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Endsley, J.

Publications and source records attributed to Endsley, J..

2 recordsLinked to original sources
bioRxiv2024

Sirtuin2 blockade inhibits replication of Human Immunodeficiency Virus-1 and 1 Mycobacterium tuberculosis in macrophages and humanized mice

Coinfections with Mycobacterium tuberculosis (Mtb) and HIV-1 present a critical health challenge and require treatment for survival. We found that human M1 macrophages inhibit Mtb growth, while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, we found that HIV-1 augmented Sirt2 gene expression in M[FE]s. Therefore, we explored the therapeutic potential of sirtuin-modulating drugs in M[FE]s. Sirtinol, a Sirt2 inhibitor, significantly reduced HIV-1 growth in M0, M1, and M2-M[FE]s by >1 log10 over 7 days. Conversely, individual doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with resveratrol was neither synergistic nor antagonistic. Sirtinol upregulated iNOS and ATG5 mRNA in HIV-1 infected M[FE]s in a phenotype-dependent manner. In a humanized mouse model (Hu-NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, or in combination with combination antiretroviral therapy (cART), showed promising results; Sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel dual therapeutic strategy for treating HIV-1 and Mtb coinfections.

immunology↗
bioRxiv2023

HIV Infection impairs the Host Response to Mycobacterium tuberculosis Infection by altering Surfactant Protein D function in the Human Lung Alveolar Mucosa

Tuberculosis is the leading cause of death for people living with HIV (PLWH). We hypothesized that altered functions of innate immune components in the human alveolar lining fluid of PLWH (HIV-ALF), drive susceptibility to Mycobacterium tuberculosis (M.tb) infection. Our results indicate a significant increase in oxidation of innate proteins and chemokine levels, and significantly lower levels and function of complement components and Th1/Th2/Th17 cytokines in HIV-ALF vs. control-ALF (non-HIV infected people). We further found a deficiency of surfactant protein-D (SP-D) and reduced binding of SP-D to M.tb that had been exposed to HIV-ALF. Primary human macrophages infected with M.tb exposed to HIV-ALF were significantly less capable of controlling the infection, which was reversed by SP-D replenishment in HIV-ALF. Thus, our data suggest that PLWH without antiretroviral therapy (ART) have declining host innate defense function in their lung mucosa, thereby favoring M.tb and potentially other pulmonary infections.

cell biology↗