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Introduction The human innate immune system provides early and effective responses against many invading pathogens and potential environmental threats. A critical component of innate immunity is pattern recognition of a [...], The Toll-like receptor 8 (TLR8) has an important role in innate immune responses to RNA viral infections, including respiratory syncytial virus (RSV). We previously reported that TLR8 expression was increased directly by the tumor suppressor and transcription factor p53 via a single nucleotide polymorphism (SNP) (rs3761624) in the TLR8 promoter, thereby placing TLR8 in the p53/immune axis. Because this SNP is in linkage disequilibrium with other SNPs associated with several infectious diseases, we addressed the combined influence of p53 and the SNP on downstream inflammatory signaling in response to a TLR8 cognate ssRNA ligand. Using human primary lymphocytes, p53 induction by chemotherapeutic agents such as ionizing radiation caused SNP-dependent synergistic increases in IL-6 following incubation with an ssRNA ligand, as well as TLR8 RNA and protein expression along with p53 binding at the TLR-p53 SNP site. Because TLR8 is X-linked, the increases were generally reduced in heterozygous females. We found a corresponding association of the p53-responsive allele with RSV disease severity in infants hospitalized with RSV infection. We conclude that p53 can strongly influence TLR8-mediated immune responses and that knowledge of the p53-responsive SNP can inform diagnosis and prognosis of RSV disease and other diseases that might have a TLR8 component, including cancer.

Introduction A paradigm of host immunity is that an individual's susceptibility to pathogens indicates a specific molecular defect. Yet, there are apparent exceptions to this paradigm: individuals who develop infections [...], Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-[gamma] receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 ([IFNAR1.sup.*557Gluext*46]), which encodes the IFN-[alpha] receptor signaling subunit. The [IFNAR1.sup.*557Gluext*46] resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of [IFNAR1.sup.*557Gluext*46] mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-[alpha]-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-[alpha]-stimulated genes critical for CMV immunity. Pretreatment with IFN-[alpha] failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-[alpha]-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.

Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss [...]

The cytotoxic activity of lymphocytes is crucial for immune surveillance and homeostasis. Several independent, naturally occurring genetic models characterized by defects in granule trafficking or exocytosis have helped to decipher the multiple steps and molecules that regulate the cytotoxic process. The study by Ruder and colleagues in this issue of the JCI shows that an engineered absence of EBAG9, previously reported as a tumor-associated antigen, enhances cytotoxic activity of CTLs but not NK cells, likely acting on the endosomal-lysosomal trafficking of the cytotoxic effectors (see the related article beginning on page 2184). This finding adds a new piece to the puzzle of complex mechanisms that tightly regulate the capacity of the cytotoxic response and suggests a new target to negatively modulate CTL responsiveness., CTLs and NK cells (collectively known as "cytotoxic lymphocytes") are major players in the body's defense against viral infection and cancer via their ability to seek out and kill infected [...]

In vertebrates, the detection of viral nucleic acids is the first step toward innate and subsequent adaptive antiviral immune responses. A sophisticated, protein receptor--based sensor system has evolved to recognize viral nucleic acids and to trigger a variety of antiviral defense mechanisms. The more we learn about this elaborate sensor system, the more it becomes evident how difficult it is to introduce exogenous nucleic acids such as siRNA into cells without triggering antiviral immunoreceptors. In this issue of the JCI, Judge and colleagues provide evidence that siRNA can be designed and delivered in a way that allows specific and successful silencing of target genes in tumor cells in vivo, leading to tumor cell death and prolonged survival of tumor-bearing mice in the absence of immune activation (see the related article beginning on page 661). This study represents a major technological advance, setting new standards for well-controlled siRNA applications in vivo, and has the potential to guide clinical development toward siRNA therapeutics with well-defined and selective gene-silencing activities., Nature has evolved two major antiviral defense strategies: one is based on degradation of long, viral dsRNA molecules to short, viral dsRNA molecules and amplification thereof, resulting in RNAi-mediated cleavage [...]

Genetic studies suggest a role for killer cell immunoglobulin-like receptor/HLA (KIR/HLA) compound genotypes in the outcome of viral infections, but functional data to explain these epidemiological observations have not been reported. Using an in vitro model of infection with influenza A virus (IAV), we attribute functional differences in human NK cell activity to distinct KIR/HLA genotypes. Multicolor flow cytometry revealed that the HLA-C--inhibited NK cell subset in HLA-C1 homozygous subjects was larger and responded more rapidly in IFN-[gamma] secretion and CD107a degranulation assays than its counterpart in HLA-C2 homozygous subjects. The differential IFN-[gamma] response was also observed at the level of bulk NK cells and was independent of KIR3DL1/HLA-Bw4 interactions. Moreover, the differential response was not caused by differences in NK cell maturation status and phenotype, nor by differences in the type I IFN response of IAV-infected accessory cells between HLA-C1 and HLA-C2 homozygous subjects. These results provide functional evidence for differential NK cell responsiveness depending on KIR/HLA genotype and may provide useful insights into differential innate immune responsiveness to viral infections such as IAV., Introduction As part of the innate immune system, NK cells present a first line of defense against viral infections and tumors (1). NK cell effector functions, such as cytotoxicity and [...]