CXCL9 and CXCL10 Expression Are Critical for Control of Genital Herpes Simplex Virus Type 2 Infection through Mobilization of HSV-Specific CTL and NK Cells to the Nervous System

Abstract

CXCL9 and CXCL10 mediate the recruitment of T lymphocytes and NK cells known to be important in viral surveillance. The relevance of CXCL10 in comparison to CXCL9 in response to genital HSV-2 infection was determined using mice deficient in CXCL9 (CXCL9−/−) and deficient in CXCL10 (CXCL10−/−) along with wild-type (WT) C57BL/6 mice. An increased sensitivity to infection was found in CXCL10−/− mice in comparison to CXCL9−/− or WT mice as determined by detection of HSV-2 in the CNS at day 3 postinfection. However, by day 7 postinfection both CXCL9−/− and CXCL10−/− mice possessed significantly higher viral titers in the CNS in comparison to WT mice consistent with mortality (18–35%) of these mice within the first 7 days after infection. Even though CXCL9−/− and CXCL10−/− mice expressed elevated levels of CCL2, CCL3, CCL5, and CXCL1 in the spinal cord in comparison to WT mice, there was a reduction in NK cell and virus-specific CD8+ T cell mobilization to this tissue, suggesting CXCL9 and CXCL10 are critical for recruitment of these effector cells to the spinal cord following genital HSV-2 infection. Moreover, leukocytes from the spinal cord but not from draining lymph nodes or spleens of infected CXCL9−/− or CXCL10−/− mice displayed reduced CTL activity in comparison to effector cells from WT mice. Thus, the absence of CXCL9 or CXCL10 expression significantly alters the ability of the host to control genital HSV-2 infection through the mobilization of effector cells to sites of infection.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…CXCL10 deficiency was associated with a reduction in the mobilization of HSV-specific CD8 ϩ T cells into the brain as a result of dysregulation of CXCR3 signaling (31). CXCR3 Ϫ/Ϫ deficient mice are also reported to be susceptible to primary genital HSV-2 infection (61)(62)(63)(64). This susceptibility appeared to be associated with reduced cytotoxic function of CD8 ϩ T cells through impairment in expression of T-bet, perforin, and GzmB, as well as a reduction in the recruitment of pDC and impairment in CD80 expression on CD11c ϩ DC (61)(62)(63)(64).…”

“…CXCR3 Ϫ/Ϫ deficient mice are also reported to be susceptible to primary genital HSV-2 infection (61)(62)(63)(64). This susceptibility appeared to be associated with reduced cytotoxic function of CD8 ϩ T cells through impairment in expression of T-bet, perforin, and GzmB, as well as a reduction in the recruitment of pDC and impairment in CD80 expression on CD11c ϩ DC (61)(62)(63)(64). It is important to underline that, unlike the above studies that were done using mouse models of acute ocular and genital primary infections, our present studies used a mouse model of induced virus reactivation and recurrent herpes.…”

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

“…CXCL10 is an inflammatory chemokine that mainly recruits activated T cells and NK cells to sites of infection and/or inflammation. Using mouse animal models, it has been shown that CXCL10 expression is significantly induced and plays a critical role in a variety of viral infections, including infection with measles virus (20), West Nile virus (21), lymphocytic choriomeningitis virus (42), murine hepatitis virus (19,22), and herpes simples virus (24,43). The primary function of CXCL10 in these viral diseases is to recruit effector cells to the sites of infection.…”

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

“…Recently, it has been reported that the expression of CXCL9 was enhanced in HSV-2-infected mice (22), although the underlying mechanism remains to be addressed. CXCL9 levels in cervical mucus from HSV-2-negative (n = 41) and HSV-2-positive (n = 45) women were determined by ELISA.…”

“…The four subfamilies of chemokines, CXC, CC, C, and CX3C, are characterized by the position of the N-terminal cysteine residues (20,21). Recent study indicates that chemokine CXCL9 can be induced in mice after HSV-2 infection and its expression is crucial for control of genital HSV-2 infection (22), although the mechanism remains to be addressed. The receptor for CXCL9, CXCR3, is functionally expressed on activated T and B cells, NK cells, and endothelial cells (23,24).…”