Microevolution and Patterns of Transmission of Shigella sonnei within Cyclic Outbreaks of Shigellosis, Israel

Whole-genome sequencing unveiled host and environment-related insights to Shigella sonnei transmission within cyclic epidemics during 2000-2012 in Israel. The Israeli reservoir contains isolates belonging to S. sonnei lineage III but of different origin, shows loss of tetracycline resistance genes, and little genetic variation within the O antigen: highly relevant for Shigella vaccine development

Down Regulation of the TCR Complex CD3ζ-Chain on CD3+ T Cells: A Potential Mechanism for Helminth-Mediated Immune Modulation.

The CD3ζ forms part of the T cell receptor (TCR) where it plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways leading to T cell effector functions. Down regulation of CD3ζ leads to impairment of immune responses including reduced cell proliferation and cytokine production. In experimental models, helminth parasites have been shown to modulate immune responses directed against them and unrelated antigens, so called bystander antigens, but there is a lack of studies validating these observations in humans. This study investigated the relationship between expression levels of the TCR CD3ζ chain with lymphocyte cell proliferation during human infection with the helminth parasite, Schistosoma haematobium, which causes uro-genital schistosomiasis. Using flow cytometry, peripheral blood mononuclear cells (PBMCs) from individuals naturally exposed to S. haematobium in rural Zimbabwe were phenotyped, and expression levels of CD3ζ on T cells were related to intensity of infection. In this population, parasite infection intensity was inversely related to CD3ζ expression levels (p < 0.05), consistent with downregulation of CD3ζ expression during helminth infection. Furthermore, PBMC proliferation was positively related to expression levels of CD3ζ (p < 0.05) after allowing for confounding variables (host age, sex, and infection level). CD3ζ expression levels had a differing relationship between immune correlates of susceptibility and immunity, measured by antibody responses, indicating a complex relationship between immune activation status and immunity. The relationships between the CD3ζ chain of the TCR and schistosome infection, PBMC proliferation and schistosome-specific antibody responses have not previously been reported, and these results may indicate a mechanism for the impaired T cell proliferative responses observed during human schistosome infection

Azithromycin non-susceptible Shigella circulating in Israel, 2014-2016.

Shigella species remains a major diarrhoeagenic agent, affecting mostly children, with global high incidence and high mortality rate specially in developing areas. Although azithromycin is recommended for treatment of shigellosis, there are currently no CLSI susceptibility breakpoints, accordingly no routine antimicrobial susceptibility test is performed in the clinical laboratory. The purpose of this study was to estimate the prevalence, resistance profile and molecular epidemiology of azithromycin non-susceptible Shigella strains in Israel during a three year period. Shigella isolates (n = 1,170) referred to the National Reference Center during 2014-2016, were included in this study. Serotyping was performed by slide agglutination. Resistance genes, mph(A) and erm(B), were identified by PCR and the phenotype profile was determined by broth microdilution (BMD). Genetic relatedness was assessed by wgMLST. Decreased susceptibility to azithromycin (DSA) phenotype and genotype were detected in various Shigella species and serotypes related to diverse genetic backgrounds and antimicrobial profiles: 6% (26/423) of Shigella flexneri and 2% (16/747) of Shigella sonnei displayed DSA (MIC16 mg/L). Correlation of this phenotype with the presence of mph(A) and erm(B) genes was confirmed. All DSA-strains displayed resistance to ≥3 different antimicrobial classes. Among DSA-strains, 14% were resistant to quinolones and 5% displayed resistance to ceftriaxone. Most of these strains (32/42) were isolated from children in the southern and central regions of Israel. Clonality and significant relatedness was confirmed by PFGE and wgMLST. The presence of macrolide resistance genes among the different species and lineages reflects the transmissible nature of these genes. The emergence of DSA-Shigella reinforces the necessity to establish clinical breakpoints that would warrant routine testing, reporting and surveillance for this drug of choice

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy