Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Abstract

Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR] = 11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis. Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis. In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility. IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.

Impact of Persistent Anemia on Systemic Inflammation and Tuberculosis Outcomes in Persons Living With HIV

“…Finally, iron supplementation in such cases is still a matter of debate, with inconsistent results reported by clinical trials. The probable determinants of anemia in the context of HIV/AIDS and TB are likely multifactorial and involve several factors including nutritional status ( 31 ), chronic inflammation and antibody-mediated erythrophagocytosis ( 32 ). Our results demonstrated that anemic patients also exhibit lower counts of other cell types, suggesting that a global effect on the bone marrow may be occurring.…”

Mitochondrial fusion mediated by mitofusin 1 regulates macrophage mycobactericidal activity by enhancing autophagy

“…The link between the inhibition of cellular ATP production and autophagy were further confirmed by inhibitors of the electron transport chain (Fig. S6 C-D).Next, we then used a stably transformed mRFP-GFP-LC3 reporter in the THP-1 macrophages(26) to further determine the effect of MFN1 on autophagy flux. Silencing of MFN1 significantly reduced the numbers of autophagosomes and autolysosomes, which formed puncta structures in H37Ra-infected cells,(Fig.…”

Flunarizine suppressesMycobacterium tuberculosisgrowth via calmodulin-dependent phagosome maturation

“…Nonadherent cells were washed twice with prewarmed RPMI‐1640 and adherent cells were treated with 50 ng/ml human macrophage CSF (PeproTech) in RPMI‐1640 with 10% fetal calf serum and 2 mM l ‐glutamine for adhesion processing. The monocytes were incubated for 5 days to differentiate into human monocyte‐derived macrophages (hMDMs) at 37°C in an atmosphere of 5% CO 2 16 …”

“…Digital images of the protein bands were acquired using the Chemiluminescence Image System (Minichem™, China). 16…”

“…The monocytes were incubated for 5 days to differentiate into human monocytederived macrophages (hMDMs) at 37 • C in an atmosphere of 5% CO 2 . 16 To chelate the calcium, 3 μM of MAPTAM (acety- MCE) 17 was used as an inhibitor of CAMKII enzyme activity in the THP-1 macrophages. The final quantity of DMSO reagent used in this study did not exceed 0.1% (v/v).…”