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    • Lipid metabolism was the only host process

    2018-10-23

    Lipid metabolism was the only host process with a qualitatively different induction early in Mtb infection. Host lipid metabolism is known to be significantly impacted by Mtb infection. Fatty acids are accessed by mycobacteria during host cell infection (Lee et al., 2013), and host o6 methylguanine methyltransferase involved in lipid metabolism are highly expressed in caseous TB granulomas (Kim et al., 2010). Host lipid metabolism is also systemically affected by the acute phase response, for example by reducing levels of high density lipoprotein (HDL) and proteins such as LCAT (Khovidhunkit et al., 2004). Early in infection we observed an increase in lipid metabolism associated proteins which was reversed during active disease. This suggests that initially plasma levels of these proteins may reflect localized remodelling in the lung, an effect later overwhelmed by the influence of the acute phase response during active disease. We conclude that lipid metabolism associated peripheral blood proteins may be used to follow progression of Mtb infection. Small panels of candidate biomarkers representing key host response processes were able to predict 3–6months ahead of time the conversion from a TST-negative to a TST-positive state and thus predicted the establishment of LTBI. The key host response processes were represented by several different host proteins, though the most frequently observed are presented in the panel reported in Table 2. This panel included two proteins, CLEC3B and ECM1, involved in tissue remodelling (Holtet et al., 1997; Chan, 2004). ECM1 levels have also been linked with response to TB therapy (Nahid et al., 2014). Two other panel proteins, IGFALS and IGFBP3, are members of the insulin-like growth factor (IGF) pathway. Both proteins are found in ternary complexes with IGF, which substantially prolong IGF half-life and help regulate its activity (Boisclair et al., 2001). In active TB, we observed that IGFALS and IGFBP3 as well as IGFBP5, IGFBP6, IGF1 and IGF2 were reduced. Plasma levels of IGFBP3 have also been shown to be reduced in active M. leprae infection (Rodrigues et al., 2011) but increased in PBMC cultures from LTBI subjects (Stern et al., 2009). The IGFs display pleiotropic properties and can be negatively regulated by pro-inflammatory cytokines (O\'Connor et al., 2008), suggesting that the elevated inflammatory response during active TB might be responsible for the observed reduction. Early in infection, however, IGF2, IGFBP3, and IGFALS were elevated in subjects that would become TST-positive, although that appeared to be a short-term change as only IGFBP3 remained significantly elevated 3months after TST conversion. Currently it remains unclear which of the many functions of the IGF pathway are induced at this stage of Mtb infection. The two remaining panel proteins, SELL and VWF, have roles in the host immune response. SELL is involved in leukocyte homing and infiltration (Wedepohl et al., 2012), and was part of a host blood panel of proteins able to distinguish active TB from other respiratory diseases (Achkar et al., 2015). VWF promotes adhesion of platelets to sites of vascular injury, and is thus involved not only in tissue repair but also in the modulation of the inflammatory response (Lenting et al., 2012; Schattner, 2014). However, it is unclear if this number of host proteins represented the minimum combination necessary. Further studies may help elucidate this question. Limitations of this study include that specimens used for the discovery and validation studies were from HIV-negative participants in a single cohort, and may not be generalizable to other settings and populations. The second verification sample size was small, which could limit the reproducibility of our findings. Additionally, household contacts were identified after the index case was diagnosed with active TB, and therefore were likely exposed and potentially already had early Mtb infection at the time of their baseline evaluation. Therefore, our TST-negative household contacts do not represent truly unexposed persons at baseline. Despite this we were able to identify protein signatures that predicted TST conversion, and these could be useful in TB contact investigations to identify and treat TST-negative contacts who would later develop LTBI. Similarly, given the extent of Mtb exposure in household contacts, as well as in the general population of this study, the NI contacts could represent a subgroup of people who may be resistant to LTBI (Ma et al., 2014). These individuals might have different peripheral protein expression from persons who are not exposed to Mtb. Alternatively, some may have had depressed immunity due to conditions such as malnutrition. Given these limitations, further study and verification of these protein signature biomarkers in a low TB-incidence population would be useful. This would allow for further distinction of very recent and remote Mtb infection. Strengths of our study include a well-characterized epidemiological cohort of patients with newly-diagnosed culture-confirmed smear positive pulmonary TB, and contacts followed serially for TST conversion with testing done using standardized methods by a well-trained staff.