Antibodies against immunodominant antigens of Mycobacterium tuberculosis in subjects with suspected tuberculosis in the United States compared by HIV status

Abstract

The immunodominance of Mycobacterium tuberculosis proteins malate synthase (MS) and MPT51 has been demonstrated in case-control studies with patients from countries in which tuberculosis (TB) is endemic. The value of these antigens for the serodiagnosis of TB now is evaluated in a cross-sectional study of pulmonary TB suspects in the United States diagnosed to have TB, HIV-associated TB, or other respiratory diseases (ORD). Serum antibody reactivity to recombinant purified MS and MPT51 was determined by enzyme-linked immunosorbent assays (ELISAs) of samples from TB suspects and well-characterized control groups. TB suspects were diagnosed with TB (n = 87; 49% sputum microscopy negative, 20% HIV(+)) or ORD (n = 63; 58% HIV(+)). Antibody reactivity to MS and MPT51 was significantly higher in U.S. HIV(+)/TB samples than in HIV(-)/TB samples (P < 0.001), and it was significantly higher in both TB groups than in control groups with latent TB infection (P < 0.001). Antibody reactivity to both antigens was higher in U.S. HIV(+)/TB samples than in HIV(+)/ORD samples (P = 0.052 for MS, P = 0.001 for MPT51) but not significantly different between HIV(-)/TB and HIV(-)/ORD. Among U.S. HIV(+) TB suspects, a positive anti-MPT51 antibody response was strongly and significantly associated with TB (odds ratio, 11.0; 95% confidence interval, 2.3 to 51.2; P = 0.002). These findings have implications for the adjunctive use of TB serodiagnosis with these antigens in HIV(+) subjects.

FIG. 1.

Antibody reactivities to MS and MPT51 in asymptomatic U.S. control groups categorized by TST result and HIV status. Bars show median ODs with interquartile ranges. The Kruskal-Wallis test was used for the group comparison of median antibody reactivities.

FIG. 2.

Antibody reactivities to MS (A) and MPT51 (B) in subjects with TB, other respiratory diseases (ORD), and controls, categorized by HIV status. Cutoff values were derived from the mean OD of HIV⁻/TST⁻ healthy volunteers plus 3 standard deviations; ΔOD, change in optical density after the subtraction of the cutoff value; •, sputum AFB smear positive; ○, sputum AFB smear negative; Ind, Indian; bars show median ΔODs with interquartile ranges. The Mann-Whitney U test was used for two-group comparisons of median antibody reactivities. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

FIG. 3.

Antibody reactivities to MS and MPT51 by type of ORD. Cutoff values were derived from the mean OD of HIV⁻/TST⁻ healthy volunteers plus 3 standard deviations; ΔOD, change in optical density after the subtraction of the cutoff value; ⧫, HIV⁺; ⋄, HIV⁻; □, HIV status unknown; CAP, community-acquired pneumonia; PCP, Pneumocystis jiroveci pneumonia; NTM, nontuberculous mycobacterial lung disease; bronch, bronchitis; other, respiratory diseases other than TB, such as lung cancer, sarcoidosis, lung abscess, empyema, immune reconstitution syndrome, etc.

FIG. 4.

Correlation between antibody reactivity to MS and MPT51 in Indian HIV⁻/TB (A), U.S. HIV⁻/TB (B), Indian HIV⁺/TB (C), U.S. HIV⁺/TB (D), U.S. HIV⁻/ORD (E), and U.S. HIV⁺/ORD subjects (F). Spearman rank correlation was used to test for statistical significance.