Recognition of Stage-Specific Mycobacterial Antigens Differentiates between Acute and Latent Infections with Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis is estimated to infect 80 to 100 million people annually, the majority of whom do not develop clinical tuberculosis (TB) but instead maintain the infection in a latent state. These individuals generally become positive in response to a tuberculin skin test and may develop clinical TB at a later date, particularly if their immune systems are compromised. Latently infected individuals are interesting for two reasons. First, they are an important reservoir of M. tuberculosis, which needs to be considered for TB control. Second, if detected prior to recrudescence of the disease, they represent a human population that is making a protective immune response to M. tuberculosis, which is very important for defining correlates of protective immunity. In this study, we show that while responsiveness to early secretory antigenic target 6 is a good marker for M. tuberculosis infection, a strong response to the 16-kDa Rv2031c antigen (HspX or ␣-crystallin) is largely restricted to latently infected individuals, offering the possibility of differential immunodiagnosis of, or therapeutic vaccination against, TB. Tuberculosis (TB) is easily transmitted by inhalation of infectiousMycobacterium tuberculosis bacilli from the air and is one of the leading causes of death in adults between the ages of 15 and 45 years (43). The global incidence rate of TB is increasing by approximately 0.4% per year (43), driven by factors such as the human immunodeficiency virus (HIV)/ AIDS epidemic, poverty, and increasing population density. Despite the existence of effective treatment regimens, control of TB is complicated by the chronic nature of the disease. Only 5 to 10% of recently exposed individuals develop clinically active TB in the first 2 years after exposure, and this, together with the often transient nature of exposure, makes accurate tracing of recently exposed and potentially infected individuals extremely difficult.A higher percentage of exposed individuals become infected but are able to limit the growth of the mycobacteria and become latently infected. The exact incidence of latent infection remains unclear, but it is estimated that up to 2 billion people globally may harbor latent TB infections (17,22,43). Latency can only be understood as a dynamic process-an active host immune response is essential to keep the disease in the latent stage, as demonstrated by the high rate of TB recrudescence in individuals with HIV infection (8) or the reactivation of the latent infection in individuals given anti-tumor necrosis factor alpha therapy (29). The decline of the immune system due to old age or malnutrition also increases the risk of latent disease becoming clinically significant.Thus, latently infected individuals provide a highly relevant population to study what human protective immune responses against M. tuberculosis look like. However, identifying these people has been problematic in the past. The classical definition of latent infection (conversion to positivity in the purified protein derivative-ba...

Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection

“…At present, the exact role of DosR regulon products in human M. tuberculosis infection is incompletely understood. Rv2031c, the archetypal DosR regulon product, is a small heat shock protein, and cellular immune responses to Rv2031c have been observed in individuals with LTBI [25]. More recently, LEYTEN et al [14] studied human T-cell responses to a set of the 25 DosR encoded proteins, using long-term cultured thawed PBMCs.…”

Accuracy of Three Diagnostic Tests for Determining Mycobacterium Bovis Infection Status in Live-Sampled Wild Meerkats (Suricata Suricatta)

“…17 Magnitude of humoral immune response was associated with severity of disease due to M. bovis infection in a study of racing dromedary camels (Camelus dromedarius), 43 although because of the small sample size of infected camels (n 5 3), further observations are needed to validate this observation. Progression in antibody production to different antigens was noted in captive Asian elephants (Elephas maximus) infected with M. tuberculosis and tested using MAPIA.…”

Interferon Gamma Response to Combinations 38 kDa/CFP‐10, 38 kDa/MPT‐64, ESAT‐6/MPT‐64 and ESAT‐6/CFP‐10, Each Related to a Single Recombinant Protein of Mycobacterium tuberculosis in Individuals from Tuberculosis Endemic Areas

“…However, in populations inhabiting tropical areas where human mycobacteriosis are endemic, new studies must be undertaken as IFN-γ production in healthy donors from this type of geographic area may merely represent a cross-reactive immune response to exposure to leprosy, environmental atypical mycobacteria or orthologs present in other bacterial species (4,14,15). More recently, ESAT-6 has been reported as a marker for infection but less effective for latent infection, while 16 kDa was suggested to be a potential marker for latently infected individuals (6). Correlation between 38 kDa/CFP-10 and ESAT-6, CFP-10 and ESAT-6/CFP-10 was significantly high, and in a TST converted healthy donor, IFN-γ conversion response was not observed for 38 kDa, CFP-10 or MPT-64, therefore suggesting that the 38 kDa/CFP-10 combination is suitable also for diagnosis in recently infected individuals.…”