The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

AcrAB, the major RND-type efflux pump of Photorhabdus laumondii, confers intrinsic multidrug-resistance and contributes to virulence in insects.

The resistance-nodulation-division (RND)-type efflux pumps AcrAB and MdtABC contribute to multidrug-resistance (MDR) in Gram-negative bacteria. Photorhabdus is a symbiotic bacterium of soil nematodes that also produces virulence factors killing insects by septicaemia. We previously showed that mdtA deletion in Photorhabdus laumondii TT01 resulted in no detrimental phenotypes. Here, we investigated the roles of the last two putative RND transporters in TT01 genome, AcrAB and AcrAB-like (Plu0759-Plu0758). Only ΔacrA and ΔmdtAΔacrA mutants were multidrug sensitive, even to triphenyltetrazolium chloride and bromothymol blue used for Photorhabdus isolation from nematodes on the nutrient bromothymol blue-triphenyltetrazolium chloride agar (NBTA) medium. Both mutants also displayed slightly attenuated virulence after injection into Spodoptera littoralis. Transcriptional analysis revealed intermediate levels of acrAB expression in vitro, in vivo and post-mortem, whereas its putative transcriptional repressor acrR was weakly expressed. Yet, plasmid-mediated acrR overexpression did not decrease acrAB transcript levels neither MDR in TT01 WT. While no pertinent mutations were detected in acrR of the same P. laumondii strain grown either on NBTA or nutrient agar, we suggest that AcrR-mediated repression of acrAB is not physiologically required under conditions tested. Finally, we propose that AcrAB is the primary RND-efflux pump, which is essential for MDR in Photorhabdus and may confer adaptive advantages during insect infection.