The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223 -/-mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223 -/-animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

Background Descriptions of the pathological features of COronaVIrus Disease-2019 (COVID-19) caused by the novel zoonotic pathogen Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) emanate from tissue biopsies, case reports and small post-mortem studies restricted to the lung and specific organs. Whole body autopsy studies of COVID-19 patients have been sparse. To further define the pathology caused by SARS-CoV-2 across all body organs in both individuals with and without co-morbidities Italian patients who died of COVID-19. Methods We performed autopsies on 22 patients with COVID-19 (18 with co-morbidities and 4 without co-morbidities) who died at the National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS Hospital, Rome, Italy. Tissues from the lung, heart, liver, kidney, spleen and bone marrow (but not the brain) were examined. Only lung tissues were subject to transmission electron microscopy. Results COVID-19 causes multisystem pathology. Pulmonary and cardiovascular involvement are dominant pathological features. Extra-pulmonary manifestations include hepatic, kidney, splenic and bone marrow involvement, and microvascular injury and thrombosis were also detected. These findings were similar in patients with or without pre-existing medical co-morbidities. Conclusions SARS-CoV-2 infection causes multisystem disease and significant pathology in most organs in patients with and without co-morbidities.

Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis). Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.