years ago revealed that the Mtb chromosome was clearly larger than the Mb chromosome, and the size difference was predominantly due to deletions [4, 5, 6]. More recent whole genome analysis of Mtb strains representing the sequence diversity in the Mtb complex

Mtb proteins exhibit minimal evidence for antigenic diversity

But what of the evolutionary pressures that shape the Mtb genome? The bacterium requires the human host in order to replicate so clearly must have evolved under consistent selective pressure. However, this selective pressure lacks the environmental diversity experienced by free-living organisms and, like many pathogenic organisms, Mtb has experienced genomic down-sizing [13]. As with any pathogenic organism immune avoidance would constitute a major evolutionary pressure. However, when Hershberg

Why would Mtb not care if it is immunogenic?

At the level of the infected macrophage this seems a bad idea. The macrophage is an antigen-presenting cell capable of informing both CD4⁺ and CD8⁺ cells of its infection status, and if activated by interferon-γ (IFN-γ) capable of either killing Mtb or rendering it nonreplicative [22]. In the majority of animal models infection by Mtb is marked by a period of rapid bacterial replication preceding the development of the adaptive immune response. Several investigators have noted that this immune

Tempering the impact of immunity through the granuloma

The key to appreciating how Mtb manages hostimmune pressure comes with the realization that Mtb actually requires the adaptive immune response to complete its life cycle. The late-stage tissue damage that culminates in transmission is driven by the host immune response therefore the bacterium has to find other means of modulating host immune function without impairing the robustness of the systemic immune response.

A human TB granuloma exhibits several conserved characteristics, however, within

The intracellular environment shapes bacterial metabolism

Mtb is able to arrest the normal maturation of its phagosome and resides in a vacuole that retains many of the characteristics of a sorting endosome [33]. It has a pH of 6.4, and it remains accessible to early endosomal contents. However, upon activation of the macrophage this blockage is overcome and the bacterium is exposed to a lower pH, more hydrolytically competent environment. The physiological gradients in the endosome–lysosome continuum provide useful cues to Mtb. pH is well studied and

Subversion of host tissue metabolism to support infection

Transcriptional profiling of caseous human TB granulomas [56••, 57] revealed dysregulation of lipid metabolism as a pathogen-induced pathology that may drive tissue breakdown. Host proteins key to lipid overload and sequestration localized to cells subtending the caseum by immunohistology. Furthermore, the caseous core of the TB granuloma contained triacylglycerides, cholesterol and cholesterol ester, together with sphingomyelin and lactosylceramide. The presence of cholesterol ester indicated

Concluding remarks

Mycobacterium spp. are highly immunogenic and were used previously as constituents in Freund's Complete Adjuvant. While it is not unusual for pathogens to induce an inflammatory response to promote transmission, such as Vibrio cholera and Salmonella, such a trait is atypical of a chronic infection. Instead of diminishing its immunogenicity Mtb has evolved to model its site of infection to support its persistence despite a strong immune response. This remodeling of the granuloma leads to the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

DGR is supported by US Public Health Services grants AI067027, AI095519, and HL055936 from the National Institutes of Health.

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The enzyme isocitrate lyase 1 (Icl1) is a key enzyme of the glyoxylate cycle in bacteria. Thus, as fatty acids are probably an important carbon source for energy metabolism of M. tuberculosis in chronically infected lung tissues (Russell, 2013), Icl1 would be important for sustaining bacterial growth on fatty acids as carbon source. The increased expression of icl1 in M. bovis could result in a metabolic flow towards the glyoxylate cycle, for the generation of glucose from fatty acids.
Members of the Mycobacterium tuberculosis complex (MTBC) are responsible for tuberculosis in several mammals. In this complex, Mycobacterium tuberculosis and Mycobacterium bovis, which are closely related, show host preference for humans and cattle, respectively. Although human and bovine tuberculosis are clinically similar, M. tuberculosis mostly causes latent infection in humans, whereas M. bovis frequently leads to an acute infection in cattle. This review attempts to connect the pathology in experimental animal models as well as the cellular responses to M. bovis and M. tuberculosis regarding the differences in protein expression and regulatory mechanisms of both pathogens that could explain their apparent divergent latency behaviour. The occurrence of latent bovine tuberculosis (bTB) would represent a serious complication for the eradication of the disease in cattle, with the risk of onward transmission to humans. Thus, understanding the physiological events that may lead to the state of latency in bTB could assist in the development of appropriate prevention and control tools.
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A vaccine that prevents transmission of infection is urgently needed in the fight against tuberculosis (TB). Results of clinical trials have been disappointing. Major problems include lack of biomarkers and understanding of the mechanisms of disease and protection. A more fundamental problem is that the scientific community seldom recognizes that primary and post-primary TB are distinct disease entities. Nearly all vaccine candidates have been designed and tested in models of primary TB, while transmission of infection is mediated by post-primary TB. Post-primary TB is seldom studied because no animal develop complete symptoms of the disease as it exists in humans. Nevertheless, mice, guinea pigs and rabbits all develop infections that at certain points appear to be models of human post-primary TB. Slowly progressive pulmonary TB in immunocompetent mice is an example. It is characterized by an alveolitis with infected foamy macrophages that have multiple characteristics of the human disease. We demonstrated that inclusion of an immune modulating agent, lactoferrin, with a BCG vaccine in this model induced a sustained reduction in lung pathology, but not numbers of organisms in tissue. Since the animals die of expanding pathology, this demonstrates the feasibility of using selected animal models for studies of vaccines against post-primary TB.
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MTB is one of the most successful pathogens of humankind; emerging data indicate that this remarkable pathogen coevolved with humanity as it emerged from Africa 50,000 years ago.37 MTB has infected humans for such a long time with a high degree of penetration; it causes chronic, rather than acute, infections, illustrating that MTB infections are able to be extremely well managed.38 Thus, numerous examples exist in the literature, which point to the fact that MTB successfully engages with and modulates the protective response mounted by the host.39,40
Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus–induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4⁺ T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response.
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Mycobacterium tuberculosis (Mtb) is the leading cause of death from an infectious disease worldwide and is the causative agent of tuberculosis (Chao, M. C., and Rubin, E. J. (2010) Annu. Rev. Microbiol. 64, 293–311). Throughout infection, Mtb encounters a variety of host pressures. Thus, responding to these host stresses via the induction of multiple regulatory networks is needed for survival within the host. The Clp protease gene regulator, Rv2745c (clgR), is induced in response to environmental stress conditions, implicating its potential role in Mtb pathogenesis. Transcriptional activation of genes downstream of Rv2745c occurs in a condition-dependent manner. Our isogenic Mtb:ΔRv2745c mutant expresses a significantly different phenotype upon reaeration conditions. Transcriptional analysis revealed differential gene expression profiles relative to wild-type Mtb. Rv2745c is strongly induced in response to hypoxic and reaeration conditions, implicating a role of Rv2745c in vivo during both establishment of infection and reactivation. We found dysregulation of downstream genes within both the σ^H/σ^E regulon as well as the dosR regulon in the isogenic mutant, Mtb:ΔRv2745c. Upon hypoxic and reaeration conditions, Clp protease induction occurred within wild-type Mtb, indicating that activation of clgR, which subsequently leads to Clp protease induction, is crucial for degradation of misfolded proteins and ultimately survival of Mtb upon specific stress conditions. Our data indicate the diverse response of Rv2745c, σ^H and σ^E in response to a variety of stress conditions. Activation of Rv2745c in response to various stress conditions leads to differential activation of downstream genes, indicating the diverse role of Rv2745c and its importance for Mtb survival in vivo.The Mycobacterium tuberculosis gene, Rv2745c, leads to induction of downstream genes that is condition-dependent.
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The evolutionary pressures that have molded Mycobacterium tuberculosis into an infectious adjuvant

Highlights

Introduction

Section snippets

Co-evolution of Mtb and mankind

Mtb proteins exhibit minimal evidence for antigenic diversity

Why would Mtb not care if it is immunogenic?

Tempering the impact of immunity through the granuloma

The intracellular environment shapes bacterial metabolism

Subversion of host tissue metabolism to support infection

Concluding remarks

References and recommended reading

Acknowledgements

Clin Chest Med

J Exp Med

Immunol Rev

Nat Med

Mol Microbiol

Proc Natl Acad Sci U S A

Proc Natl Acad Sci U S A

J Bacteriol

PLoS Pathog

PLoS Med

PLoS Pathog

Guns, Germs and Steel: The Fates of Human Societies

Origins of major human infectious diseases

Nature

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence

Nature

The complete genome sequence of Mycobacterium bovis

Proc Natl Acad Sci U S A

Revisiting the evolution of Mycobacterium bovis

J Bacteriol

High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography

PLoS Biol

Innate immune recognition of Mycobacterium tuberculosis

Clin Dev Immunol

Past, present and future directions in human genetic susceptibility to tuberculosis

FEMS Immunol Med Microbiol

The contribution of host genetics to tuberculosis pathogenesis

Kekkaku

Genetic susceptibility in tuberculosis

Respirology

Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette–Guerin infection and a sibling with clinical tuberculosis

J Clin Invest

Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis

Nat Rev Microbiol

Frequent homologous recombination events in Mycobacterium tuberculosis PE/PPE multigene families: potential role in antigenic variability

J Bacteriol

Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints

PLoS One

Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved

Nat Genet

MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis

PLoS Pathog

NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis

PLoS Pathog

In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette–Guerin is due principally to trehalose mycolates

J Immunol

Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle

J Exp Med