## 5 USPs of Pathogenic Bacteria  
### Tuberculosis  
Tuberculosis (TB) is an infection caused by a single organism (_Mycobacterium tuberculosis_) and is regarded, alongside HIV/AIDS and malaria, as one of the world's big three deadliest diseases [64,65]. An estimated 8.9-9.9 million new cases were accounted for in 2008 and this value has not receded, considering the 1.3 million deaths reported worldwide in 2012. It is estimated that at least a third of the world's population is infected with the causative agent in its latent form. Since 1974, BCG has been the sole vaccine mostly administered to neonates and school children, providing protection of up to 80% in children and 50% in adults [66]. _Mtb_ has over 10 USPs that are present during infection and yet their functions remain unidentified [25]. However, researchers have suggested their potential roles in vaccine or drug production, as well as in diagnostics. The persistence of _Mtb_ within the human host in a clinically latent stage for years without causing severe disease, unlike so many other toxic pathogens, is one of the main attributes of this infection's success [67]. A large contributor to latent TB has been the hypoxic environment. It has been suggested that the limitations associated with the inhibition of _Mtb_ growth in vivo is due to reduced levels of oxygen, since TB infection is most often associated with oxygen-enriched sites in the human body. The formation of a granuloma triggered by activated macrophages stunts _Mtb_ replication by curbing bacterial access to oxygen and nutrient supply [68]. Ultimately co-infection with other opportunistic diseases, particularly HIV/AIDS, triggers a high chance of developing active disease. There are at least 48 genes under the DosR/DosS/DosT regulatory system that become up-regulated during conditions of nitric oxide stress and hypoxia that play a role in _Mtb_ persistence and/or intracellular survival. Of these genes, 44 encode conserved hypothetical proteins and six of these are from the USP family [25]. _Mtb_ has 10 USPs altogether, four of which are not regulated by DosR. There used to be eight USPs known to be encoded by _Mtb_ H37 Rv that were divided into three classes based on domain organization: Rv1636, which is made up of 146 amino acids and contains one USP domain; Rv2028c (279 aa), Rv2624c (279 aa) and RV3134c (268 aa), which all belong to the second class and possess one domain and a second C-terminal domain, and the final class, which consists of two USP domains made up of four USPs: Rv1996 (317 aa), Rv2623c (297 aa), Rv2005c (295 aa) and Rv2026c (294 aa) [24]. This has since increased to ten proteins organized into five classes, as shown in (Figure 3) [14]. It has been suggested that _Mtb_ USPs are highly related to Actinobacteria [69]. A significant amount of interest is directed at the presence of USPs, the underlying mechanisms involved in their up-regulation and the roles they play in _Mtb_ infection, which are very evasive. Many studies have, however, pointed toward their potential use in vaccine design or the development of novel diagnostic tools. One of the most effective methods for preventing TB transmission is early diagnosis. However, available diagnostic procedures display various shortfalls, such as failure to produce detectable sputum and reduced cost efficiency for sputum smear microscopy, as well as their limitations in clinical use due to variable accuracies for serologically based antibody tests [70]. One of the key characteristics of active TB is the activation of the humoral response and the presence of circulating antibodies, which have surprisingly been overlooked as a vaccine target [71; 72]. Using proteome microarrays, the combination of Rv2026c and Rv2421c has been identified as a new detectable and reliable biomarker for the diagnosis of active TB [70]. The up-regulation of the _Rv2026c_ gene along with three others, _Rv2005c_, _Rv1996_ and _Rv2028c_, has already been shown during _Mtb_ hypoxic conditions.