Increasing incidence of inflammatory bowel diseases such as Crohn’s disease (CD) in developed nations is associated with changes to the environment, such as decreased prevalence of helminth colonization and alterations to the gut microbiota. We find that helminth infection protects mice deficient in the CD susceptibility gene Nod2 from intestinal abnormalities by inhibiting colonization with an inflammatory Bacteroides species. Colonization resistance to Bacteroides was dependent on type-2 immunity, which promoted the establishment of a protective microbiota enriched in Clostridiales. Additionally, we show that individuals from helminth-endemic regions harbor a similar protective microbiota, and that deworming treatment reduced Clostridiales and increased Bacteroidales. These results support a model of the hygiene hypothesis whereby certain individuals are genetically susceptible to the consequences of a changing microbial environment.

Soil-transmitted helminths colonize more than 1.5 billion people worldwide, yet little is known about how they interact with bacterial communities in the gut microbiota. Differences in the gut microbiota between individuals living in developed and developing countries may be partly due to the presence of helminths, since they predominantly infect individuals from developing countries, such as the indigenous communities in Malaysia we examine in this work. We compared the composition and diversity of bacterial communities from the fecal microbiota of 51 people from two villages in Malaysia, of which 36 (70.6%) were infected by helminths. The 16S rRNA V4 region was sequenced at an average of nineteen thousand sequences per samples. Helminth-colonized individuals had greater species richness and number of observed OTUs with enrichment of Paraprevotellaceae, especially with Trichuris infection. We developed a new approach of combining centered log-ratio (clr) transformation for OTU relative abundances with sparse Partial Least Squares Discriminant Analysis (sPLS-DA) to enable more robust predictions of OTU interrelationships. These results suggest that helminths may have an impact on the diversity, bacterial community structure and function of the gut microbiota.

Key Points Alternatively activated macrophages derived from monocytes and tissue macrophages have distinct transcriptional profiles and phenotypes. Monocyte-derived AAMs are more involved with immune regulation than tissue-derived AAMs.

SUMMARY Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohn’s disease, which involves an exaggerated immune response directed at intestinal bacteria. Here, we identified several abnormalities in the small intestinal epithelium of Nod2−/− mice including inflammatory gene expression and goblet cell dysfunction, which were associated with excess interferon-γ production by intraepithelial lymphocytes and Myd88 activity. Remarkably, these abnormalities were dependent on the expansion of a common member of the intestinal microbiota, Bacteroides vulgatus, which also mediated exacerbated inflammation in Nod2−/− mice upon small intestinal injury. These results indicate that Nod2 prevents inflammatory pathologies by controlling the microbiota, and support a multi-hit disease model involving specific gene-microbe interactions.

Background The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a rapid proliferation of serologic assays. However, little is known about their clinical performance. Here, we compared two commercial SARS-CoV-2 IgG assays. Methods 103 specimens from 48 patients with PCR-confirmed SARS-CoV-2 infections and 153 control specimens were analyzed using SARS-CoV-2 serologic assays by Abbott and EUROIMMUN (EI). Duration from symptom onset was determined by medical record review. Diagnostic sensitivity, specificity, and concordance were calculated. Results The Abbott SARS-CoV-2 assay had a diagnostic specificity of 99.4% (95% CI; 96.41–99.98%), and sensitivity of 0.0% (95% CI; 0.00–26.47%) at <3 days post symptom onset, 30.0% (95% CI; 11.89–54.28) at 3–7d, 47.8% (95% CI; 26.82–69.41) at 8–13d and 93.8% (95% CI; 82.80–98.69) at ≥14d. Diagnostic specificity on the EI assay was 94.8% (95% CI; 89.96–97.72) if borderline results were considered positive and 96.7% (95% CI; 92.54–98.93) if borderline results were considered negative. The diagnostic sensitivity was 0.0% (95% CI; 0.00–26.47%) at <3d, 25.0% (95% CI; 8.66–49.10) at 3–7d, 56.5% (95% CI; 34.49–76.81) at 3–7d and 85.4% (95% CI; 72.24–93.93) at ≥14d if borderline results were considered positive. The qualitative concordance between the assays was 0.83 (95% CI; 0.75–0.91). Conclusion The Abbott SARS-CoV-2 assay had fewer false positive and false negative results than the EI assay. However, diagnostic sensitivity was poor in both assays during the first 14 days of symptoms.

Whether activated inflammatory macrophages can adopt features of tissue resident macrophages and what mechanisms mediate this phenotypic conversion remain unclear. Here we show that vitamin A was required for phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206−PD-L2−MHCII−UCP1+ phenotype in the peritoneal cavity of mice and during liver granuloma formation in mice infected with Schistosoma mansoni. Phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206− macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, indicating that failure to convert from F4/80intCD206+ macrophages to F4/80hiCD206− macrophages may lead to dysregulated inflammation during helminth infection.

Purpose To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in head and neck cancer patients through inhibition of myeloid derived suppressor cells (MDSCs). Experimental Design We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in head and neck squamous cell carcinoma (HNSCC) patients. Results Tadalafil augmented immune response, increasing ex vivo T cell expansion to a mean 2.4 fold increase compared to 1.1 fold in control patients (P= 0.01), reducing peripheral MDSC numbers to mean 0.81 fold change compared to a 1.26 fold change in control patients (P=0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P=0.002). Tumor specific immunity in response to HNSCC tumor lysate was augmented in tadalafil treated patients (P=0.04). Conclusions These findings demonstrate that tadalafil augments general and tumor-specific immunity in HNSCC patients and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor specific immune suppression in head and neck cancer patients, with potential for therapeutic application.

Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by , the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with-infected erythrocytes activated antigen-specific naïve CD4 T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to exhibited a transcriptional program distinct from a classical LPS response, pointing to unique -induced activation pathways that may explain the uncharacteristic immune response to malaria.