Investigation of immune correlates, and impact of human cytomegalovirus and immune activation, on tuberculosis disease risk

Background: Recent evidence implicates human cytomegalovirus (HCMV), immune activation and inflammation as risk factors for tuberculosis (TB) disease. Evidence also points towards the underappreciated importance of humoral immunity in protection against TB. Methods: This PhD thesis uses stored serum samples from an established rural Ugandan cohort to investigate associations between HCMV, inflammation and TB. Firstly, HCMV epidemiology is investigated, and levels of mycobacterial antibodies are characterised in a cross-sectional study design including over 2,000 individuals. Secondly, a nested case-control study design was employed to explore longitudinal relationships prior to TB diagnosis in 343 matched samples. Results: This work has characterised the HCMV seropositivity in this population and found that 95% of individuals are infected by age 5. Mycobacteria-specific antibody levels increased in all individuals until a plateau was reached at approximately age 20. HIV positivity and high HCMV IgG levels were independently associated with decreased levels of mycobacterial antibodies. HCMV IgG levels, but not other chronic herpes infections EBV and HSV, are associated with increased risk of TB up to 14 years prior to TB diagnosis. HCMV IgG levels, but not EBV or HSV, are positively correlated with the inflammatory serum marker IP10. Increased antibody avidity against the mycobacterial antigen mixture, PPD, showed a directional trend towards decreased risk of TB at early time points prior to TB diagnosis. Conclusions: Data presented in this thesis confirm that HCMV burden is high in this rural Ugandan population. Anti-mycobacterial antibody levels increase with age, suggestive of cumulative exposure to either antigenically related non-tuberculous mycobacteria (NTM) or to M.tb itself. This body of work provides more evidence that HCMV infection is associated with TB disease risk. As opposed to a simple binary seropositive measurement, I have found that risk of TB disease is associated with magnitude of HCMV IgG response.