ABSTRACT
The main purpose of this review is to present justification for the urgent need to implement specific prophylaxis of invasive Staphylococcus aureus infections. We emphasize the difficulties in achieving this goal due to numerous S. aureus virulence factors important for the process of infection and the remarkable ability of these bacteria to avoid host defense mechanisms. We precede these considerations with a brief overview of the global necessitiy to intensify the use of vaccines against other pathogens as well, particularly in light of an impasse in antibiotic therapy. Finally, we point out global trends in research into modern technologies used in the field of molecular microbiology to develop new vaccines. We focus on the vaccines designed to fight the infections caused by S. aureus, which are often resistant to the majority of available therapeutic options.
Subject(s)
Staphylococcal Infections/prevention & control , Staphylococcal Vaccines/therapeutic use , Staphylococcus aureus/immunology , Drug Resistance, Bacterial/drug effects , Humans , Staphylococcal Infections/immunology , Staphylococcal Vaccines/immunology , Staphylococcal Vaccines/pharmacology , Staphylococcus aureus/genetics , Staphylococcus aureus/pathogenicity , Vaccine Development , Virulence Factors/genetics , Virulence Factors/immunologyABSTRACT
The newly identified 13-series (T-series) resolvins (RvTs) regulate phagocyte functions and accelerate resolution of infectious inflammation. Because severe acute respiratory syndrome coronavirus 2 elicits uncontrolled inflammation involving neutrophil extracellular traps (NETs), we tested whether stereochemically defined RvTs regulate NET formation. Using microfluidic devices capturing NETs in phorbol 12-myristate 13-acetate-stimulated human whole blood, the RvTs (RvT1-RvT4; 2.5 nM each) potently reduced NETs. With interleukin-1ß-stimulated human neutrophils, each RvT dose and time dependently decreased NETosis, conveying â¼50% potencies at 10 nM, compared with a known NETosis inhibitor (10 µM). In a murine Staphylococcus aureus infection, RvTs (50 ng each) limited neutrophil infiltration, bacterial titers, and NETs. In addition, each RvT enhanced NET uptake by human macrophages; RvT2 was the most potent of the four RvTs, giving a >50% increase in NET-phagocytosis. As part of the intracellular signaling mechanism, RvT2 increased cyclic adenosine monophosphate and phospho-AMP-activated protein kinase (AMPK) within human macrophages, and RvT2-stimulated NET uptake was abolished by protein kinase A and AMPK inhibition. RvT2 also stimulated NET clearance by mouse macrophages in vivo. Together, these results provide evidence for novel pro-resolving functions of RvTs, namely reducing NETosis and enhancing macrophage NET clearance via a cyclic adenosine monophosphate-protein kinase A-AMPK axis. Thus, RvTs open opportunities for regulating NET-mediated collateral tissue damage during infection as well as monitoring NETs.
Subject(s)
Extracellular Traps/immunology , Staphylococcal Infections/immunology , Staphylococcus aureus/immunology , Animals , COVID-19/immunology , Humans , Inflammation/immunology , Macrophages/immunology , Mice , Neutrophils/immunology , Phagocytosis , SARS-CoV-2/immunologySubject(s)
Asthma/immunology , COVID-19/immunology , Common Variable Immunodeficiency/immunology , IgG Deficiency/immunology , Obesity, Morbid/immunology , Staphylococcal Infections/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Asthma/pathology , Asthma/therapy , Asthma/virology , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Common Variable Immunodeficiency/pathology , Common Variable Immunodeficiency/therapy , Common Variable Immunodeficiency/virology , Fatal Outcome , Humans , IgG Deficiency/pathology , IgG Deficiency/therapy , IgG Deficiency/virology , Immunization, Passive , Immunoglobulin G/blood , Immunoglobulins, Intravenous/therapeutic use , Male , Methicillin-Resistant Staphylococcus aureus , Obesity, Morbid/pathology , Obesity, Morbid/therapy , Obesity, Morbid/virology , SARS-CoV-2 , Staphylococcal Infections/pathology , Staphylococcal Infections/therapy , Staphylococcal Infections/virology , COVID-19 SerotherapyABSTRACT
The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.