Pulmonary pathology of the new coronavirus disease (COVID-19). The preliminary analysis of post-mortem findings

Background. Currently, the patho- and morphogenesis of the new coronavirus infection (COVID-19) is being studied in depth. A comparative analysis of the morphological changes in the lungs of deceased patients is of importance, for various time periods after the onset of the first clinical symptoms. The clinical and morphological comparison should help to increase the qualified medical care for patients in the resuscitation profile and reduce the hospital mortality. The aim of the study was to formulate a working hypothesis for a conceptual scheme of clinical and morphological phases of development of the new coronavirus infection (COVID-19). Methods. An analysis of 80 fatal cases was carried out in the COVID-center of the Federal Research Clinical Center of FMBA of Russia. Along with the assessment of macro- and microscopic changes in the respiratory tract, additional histochemical van Gieson staining was applied and immunohistochemical studies were performed to assess the condition of the COVID-19-affected lungs. Results. The revealed features of diffuse alveolar damage in the case of the new coronavirus infection (COVID-19) made it possible to present a working hypothesis of the pathomorphogenesis of COVID-19 interstitial pneumonia. It proceeds through 3 phases: fulminant, persistent and fibrotic. Each phase is conditionally limited by certain time parameters and is characterized by certain morphological signs Dysregulatory activation of monocytic phagocytes, development of generalized microthrombosis, persistent signs of the exudative phase, pathological repair, progressive intraalveolar and interstitial fibrosis are the main links in the pathomorphogenesis of COVID-19 interstitial pneumonia. In response to the penetration of SARS-CoV-2, the T-cell immunity reactions prevail at the exudative and proliferative stages. At the fibrotic stage, the overall number of T-lymphocytes is drastically decreased, the cells of humoral immunity are not revealed. The CD8+ T-lymphocytes prevailing over CD4+ T-lymphocyte helpers is probably related to the autoimmune damage mechanisms. Conclusions. Damage to the lungs with the development of COVID-19 interstitial pneumonia is the main cause of the severe course of the disease and deaths. The revealed features of the pathomorphogenesis of the clinical and morphological phases of COVID-19 interstitial pneumonia will improve the quality of diagnosis and treatment of a new coronavirus infection (COVID-19)

Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response

We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer