Immunogenicity of the Mycobacterium tuberculosis PPE55 (Rv3347c) Protein during Incipient and Clinical Tuberculosis

Abstract

Approximately 5 to 10% of individuals who get infected with Mycobacterium tuberculosis progress to clinical tuberculosis (TB), whereas the remaining individuals develop a latent infection with the organism. Another 5 to 10% of these latently infected individuals reactivate their infection and progress to clinical TB during subsequent years/decades. In either case, active infection with M. tuberculosis is identified only when progression to bacteriologically detectable disease occurs. Thus, clinical TB, whether noncavitary paucibacillary or cavitary multibacillary disease, represents the late stages of a chronic disease process.Our studies of humoral immune responses elicited by M. tuberculosis at different stages of infection and disease progression have shown that the profile of antigenic proteins expressed by the in vivo bacteria that elicit antibodies correlates with the stage of the infection (21-23, 35-37, 45). Thus, purified-protein derivative-positive (PPD ϩ ) healthy individuals have antibodies to only a small subset (4-6) of the Ͼ100 culture filtrate proteins (CFP) of M. tuberculosis. In contrast, patients with noncavitary paucibacillary TB have antibodies directed against ϳ10 to 12 additional CFP antigens (35). As the disease progresses to the development of cavitary lesions, besides the presence of antibodies to the above-mentioned antigens, antibodies to an additional ϳ10 to 12 antigens appear. These results provide evidence that as M. tuberculosis adapts to different in vivo environments, the profile of antigenic proteins that are expressed changes. Evidence for adaptation by M. tuberculosis to different environmental conditions by altering gene/protein expression has also come from several other labs (3,11,12,29,32,41,42,47,49).M. tuberculosis is a slowly growing organism, and it takes weeks to months for the infection to progress to primary clinical TB. The time that elapses between the initiation of reactivation of latent infection and the manifestation of clinical TB is not known. The goal of the current studies was to identify antigenic proteins that are expressed during the asymptomatic, subclinical stages of infection when the in vivo M. tuberculosis bacilli replicate actively but the infection has not progressed to clinically identifiable disease (incipient, subclinical TB). Insight into these antigenic proteins will aid understanding of the host-pathogen interactions that lead to the progression of infection to clinical disease, and modulation of these host-pathogen interactions could potentially alter the outcome of infection. Moreover, antigenic proteins expressed during subclinical stages of active infection would also be useful for devising diagnostic markers that can differentiate between truly latent TB that is unlikely to progress to clinical disease and incipient, subclinical TB.

Src Homology 3-interacting Domain of Rv1917c of Mycobacterium tuberculosis Induces Selective Maturation of Human Dendritic Cells by Regulating PI3K-MAPK-NF-κB Signaling and Drives Th2 Immune Responses

“…In this regard, restriction of the distinctive PE/PPE family of antigens to mycobacterial species as well as their unique expression profiles upon infection suggest their important role in adaptation or persistence of the pathogenic mycobacteria. Further- more, multiple PPE antigens such as Rv2430c, Rv2608, and Rv3347c were found to be recognized by antibodies in the sera of infected patients suggesting elicitation of strong B cell responses to these antigens in patients with tuberculosis (28,71,72). Rv1196 was demonstrated to interact with TLR2 on the macrophage cell surface and induce IL-10 secretion (45).…”

Polymorphic Exact Tandem Repeat A (PETRA): a Newly Defined Lineage ofMycobacterium tuberculosisin Israel Originating Predominantly in Sub-Saharan Africa

“…Various PPE proteins have been shown to be immunogenic (for example, PPE41 [reviewed in reference 1], PPE44 [11], PPE55 [59], and PPE68 [20]), cell surface associated (for example, recombinant PPE34 in Mycobacterium smegmatis [55]), and secreted (for example, PPE41 [1]). Clusters of PE and PPE genes of Mycobacterium tuberculosis have been reported to be organized in operons (73).…”

PE_PGRS Antigens ofMycobacterium tuberculosisInduce Maturation and Activation of Human Dendritic Cells

“…Several PE genes are reported to be expressed upon infection of macrophages, and polymorphisms in PGRS region are suggested to play a critical role in antigenic diversity and to evade host immune recognition (30,31). Many PE/PPE proteins are also known to induce a strong B cell response in humans (32)(33)(34)(35). A number of PE_PGRS proteins associate with the cell wall, and following surface exposure, these proteins traffic out of the mycobacterial phagosome into endocytic compartments.…”