The Nitric Oxide Pathway Provides Innate Antiviral Protection in Conjunction with the Type I Interferon Pathway in Fibroblasts

The innate host response to virus infection is largely dominated by the production of type I interferon and interferon stimulated genes. In particular, fibroblasts respond robustly to viral infection and to recognition of viral signatures such as dsRNA with the rapid production of type I interferon; subsequently, fibroblasts are a key cell type in antiviral protection. We recently found, however, that primary fibroblasts deficient for the production of interferon, interferon stimulated genes, and other cytokines and chemokines mount a robust antiviral response against both DNA and RNA viruses following stimulation with dsRNA. Nitric oxide is a chemical compound with pleiotropic functions; its production by phagocytes in response to interferon-γ is associated with antimicrobial activity. Here we show that in response to dsRNA, nitric oxide is rapidly produced in primary fibroblasts. In the presence of an intact interferon system, nitric oxide plays a minor but significant role in antiviral protection. However, in the absence of an interferon system, nitric oxide is critical for the protection against DNA viruses. In primary fibroblasts, NF-κB and interferon regulatory factor 1 participate in the induction of inducible nitric oxide synthase expression, which subsequently produces nitric oxide. As large DNA viruses encode multiple and diverse immune modulators to disable the interferon system, it appears that the nitric oxide pathway serves as a secondary strategy to protect the host against viral infection in key cell types, such as fibroblasts, that largely rely on the type I interferon system for antiviral protection

118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

<p>Abstract</p> <p>Background</p> <p>Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.</p> <p>Methods</p> <p>Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983–86 or 1994–95. It also included 214 infants with conotruncal heart defects born during 1983–86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.</p> <p>Results</p> <p>Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: <it>BHMT </it>(rs3733890) OR = 1.8 (1.1–3.1), <it>CBS </it>(rs2851391) OR = 2.0 (1.2–3.1); <it>CBS </it>(rs234713) OR = 2.9 (1.3–6.7); <it>MTHFD1 </it>(rs2236224) OR = 1.7 (1.1–2.7); <it>MTHFD1 </it>(hcv11462908) OR = 0.2 (0–0.9); <it>MTHFD2 </it>(rs702465) OR = 0.6 (0.4–0.9); <it>MTHFD2 </it>(rs7571842) OR = 0.6 (0.4–0.9); <it>MTHFR </it>(rs1801133) OR = 2.0 (1.2–3.1); <it>MTRR </it>(rs162036) OR = 3.0 (1.5–5.9); <it>MTRR </it>(rs10380) OR = 3.4 (1.6–7.1); <it>MTRR </it>(rs1801394) OR = 0.7 (0.5–0.9); <it>MTRR </it>(rs9332) OR = 2.7 (1.3–5.3); <it>TYMS </it>(rs2847149) OR = 2.2 (1.4–3.5); <it>TYMS </it>(rs1001761) OR = 2.4 (1.5–3.8); and <it>TYMS </it>(rs502396) OR = 2.1 (1.3–3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with <it>TYMS</it>, <it>MTHFR</it>, <it>BHMT </it>and <it>MTR </it>for spina bifida.</p> <p>Conclusion</p> <p>Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.</p

Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus 1 (HSV-1) infection have not fully been elucidated. Here, we report that Cav-1 downregulates the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in dendritic cells (DCs) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to wild-type (WT) mice. In addition, Cav-1 knockout (KO) (Cav-1(−/−)) mice treated with an iNOS inhibitor exhibited significantly reduced survival compared to that of the nontreated controls. We found that Cav-1 colocalized with iNOS and HSV-1 in caveolae in HSV-1-infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade the host antiviral response mediated by NO production. Therefore, Cav-1 might be a valuable target for therapeutic approaches against herpesvirus infections

A molecular and cellular model to explain the differences in reactivation from latency by herpes simplex and varicella–zoster viruses

There are marked similarities in the biological properties of the human neurotropic herpesviruses herpes simplex virus type 1 (HSV–1) and varicella–zoster virus (VZV), including their ability to establish lifelong latent infections in human peripheral sensory ganglia (PSG). Despite this, their patterns of reactivation are quite different: HSV–1 reactivations occur many times during a lifetime, they are localized to the cutaneous distribution of a single sensory nerve, they are not associated with sensory symptomatology and their frequency decreases with age. VZV recurrence on the other hand is usually a single event which tends to appear with advancing age, its cutaneous eruption involves an entire dermatome and is usually extremely painful. To help explain these differences, we have formulated a model based on current knowledge of the molecular and cellular basis of latent infection in the nervous system. We suggest that the amount of latent viral DNA and RNA in the latently infected tissue (higher with HSV–1), the cellular location of latent virus (neuronal in HSV–1, probably non–neuronal in VZV), the presence or absence of viral replication in the PSG during reactivation together with the host immune response, are all key determinants of the clinical expression of viral reactivation