Abstract
Tuberculosis (TB), caused by bacilli from the Mycobacterium tuberculosis complex, remains a serious global public health problem, representing one of the main causes of death from infectious diseases. About one quarter of the world’s population is infected with Mtb and has a latent TB infection (LTBI). According to the World Health Organization (WHO), an LTBI is characterized by a lasting immune response to Mtb antigens without any TB symptoms. Current LTBI diagnoses and treatments are based on this simplified definition, although an LTBI involves a broad range of conditions, including when Mtb remains in the body in a persistent form and the immune response cannot be detected. The study of LTBIs has progressed in recent years; however, many biological and medical aspects of an LTBI are still under discussion. This review focuses on an LTBI as a broad spectrum of states, both of the human body, and of Mtb cells. The problems of phenotypic insusceptibility, diagnoses, chemoprophylaxis, and the necessity of treatment are discussed. We emphasize the complexity of an LTBI diagnosis and its treatment due to its ambiguous nature. We consider alternative ways of differentiating an LTBI from active TB, as well as predicting TB reactivation based on using mycobacterial “latency antigens” for interferon gamma release assay (IGRA) tests and the transcriptomic analysis of human blood cells.
Highlights
An latent TB infection (LTBI) is characterized by a permanent immune response to Mtb antigens in the absence of any clinical manifestation of the disease [2]
World Health Organization (WHO) goal of limiting the spread of TB by 2035, it is necessary to understand the molecular mechanisms of Mtb persistence and an LTBI, as well as to develop and improve methods for the LTBI diagnosis and treatment [2,6,7]
A possible mistranslation using mutated transfer RNA anticodons, when glutamic acid residue was replaced by glutamine and aspartic acid residue was replaced by asparagine, led to rifampicin insusceptibility, no mutations in the β-subunit of the RNA polymerase gene were identified [25]
Summary
The term “latency” has two meanings: in biology, it means a dormant state of an organism when environmental conditions are not suitable for growth and proliferation, while in medicine, it is a stage of a disease when the symptoms are not yet clinically manifested [1]. During an LTBI, Mtb remains in an inactive state for a long time, being phenotypically insusceptible to anti-tuberculous drugs and retaining its ability to resuscitate and proliferate [3–5]. During its coevolution and long-term adaptation to humans, Mtb acquired the ability to remain asymptomatic (i.e., persist) in the body, even after treatment with high doses of anti-TB drugs targeting active and dividing cells [6,8–10]. The concept of persister existence was first introduced in 1944 to describe Staphylococcus species which survived treatment with lethal concentrations of penicillin. These cells became phenotypically insusceptible to it [10]. In contrast to genetic resistance, strictly determined by the presence of genetic mutations and polymorphisms [13], phenotypic insusceptibility is caused by changes in bacterial cell physiology as adaptive reactions to stress
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