Abstract
Monocytic cells represent important cellular elements of the innate and adaptive immune responses in viral infections. We assessed the role of Fas/FasL in promoting monocyte apoptosis during HSV-2 infection by using an in vitro model based on the murine RAW 264.7 monocytic cell line and an in vivo murine model of HSV-2 infection applied to C57BL6, MRL-Faslpr/J (Fas−/−) and C3-Faslgld/J (FasL−/−) mice. HSV-2 infection of the monocytic cell line led to early induction of apoptosis, with no protective expression of anti-apoptotic Bcl-2. HSV-2 infected monocytes up-regulated Fas and FasL expression early during in vitro infection but were susceptible to Fas induced apoptosis. The vaginal monocytes in the HSV-2 murine model of infection up-regulated FasL expression and were susceptible to Fas induced apoptosis. HSV-2 infection of Fas and FasL- deficient mice led to decreased apoptosis of monocytes and impaired recruitment of NK, CD4+ and CD8+ T cells within the infection sites. The vaginal lavages of HSV-2 infected Fas and FasL- deficient showed decreased production of CXCL9, CXCL10 and TNF-α in comparison to HSV-2 infected wild-type mice strain. The decreased recruitment of immune competent cells was accompanied by delayed virus clearance from the infected tissue. Triggering of the Fas receptor on HSV-2 infected monocytes in vitro up-regulated the expression of CXCL9 chemokines and the cytokine TNF-α. Our study provides novel insights on the role of Fas/FasL pathway not only in apoptosis of monocytes but also in regulating local immune response by monocytes during HSV-2 infection.
Highlights
Herpes simplex virus 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract mucosa and causes the most common genital ulcer disease in humans
HSV-2 Infection Induces Early Apoptosis in Monocytes Taking into account our previous results showing that HSV-2 infected mouse keratinocytes are resistant to apoptosis during the early phase HSV-2 infection, we decided to use the same keratinocyte cell line - 291.03C as a model of resistance to apoptosis during HSV-2 infection
Both cultures of monocyte (RAW264.7) and keratinocyte (291.03C) cell lines infected with HSV-2 at the same multiplicity of infection (M.O.I.) showed different percentages of HSV-2 infected cells: 81.5864.01 and 95.269.02% of keratinocytes at 24 and 48 h p.i., respectively, and 48.7664.75 and 71.6968.98% of monocytes were HSV-2 infected at the same time points (Fig. 1A)
Summary
Herpes simplex virus 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract mucosa and causes the most common genital ulcer disease in humans. Clinical and laboratory adapted HSV-2 strains can block apoptosis in cells of epithelial and keratinocyte origin [1,2,3], showing the existence of an ‘‘apoptosis prevention window’’ [1] during the first 6 hours of HSV-2 infection. This suppression of apoptosis has been shown to result from the expression of the anti-apoptotic proteins Bcl-2, NF-kB and Akt [1,2,3]. Apoptosis of murine peritoneal macrophages infected with HSV-2 was observed [9]
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