Recent Advances in Defining the Immunoproteome of Mycobacterium tuberculosis

Kunnath-Velayudhan, Shajo; Porcelli, Steven A.

doi:10.3389/fimmu.2013.00335

Cited by 25 publications

(20 citation statements)

References 31 publications

(49 reference statements)

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“…The best-documented case is for proteins secreted by the type VII secretion system [32,33]. ESAT6 and CFP10, which form a heterodimer and are important for the virulence of the bacterium, are both very immunogenic, which is dependent upon their secretion [34-36]. …”

Section: M Tuberculosis Antigens and Understanding “Protective” Imentioning

confidence: 99%

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

Behar¹,

Carpenter²,

Booty³

et al. 2014

Seminars in Immunology

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Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage.

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Section: M Tuberculosis Antigens and Understanding “Protective” Imentioning

confidence: 99%

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

Behar¹,

Carpenter²,

Booty³

et al. 2014

Seminars in Immunology

View full text Add to dashboard Cite

show abstract

“…One intriguing possibility is that the PE and PPE domains serve as targeting modules, directing any cargo domains attached to their C termini to the ESX for translocation and anchoring to the cell surface (38), a process that is important for modulating interactions with the host during infection (39). In this model, EspG would play a role akin to the signal recognition particle in the conventional secretory pathway, by binding to nascent PE-PPE complexes and directing them to ESX machinery in the plasma membrane for further processing.…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%

Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

Ekiert

Cox

2014

Proc. Natl. Acad. Sci. U.S.A.

105

131

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Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways.tuberculosis | protein secretion | antigenic variation | virulence factor | host-pathogen interactions

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“…SseB is one of many secretion system components that appear to feature strongly in the T‐cell immunome of diverse bacterial infections including Salmonella , Mycobacterium tuberculosis and Burkholderia ; perhaps the key example in this respect is ESAT‐6 (EsxA), a part of the mycobacterial type VII secretion system …”

Section: Discussionmentioning

confidence: 99%

The serodominant secreted effector protein of Salmonella, SseB, is a strong CD4 antigen containing an immunodominant epitope presented by diverse HLA class II alleles

et al. 2014

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Detailed characterization of the protective T-cell response in salmonellosis is a pressing unmet need in light of the global burden of human Salmonella infections and the likely contribution of CD4 T cells to immunity against this intracellular infection. In previous studies screening patient sera against antigen arrays, SseB was noteworthy as a serodominant target of adaptive immunity, inducing significantly raised antibody responses in HIV-seronegative compared with seropositive patients. SseB is a secreted protein, part of the Espa superfamily, localized to the bacterial surface and forming part of the translocon of the type III secretion system (T3SS) encoded by Salmonella pathogenicity island 2. We demonstrate here that SseB is also a target of CD4 T-cell immunity, generating a substantial response after experimental infection in human volunteers, with around 0·1% of the peripheral repertoire responding to it. HLA-DR/peptide binding studies indicate that this protein encompasses a number of peptides with ability to bind to several different HLA-DR alleles. Of these, peptide 11 (p11) was shown in priming of both HLA-DR1 and HLA-DR4 transgenic mice to contain an immunodominant CD4 epitope. Analysis of responses in human donors showed immunity focused on p11 and another epitope in peptide 2. The high frequency of SseB-reactive CD4 T cells and the broad applicability to diverse HLA genotypes coupled with previous observations of serodominance and protective vaccination in mouse challenge experiments, make SseB a plausible candidate for next-generation Salmonella vaccines.

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Recent Advances in Defining the Immunoproteome of Mycobacterium tuberculosis

Cited by 25 publications

References 31 publications

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

The serodominant secreted effector protein of Salmonella, SseB, is a strong CD4 antigen containing an immunodominant epitope presented by diverse HLA class II alleles

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