The deficiency of DNASE1L3 does not affect systemic sclerosis pathogenesis in two inducible murine models of the disease.

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.

Cluster analysis reveals three main patterns of beliefs and intention with respect to SARS-CoV-2 vaccination in patients with autoimmune and inflammatory diseases.

INTRODUCTION: Given the COVID-19 pandemic, it is crucial to understand the underlying behavioural determinants of SARS-CoV-2 vaccine hesitancy in patients with autoimmune or inflammatory rheumatic diseases (AIIRDs). We aimed to analyse patterns of beliefs and intention regarding SARS-CoV-2 vaccination in AIIRD patients, as a mean of identifying pragmatic actions that could be taken to increase vaccine coverage in this population. METHODS: Data relating to 1258 AIIRD patients were analysed using univariate and multivariate logistic regression models, to identify variables associated independently with willingness to get vaccinated against SARS-CoV-2. Subsets of patients showing similar beliefs and intention about SARS-CoV-2 vaccination were characterized using cluster analysis. RESULTS: Hierarchical cluster analysis identified three distinct clusters of AIIRD patients. Three predominant patient attitudes to SARS-COV-2 vaccination were identified: voluntary, hesitant and suspicious. While vaccine willingness differed significantly across the three clusters (P < 0.0001), there was no significant difference regarding fear of getting COVID-19 (P = 0.11), the presence of comorbidities (P = 0.23), the use of glucocorticoids (P = 0.21), or immunocompromised status (P = 0.63). However, patients from cluster #2 (hesitant) and #3 (suspicious) were significantly more concerned about vaccination, the use of a new vaccine technology, lack of long-term data in relation to COVID-19 vaccination, and potential financial links with pharmaceutical companies (P < 0.0001 in all) than patients from cluster #1 (voluntary). DISCUSSION: Importantly, the differences between clusters in terms of patient beliefs and intention was not related to the fear of getting COVID-19 or to any state of frailty, but was related to specific concerns about vaccination. This study may serve as a basis for improved communication and thus help increase COVID-19 vaccine coverage among AIIRD patients.

Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) expression. CXCR4 is frequently overexpressed in cancer tissues, including GBM, and usually correlates with a poor prognosis. We have created a CXCR4-retargeted oncolytic herpesvirus (oHSV) by insertion of an anti-human CXCR4 nanobody in glycoprotein D of an attenuated HSV-1 (ΔICP34.5, ΔICP6, and ΔICP47), thereby describing a proof of principle for the use of nanobodies to target oHSVs toward specific cellular entities. Moreover, this virus has been armed with a transgene expressing a soluble form of TRAIL to trigger apoptosis. In vitro, this oHSV infects U87MG CXCR4+ and patient-derived GSCs in a CXCR4-dependent manner and, when armed, triggers apoptosis. In a U87MG CXCR4+ orthotopic xenograft mouse model, this oHSV slows down tumor growth and significantly improves mice survival. Customizing oHSVs with diverse nanobodies for targeting multiple proteins appears as an interesting approach for tackling the heterogeneity of GBM, especially GSCs. Altogether, our study must be considered as a proof of principle and a first step toward personalized GBM virotherapies to complement current treatments.

COVID-19 patients display distinct SARS-CoV-2 specific T-cell responses according to disease severity.

Adaptive Immune responses generated by SARS-CoV-2 virus in convalescent patients according to disease severity remain poorly characterized. To this end, we designed a prospective study (NCT04365322) that included 60 COVID-19 convalescent patients (1-month post infection) in two cohorts respectively entitled mild illness and severe pneumonia. The monitoring of peripheral immune responses was performed using IFNᵧ ELISpot assay. The serology index of each patient was investigated at the same time. Patients with severe pneumonia were older and had more comorbidities than patients with mild illness. T-cell responses in term of frequency and intensity were clearly distinct between mild illness and severe pneumonia patients. Furthermore, our results demonstrated that recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses (Cytomegalovirus, Epstein-Barr-virus and Flu-virus). The presence of potent adaptive immunity even in patients who underwent severe pneumonia sustain the rationale for the development of protective therapeutics against SARS-CoV-2.