HSV-2 Regulates Monocyte Inflammatory Response via the Fas/FasL Pathway

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.

Role of Fas/FasL signaling in regulation of anti-viral response during HSV-2 vaginal infection in mice

“…In our study, we found significantly decreased total numbers of NK cells in the vaginal tissue at 7 but not at 3 day of infection. We have previously shown that decreased mobilization of NK cells into the vaginal tissues of Fas-and FasL-deficient mice during HSV-2 infection may be due to the monocytes producing significantly less CXCL9, CXCL10 and TNF-␣ than monocytes in the wild type mice (Krzyzowska et al 2013). Here, we also found significantly decreased percentage of NK cells with IFN-␥ expression, which can and WT (C57BL/6) mice.…”

“…as well as the total numbers of CD8+ T cells at 3 and 7 d.p.i. (Krzyzowska et al 2013). Here, decreased total counts of CD4+ T cells were followed by a significant decrease in the percentage of IFN-␥ expressing CD4+ T cells at 7 d.p.i.…”

“…(Krzyzowska et al 2013). After an intravaginal infection with 1 × 10 4 PFU of HSV-2 strain 333, which was about a 50% lethal dose for WT C57BL/6 mice, all Fas (−) mice died by 10 d.p.i., while FasL (−) showed higher mortality than wild-type mice (p < 0.00001) (Fig.…”

“…We have previously shown that infection of Fas-and FasLdeficient mice leads to increased viral titers in the vaginal tissue but not in the vaginal lavages (Krzyzowska et al 2011(Krzyzowska et al , 2013. Ishikawa et al (2009) also examined infection with virulent HSV-2 strain in Fas or FasL-deficient mice.…”

“…Furthermore, Fas and FasL-deficient mice showed delayed virus clearance from the vaginal tissue and impaired recruitment of NK, CD4+ and CD8+ T cells within the infection sites (Krzyzowska et al 2013).…”