Biology subjects

Phong, T.

Publications and source records attributed to Phong, T..

3 recordsLinked to original sources

bioRxiv2024

Inhibition of glycolysis in tuberculosis-mediated metabolic rewiring reduces HIV-1 spread across macrophages

Tuberculosis (TB) is a significant aggravating factor in individuals living with human immunodeficiency virus type 1 (HIV-1), the causative agent for acquired immunodeficiency syndrome (AIDS). Both Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using pharmacological inhibitors and glucose deprivation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 exacerbation in these macrophages. Glycolysis is essential for tunneling nanotubes (TNT) formation, which facilitates viral transfer and cell-to-cell fusion and induces the expression of the sialoadhesin Siglec-1, enhancing both HIV-1 binding and TNT stabilization. Glycolysis did not exacerbate HIV-1 infection when TNT formation was pharmacologically prevented, indicating that higher metabolic activity is not sufficient per se to make macrophages more susceptible to HIV-1. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in co-infected patients.

immunology↗

bioRxiv2024

Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections

Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As interferons are crucial for antiviral defense, pDCs are assumed to play an essential role in this process. However, robust evidence supporting this dogma is scarce. Genetic or pharmacological manipulations that eliminate pDC or disrupt their interferon production often affect other cells, confounding interpretation. To overcome this issue, we engineered pDC-less mice that are specifically and constitutively devoid of pDCs by expressing diphtheria toxin under coordinated control of the Siglech and Pacsin1 genes, uniquely co-expressed in pDCs. pDC-less mice mounted protective immunity against systemic infection with mouse Cytomegalovirus and showed higher survival and less lung immunopathology to intranasal infection with influenza virus and SARS-CoV2. Thus, contrary to the prevailing dogma, we revealed that pDCs and their interferons are dispensable or deleterious during several viral infections. pDC-less mice will enable rigorously reassessing the roles of pDCs in health and disease.

immunology↗

bioRxiv2019

Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis worsens HIV-1 pathogenesis remain poorly understood. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of the lectin receptor Siglec-1. We demonstrate Siglec-1 expression depends on TB-mediated production of type I interferon. In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of the type I interferon/STAT1 pathway. Intriguingly, Siglec-1 expression localizes exclusively on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion in macrophages decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates TB-driven exacerbation of HIV-1 infection. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection, and its localization on TNT opens new avenues to understand cell-to-cell viral spread.

cell biology↗