Inhaled carbon monoxide protects against the development of shock and mitochondrial injury following hemorrhage and resuscitation

Aims: Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation. Results: Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25-500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100-500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets). Conclusion: These preclinical studies suggest that inhaled CO can be a protective therapy in HS/R; however, further clinical studies are warranted

Identification of the Farm Animals Immune to Pathogens of Zoonotic Infectious Diseases in the Republic of Guinea

The most common anthropozoonoses on the African continent are coxiellosis and Rift Valley fever. It is known that detection of specific IgG antibodies in the blood sera of farm animals is one of the indicators of the pathogen circulation in a certain territory. The aim of the work was to identify specific IgG antibodies in the blood sera of farm animals collected on the territory of the Republic of Guinea to pathogens of zoonotic infectious diseases: coxiellosis, brucellosis, glanders, CCHF, West Nile and Rift Valley fevers, using enzyme immunoassay (ELISA). Materials and methods. A panel of 970 samples of blood sera from farm animals inhabiting all landscape-geographical zones of Guinea was compiled for the work. Identification of specific antibodies was carried out using enzyme immunoassay with preparations recommended for veterinary studies. Results and discussion. Specific antibodies to zoonoses were detected in 700 out of 1074 samples (65.2 % of the total), including: to Coxiella burnetii – in 172 (16.0 %); to Brucella spp. – in 212 (19.7 %); viruses of Rift Valley fever – 85 (7.9 %); CCHF – in 139 (12.9 %) and West Nile fever – in 92 (8.6 %). Antibodies to Burkholderia mallei were not found in the tested material. Positive samples were registered in all landscape-geographical zones. Thus, an urgent task is to continue studying the circulation of pathogens of zoonoses and anthropozoonoses in the territory of the Republic of Guinea and to organize regular monitoring over the spread of zoonotic infectious diseases in collaboration with veterinary services, which will allow timely forecasting and coordinating prophylactic (anti-epidemic) measures to prevent cases of diseases

Detection of Crimean-Congo Hemorrhagic Fever Virus Markers in Samples of Ixodes Ticks Collected in the Territory of the Republic of Guinea

Objective of the study. This work was carried out to identify markers (antigen and RNA) of CrimeanCongo hemorrhagic fever (CCHF) virus in samples from ticks, collected in all landscape-geographical areas of Guinea: Lower, Middle, Upper and Forest, to obtain up-to-date data on the distribution of the pathogen in the country.Materials and methods. Total of 4276 specimens of 8 species of ticks collected in 2016–2019 in the territory of the Republic of Guinea were studied, which were compiled into 1406 samples. Ectoparasites were collected from livestock animals, dogs, and small mammals. Viral antigen was detected using enzyme immunoassay (ELISA). The presence of RNA of the CCHF virus was determined by reverse transcription polymerase chain reaction (RT-PCR).Results and discussion. As a result of the studies, the antigen of the CCHF virus was detected in 21 samples (1.5 %), and RNA – in 37 (2.6 %). All samples, in which the viral antigen was detected, contained RNA of the CCHF virus. Positive results were obtained in samples from all geographical areas of the country. The main vectors and reservoirs of the pathogen in Guinea are ticks of the species Rh. sanguineus, Rh. geigyi, Rh. annulatus and Am. variegatum. The data obtained confirm the previously available information on the possibility of the pathogen circulation in this region and determine the need for further study of the spread of the CCHF virus in the territory of the Republic of Guinea

Molecular mechanisms and cellular functions of cGAS-STING signalling

The cGAS–STING signalling axis, comprising the synthase for the second messenger cyclic GMP–AMP (cGAS) and the cyclic GMP–AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS–STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS–STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome- dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid–liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved