Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that SET domain bifurcated 2 (Setdb2) was the only protein lysine methyltransferase induced during influenza virus infection. Setdb2 expression depended on type-I interferon signaling and it repressed the expression of the neutrophil attractant Cxcl1 and other NF-κB target genes. This coincided with Setdb2 occupancy at the Cxcl1 promoter, which in the absence of Setdb2 displayed reduced H3K9 tri-methylation. Setdb2 hypomorphic gene-trap mice exhibited increased neutrophil infiltration in sterile lung inflammation and were less sensitive to bacterial superinfection upon influenza virus infection. This suggests that a Setdb2-mediated regulatory crosstalk between the type-I interferon and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

Purpose: Oral human papillomavirus (HPV) infection is a risk factor for head and neck squamous cell carcinoma (HNSCC), and is a concern for patients with HPV-positive HNSCC and their partners. The prevalence of oral HPV infection before and after cancer therapy was investigated among patients with HPV16-positive and HPV16-negative HNSCC. Experimental Design: Serial oral rinse samples (ORS) were collected from a cohort of 135 HNSCC cases as frequently as every 3 months for up to 3 years. Tumor HPV status was determined by HPV16 in situ hybridization. HPV was detected in ORS by consensus PCR and line blot hybridization.The HPV16 variants in positive oral rinse^tumor pairs were determined by sequencing. The odds of oral HPV infection among HPV16-positive and HPV16-negative cases were compared by use of generalized estimating equations. Results: Patients were followed for a median of 21months and provided a median of 4 samples. Forty-four of 135 patients had HPV16-positive tumors. HPV16-positive cases were more likely than HPV16-negative cases to have an oral HPV infection detected before (odds ratio, 8.6; 95% confidence interval, 3.5-21) and after therapy (OR, 2.9; 95% confidence interval, 1.1-7.4). Oral infections by HPV16 and other high-risk, but not low-risk, types were more common among HPV16-positive cases both before and after therapy. Most HPV16 variants in ORS were European, unique, and identical to that in the tumor. Persistence of a type-specific oral infection was demonstrable for as long as 5 years. Conclusion: Oral high-risk HPV infections are more frequent among patients with HPV16-positive than HPV16-negative HNSCC, consistent with a behavioral and/or biological disposition to infection.Case-control studies have now established that oral human papillomavirus (HPV) infection is a strong risk factor for head and neck squamous cell carcinoma (HNSCC), and particularly for oropharyngeal cancer. High-risk oral HPV infection, but not low-risk infection, is strongly associated with cancer risk (1 -3). Risk is particularly high for oral HPV16 infection. Oral HPV16 infection was independently associated with a 15-fold increase in risk for oropharyngeal cancer in a recent case-control study (4), a risk estimate similar to the 14-fold increase in subsequent risk for oropharyngeal cancer among HPV16-seropositive individuals in a nested case-control study (5).Oral HPV infection therefore has important health consequences, and yet, little is known about risk factors for infection. Limited available data suggest that oral HPV infection is likely sexually acquired: a history of sexually transmitted disease and number of oral sexual partners are associated with both oral HPV infection (6, 7) and HPV-positive oropharyngeal cancer (4). Additionally, the presence and persistence of an oral highrisk HPV infection has been associated with a persistent oral infection in a spouse (8). Consistent with these data are the increased risk for oral cancer among husbands of women with cervical cancer (9, 10) as well as the...