Herpes Simplex Virus Type 1-induced FasL Expression in Human Monocytic Cells and Its Implications for Cell Death, Viral Replication, and Immune Evasion
Herpes simplex virus type 1 (HSV-1) is a ubiquitously occurring pathogen that infects humans early in childhood. The virus persists as a latent infection in dorsal root ganglia, especially of the trigeminal nerve, and frequently becomes reactivated in humans under conditions of stress. Monocytic cells constitute an important component of the innate and adaptive immune responses. We show here for the first time that HSV-1 stimulates human FasL promoter and induces de novo expression of FasL on the surface of human monocytic cells, including monocytes and macrophages. This virus-induced FasL expression causes death of monocytic cells growing in suspension, but not in monolayers (e.g., macrophages). The addition of a broad-spectrum caspase inhibitor, as well as anti-FasL antibodies, reduced cell death but increased viral replication in the virus-infected cell cultures.
We also show here for the first time that the virus-induced de novo expression of FasL on the cell surface acts as an immune evasion mechanism by causing the death of interacting human CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. Our study provides novel insights on FasL expression and cell death in HSV-infected human monocytic cells and their impact on interacting immune cells.
Herpes simplex virus type 1 (HSV-1; hereafter referred to as HSV) is a ubiquitously occurring human herpes virus that infects humans early in life (reviewed in 1–3). It is a member of the α-Herpesviridae subfamily. Primary infections with the virus usually occur in early childhood and are mild or symptomless. However, infected humans can never eliminate the virus and become lifelong carriers. The virus travels from the oral and facial skin nerve endings to dorsal root ganglia, especially of the trigeminal nerve, where it becomes latent. The latent infections frequently become reactivated under conditions of stress, immunosuppression, physical trauma, or exposure to UV radiation (4). These reactivations are often manifested as painful blisters or “cold sores” at the mucocutaneous junctions of the lips. The condition is called herpes labialis. The virus may also infect the cornea and cause keratitis. These conditions cause considerable discomfort and represent a serious health problem. Primary and reactivated latent infections may rarely cause encephalitis, especially in neonates and immunocompetent persons with unknown defects of the immune system (3). HSV infection is the most common cause of sporadic infectious encephalitis in apparently healthy individuals. Effective anti-HSV drugs have been developed; however, the emergence of drug-resistant viruses has also been documented, particularly in immunocompromised individuals (reviewed in 5). Unfortunately, effective vaccines against the virus are not yet available.
Monocytes and macrophages represent important cellular elements of the immune system. In response to a viral infection, they release a variety of proinflammatory cytokines and chemokines, and recruit inflammatory cells to the site of infection. Activated macrophages phagocytose pathogens and immune complexes, and present viral antigens to other immune cells. Unlike epithelial cells, in which HSV prevents apoptosis and causes cell death with predominant features of necrosis, HSV infects monocytic cells with different degrees of permissiveness, and appears to induce their cell death via apoptosis (6–8). However, little is known about the mechanism of this virus-induced apoptosis, or its consequences for antiviral immunity as well as for viral replication. We addressed these questions and show here that HSV infection causes apoptosis in human monocytic cells by inducing expression of FasL on their surface. Our data provide experimental evidence showing for the first time that the virus induces FasL at the transcriptional level by stimulating FasL promoter. Interference with this apoptotic pathway prevents cell death, but enhances viral replication. Furthermore, HSV-infected human monocytic cells were able to kill Fas-positive human CD4+ T cells, CD8+ T cells, and natural killer (NK) cells in in vitro co-culture assays. These observations provide valuable insights about the relevance of apoptosis to viral replication and immune evasion in this viral infection.
Alexandre Iannello,1,,2,,3,,6,* Olfa Debbeche,1,,2,,3,,6,* Raoudha El Arabi,1,,2,,3,,6 Suzanne Samarani,1,,2,,3,,6 David Hamel,2,,5,,6 Flore Rozenberg,7 Nikolaus Heveker,2,,4,,6 and Ali Ahmadcorresponding author1,,2,,3,,6
Herpes Simplex Virus Type 1-induced FasL Expression in Human Monocytic Cells and Its Implications for Cell Death, Viral Replication, and Immune Evasion https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117309/