Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models.

Studies over the past decade have revealed a central role for innate immune sensors in autoimmune and autoinflammatory diseases. cGAS, a cytosolic DNA sensor, detects both foreign and host DNA and generates a second-messenger cGAMP, which in turn binds and activates stimulator of IFN genes (STING), leading to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients present with early-onset systemic inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. Here, we describe two independent SAVI mouse models, harboring the two most common mutations found in patients. A direct comparison of these strains reveals a hierarchy of immune abnormalities, lung inflammation and fibrosis, which do not depend on either IFN-α/ß receptor signaling or mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptotic cell death pathways. Furthermore, radiation chimera experiments reveal how bone marrow from the V154M mutant mice transfer disease to the WT host, whereas the N153S does not, indicating mutation-specific disease outcomes. Moreover, using radiation chimeras we find that T cell lymphopenia depends on T cell-intrinsic expression of the SAVI mutation. Collectively, these mutant mice recapitulate many of the disease features seen in SAVI patients and highlight mutation-specific functions of STING that shed light on the heterogeneity observed in SAVI patients.

CNBP controls IL-12 gene transcription and Th1 immunity.

An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Recently, cellular nucleic acid-binding protein (CNBP) was identified as a regulator of nuclear factor-kappaB (NF-κB)-dependent proinflammatory cytokine gene expression. Here, we generated mice lacking CNBP and found that CNBP regulates a very restricted gene signature that includes IL-12ß. CNBP resides in the cytosol of macrophages and translocates to the nucleus in response to diverse microbial pathogens and pathogen-derived products. Cnbp-deficient macrophages induced canonical NF-κB/Rel signaling normally but were impaired in their ability to control the activation of c-Rel, a key driver of IL-12ß gene transcription. The nuclear translocation and DNA-binding activity of c-Rel required CNBP. Lastly, Cnbp-deficient mice were more susceptible to acute toxoplasmosis associated with reduced production of IL-12ß, as well as a reduced T helper type 1 (Th1) cell IFN-γ response essential to controlling parasite replication. Collectively, these findings identify CNBP as important regulator of c-Rel-dependent IL-12ß gene transcription and Th1 immunity.

Serotype distribution of invasive Streptococcus pneumoniae in adults 65 years of age and over after the introduction of childhood 13-valent pneumococcal conjugate vaccination programs in Canada, 2010-2016.

The 13-valent conjugate vaccine (PCV13) was recommended for childhood immunization programs in 2010 in Canada and has decreased the incidence of invasive pneumococcal disease (IPD) in children and changed the epidemiology of IPD in adults. This study investigated the epidemiology of IPD in adults 65 years of age and older in Canada. A total of 7282 invasive S. pneumoniae isolated from adults ≥65 years old were serotyped from 2010 to 2016 and antimicrobial susceptibility was performed on 2527 isolates. Serotyping was performed by Quellung reaction using commercial antisera and antimicrobial susceptibilities were determined by broth microdilution. PCV7 serotypes decreased non-significantly from 2010 to 2016 from 9.1% (n = 96) to 6.7% (n = 72) while the additional six PCV13 serotypes declined significantly from 39.5% (n = 418) to 18.6% (n = 201) (p < 0.05). The 23-valent pneumococcal polysaccharide vaccine (PPV23) and non-vaccine (NVT) serotypes increased from 26.3% (n = 278) to 36.2% (n = 393) (p < 0.05), and from 25.1% (n = 266) to 38.4% (n = 416) (p < 0.05), respectively. There were no significant changes in antimicrobial resistance rates from 2011 to 2016: 24.1% of the IPD from adults ≥65 years were resistant to clarithromycin (n = 609), 10.0% to doxycycline (n = 254), 11.8% to penicillin (n = 299), 5.2% to cefuroxime (n = 131), 6.6% to clindamycin (n = 168), 6.0% to trimethoprim-sulfamethoxazole (n = 152), and 0.5% (n = 12) to ceftriaxone. Although overall incidence of IPD in adults ≥65 years has remained relatively constant from 2010 to 2016, childhood PCV13 vaccination programs have been successful in indirectly reducing IPD caused by PCV13 serotypes in adults through herd immunity effects.

Phylogenetic analysis of emergent Streptococcus pneumoniae serotype 22F causing invasive pneumococcal disease using whole genome sequencing.

Since implementation of the 13-valent polyvalent conjugate vaccine (PCV13) in Canada during 2010, the proportion of PCV13 serotypes causing invasive pneumococcal disease (IPD) has declined from 55% (n = 1492) in 2010 to 31% (n = 764) in 2014. A concurrent increase of non-PCV13 serotypes has occurred and 22F has become the most prevalent serotype in Canada increasing from 7% (n = 183) to 11% (n = 283). Core single nucleotide variant phylogenetic analysis was performed on 137 Streptococcus pneumoniae serotype 22F isolates collected across Canada from 2005-2015. Six phylogenetic lineages (n = 117) were identified among a serotype 22F/ST433 clonal complex (CC), including a recently expanding erythromycin-resistant clone. Erythromycin-resistance was observed in 25 isolates possessing ermB, mef or a 23S rRNA A2061G point mutation; 2 penicillin-resistant isolates had recombinant pbp1a, pbp2a and/or pbp2x; 3 tetracycline-resistant isolates contained tetM; and 1 isolate was multidrug-resistant. Virulence factor analysis indicated a high level of homogeneity among the 22F/ST433 clonal complex strains. A group of 6 phylogenetic outlier strains had differing MLST, antimicrobial resistance and molecular profiles suggestive of capsule switching events. While capsule switch events among S. pneumoniae serotype 22F has been observed, increasing prevalence of S. pneumoniae serotype 22F can be attributed to an evolving homogenous clone expanding nationally through local transmission events.

Examining the relationships between posttraumatic stress disorder symptoms, positive smoking outcome expectancies, and cigarette smoking in people with substance use disorders: a multiple mediator model.

Cigarette smoking is highly prevalent in people with substance use disorders (SUDs) and is associated with significant physical health problems. Posttraumatic stress disorder (PTSD) is also highly associated with both SUDs and cigarette smoking and may serve as a barrier to smoking cessation efforts. In addition, people with PTSD are more likely to hold positive smoking outcome expectancies (i.e., beliefs that smoking cigarettes results in positive outcomes); these beliefs may contribute to cigarette smoking in people with SUDs experiencing PTSD symptoms. The present study examined the relationship between PTSD symptoms and typical daily cigarette smoking/cigarette dependence symptoms in a sample of 227 trauma-exposed current smokers with SUDs (59.9% male, 89.4% Caucasian) seeking detoxification treatment services. Additionally, the indirect effects of multiple types of positive smoking outcome expectancies on these relationships were examined. Participants completed questionnaires assessing PTSD symptoms, positive smoking outcome expectancies, cigarette consumption, and cigarette dependence symptoms. Results indicated that PTSD symptoms were not directly related to cigarette consumption or cigarette dependence symptoms. However, negative affect reduction outcome expectancies were shown to have a significant indirect effect between PTSD symptoms and cigarette consumption, while negative affect reduction, boredom reduction, and taste-sensorimotor manipulation outcome expectancies were all found to have significant indirect effects between PTSD symptoms and cigarette dependence symptoms. The indirect effect involving negative affect reduction outcome expectancies was statistically larger than that of taste sensorimotor manipulation outcome expectancies, while negative affect reduction and boredom reduction outcome expectancies were comparable in magnitude. These results suggest that expectancies that smoking can manage negative affective experiences are related to cigarette smoking in people with SUDs experiencing PTSD symptoms and suggest that effective smoking cessation treatments should take into account these expectancies.