Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.

The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.

[Seroprevalence of viral hepatitis in a representative general population of an urban public health area in Castilla y León (Spain)]. / Seroprevalencia de las hepatitis virales en población general representativa de una zona básica de salud urbana en Castilla y León.

INTRODUCTION: Viral hepatitis is a major social, health and economic problem worldwide, requiring strict epidemiological control. METHODS: This study presents the viral hepatitis seroprevalence in a representative sample from an urban health care area in Valladolid (Spain). RESULTS: Antibody prevalence was as follows: anti-HAV 52%; anti-HBc, 8.2%; anti-HCV, 1.1%; anti-HEV, 0.8%; and anti-HGV 5.8%. Prevalence of anti-HAV, anti-HBc and anti-HGV increased significantly with age (P < 0.005 in all cases). In individuals younger than 20, prevalence of anti-HAV was 3.8%, anti-HBc < 0.28% and anti-HGV 1.3%. In the 20-39 year-old group, seroprevalence against HAV was associated with low educational levels (P = 0.009) and with birth in other provinces (P = 0.016). Anti-HBc seroprevalence was mainly associated with three factors: prior hospitalization before 1990 (P = 0.002; OR 3.32 [1.48-7.42]); compulsory military service before 1990 (P < 0.0001; OR 37.33 [3.68-378.03]); and acupuncture treatments (P = 0.018; OR 57.75 [26.17-127.42]). Seroprevalence against HGV was associated with hospitalizations before 1990 (P = 0.019; OR = 2.969 [1.154-7.639]). Seropositive status to HCV revealed a transfusion history (2 cases), hospitalization (1 case) or drug addiction (1 case). Only one case among those seropositive to HEV had a history of a prior trip to a HEV-endemic area. CONCLUSIONS: Our study shows that the seroprevalences of viral hepatitis in a representative sample of urban population of Castille and Leon are similar to the seroprevalences observed in the rest of Spain and other developed countries, lower than the ones observed in the studies performed in Spain in the last 20 years due to the measures of prophylaxis that were taken.