Related Experiment Video
Updated: Jun 15, 2026
Processing of Bronchoalveolar Lavage Fluid and Matched Blood for Alveolar Macrophage and CD4+ T-cell Immunophenotyping and HIV Reservoir Assessment
Published on: June 23, 2019
MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons
Souvenir D Tachado1, Xin Li, Medhavi Bole
1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. stachado@bidmc.harvard.edu
Abstract:
Alveolar macrophages (AMs) are the predominant effector cell in the lungs and contribute to a critical first line of defense against bacterial pathogens through recognition by pattern recognition receptors such as Toll-like receptor 4 (TLR4). TLR4-mediated tumor necrosis factor alpha (TNFalpha) release is significantly impaired in HIV(+) macrophages, but whether HIV impairs myeloid differentiation factor 88 (MyD88)-dependent and/or MyD-independent TLR4 signaling pathways in human macrophages is not known. Comparing human U937 macrophages with HIV(+) U1 macrophages (HIV-infected U937 subclone), the current study shows that HIV infection is associated with impaired macrophage TLR4-mediated signaling, specifically targeting the MyD88-dependent TLR4-mediated signaling pathway (reduced MyD88-interleukin-1 receptor-associated kinase [IRAK] interaction, IRAK phosphorylation, nuclear factor [NF]-kappaB nuclear translocation, and TNFalpha release) while preserving the MyD88-independent TLR4-mediated signaling pathway (preserved STAT1 phosphorylation, interferon regulatory factor [IRF] nuclear translocation, and interleukin-10 [IL-10] and RANTES release). Extracellular TLR4 signaling complex was intact (similar levels of CD14 and MD2), and similar patterns of response were observed in clinically relevant AMs from healthy and asymptomatic HIV(+) persons at high clinical risk of pneumonia. Taken together, these data support the concept that chronic HIV infection is associated with specific and targeted disruption of critical macrophage TLR4 signaling, which in turn may contribute to disease pathogenesis of bacterial pneumonia.
Insights
HIV impairs a specific part of macrophage Toll-like receptor 4 (TLR4) signaling, affecting defense against bacterial pneumonia. This targeted disruption impacts MyD88-dependent pathways while sparing others.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Alveolar macrophages (AMs) are key lung immune cells, using Toll-like receptor 4 (TLR4) for pathogen defense.
- HIV infection is known to impair macrophage function, but specific signaling defects remain unclear.
Purpose of the Study:
- To investigate whether HIV impairs myeloid differentiation factor 88 (MyD88)-dependent and/or MyD-independent TLR4 signaling pathways in human macrophages.
- To compare TLR4 signaling in HIV-infected U1 macrophages versus healthy U937 macrophages and in clinical samples.
Main Methods:
- Utilized human U937 and HIV-infected U1 macrophage cell lines.
- Analyzed key signaling events including protein interactions, phosphorylation, and nuclear translocation.
- Assessed responses in alveolar macrophages from healthy and HIV-infected individuals.
Main Results:
- HIV infection specifically impairs the MyD88-dependent TLR4 pathway, evidenced by reduced MyD88-IRAK interaction, IRAK phosphorylation, and NF-kappaB translocation.
- TNFalpha release is significantly reduced in HIV-infected macrophages via the MyD88-dependent pathway.
- The MyD88-independent TLR4 pathway, including STAT1 phosphorylation and IL-10/RANTES release, remains largely preserved.
- Similar impairment patterns were observed in alveolar macrophages from HIV-positive individuals.
Conclusions:
- Chronic HIV infection selectively disrupts the MyD88-dependent TLR4 signaling pathway in macrophages.
- This targeted impairment may contribute to the increased susceptibility to bacterial pneumonia seen in HIV patients.
- Understanding this specific defect offers insights into HIV-associated immune dysfunction and potential therapeutic targets.
Related Concept Videos
01:23Tuberculosis
01:29Pulmonary Tuberculosis I
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...