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Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1.

ABSTRACT: HIV-1 relies on the host's cell machinery to establish a successful infection. Surface receptors, such as CD4, CCR5, and CXCR4 of T cells and macrophages, are essential for membrane fusion of HIV-1, an initiate step in viral entry. However, it is not well defined how HIV-1 infects CD4-negative mucosal epithelial cells. Here we show that there is a specific interaction between HIV-1 and an invasive oral bacterium, Porphyromonas gingivalis. We found that HIV-1 was trapped on the bacterial surface, which led to internalization of HIV-1 virions as the bacteria invaded CD4-negative epithelial cells. Both bacterial and viral DNA was detected in HeLa and TERT-2 cells exposed to the HIV-1-P. gingivalis complexes 2 hr after the initial infection but not in cells exposed to HIV-1 alone. Moreover, epithelial cell entry of HIV-1 was positively correlated with invasive activity of the P. gingivalis strains tested, even when the binding affinities of HIV-1 to these strains were similar. Finally, it was demonstrated that the viral DNA was integrated into the genome of the host epithelial cells. These results reveal a receptor-independent HIV-1 entry into epithelial cells, which may be relevant in HIV transmission in other mucosal epithelia where complex microbial communities can be found.

SUBMITTER: Mantri CK

PROVIDER: S-EPMC4126220 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1.

Mantri C K CK Chen C C Dong X X Goodwin J S JS Xie H H

Journal of dental research 20140529 8

HIV-1 relies on the host's cell machinery to establish a successful infection. Surface receptors, such as CD4, CCR5, and CXCR4 of T cells and macrophages, are essential for membrane fusion of HIV-1, an initiate step in viral entry. However, it is not well defined how HIV-1 infects CD4-negative mucosal epithelial cells. Here we show that there is a specific interaction between HIV-1 and an invasive oral bacterium, Porphyromonas gingivalis. We found that HIV-1 was trapped on the bacterial surface, ...[more]

PMID: 24874702

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Project description:Porphyromonas gingivalis, a major opportunistic pathogen in the etiology of chronic periodontitis, successfully survives in human gingival epithelial cells (GECs). P. gingivalis abrogates the effects of a host danger molecule, extracellular ATP (eATP)/P2X7 signaling, such as the generation of reactive oxygen species (ROS) via the mitochondria and NADPH oxidases (NOX) from primary GECs. However, antimicrobial functions of ROS production are thoroughly investigated in myeloid-lineage immune cells and have not been well-understood in epithelial cells. Therefore, this study characterizes antibacterial NOX2 generated ROS and host downstream effects in P. gingivalis infected human primary GECs. We examined the expression of NOX isoforms in the GECs and demonstrate eATP stimulation increased the mRNA expression of NOX2 (p < 0.05). Specific peptide inhibition of NOX2 significantly reduced eATP-mediated ROS as detected by DCFDA probe. The results also showed P. gingivalis infection can temporally modulate NOX2 pathway by reorganizing the localization and activation of cytosolic molecules (p47phox, p67phox, and Rac1) during 24 h of infection. Investigation into downstream biocidal factors of NOX2 revealed an eATP-induced increase in hypochlorous acid (HOCl) in GECs detected by R19-S fluorescent probe, which is significantly reduced by a myeloperoxidase (MPO) inhibitor. MPO activity of the host cells was assayed and found to be positively affected by eATP treatment and/or infection. However, P. gingivalis significantly reduced the MPO product, bactericidal HOCl, in early times of infection upon eATP stimulation. Analysis of the intracellular levels of a major host-antioxidant, glutathione during early infection revealed a substantial decrease (p < 0.05) in reduced glutathione indicative of scavenging of HOCl by P. gingivalis infection and eATP treatment. Examination of the mRNA expression of key enzymes in the glutathione synthesis pathway displayed a marked increase (p < 0.05) in glutamate cysteine ligase (GCL) subunits GCLc and GCLm, glutathione synthetase, and glutathione reductase during the infection. These suggest P. gingivalis modulates the danger signal eATP-induced NOX2 signaling and also induces host glutathione synthesis to likely avoid HOCl mediated clearance. Thus, we characterize for the first time in epithelial cells, an eATP/NOX2-ROS-antibacterial pathway and demonstrate P. gingivalis can circumvent this important antimicrobial defense system potentially for successful persistence in human epithelial tissues.

Dataset Information

Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1.

Publications

Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1.

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