Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death

Bacillus anthracis lethal toxin(LT)is a determinant of lethal anthrax.Its function in myeloid cells is required for bacterial dissemination,and LT itself can directly trigger dysfunction of the cardiovascular system.The interplay between LT and the host responses is important in the pathogenesis,but our knowledge on this interplay remains limited.Tumor necrosis factor-a(TNF-a)is a pleiotropic pro-inflammatory cytokine induced by bacterial infections.Since LT accumulates and cytokines,predominantly TNF,amass during B.anthracis infection,co-treatment of TNF+LT in mice was used to mimic in vivo conditions for LT to function in inflamed hosts.Bone marrow transplantation and genetically engineered mice showed unexpectedly that the death of intestinal epithelial cells(IECs)rather than that of hematopoietic cells led to LT+TNF-induced lethality.Inhibition of p38a mitogen-activated protein kinase(MAPK)signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs,leading to intestinal damage and mouse death.Consistently,p38a inhibition by LT enhanced TNF-mediated cell death in human colon epithelial HT-29 cells.As intestinal damage is one of the leading causes of lethality in anthrax patients,the IEC damage caused by LT+TNF would most likely be a mechanism underneath this clinical manifestation and could be a target for interventions.

COVID-19 vaccines and beyond

Hundreds of vaccines have been developed worldwide for Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the cause of Coronavirus disease 2019(COVID-19),since the beginning of the pandemic.These vaccines have saved innumerable lives and contributed to partial control of the COVID-19 pandemic.Most of the vaccines approved for clinical use exhibit satisfactory initial protection rates against corresponding strains.However,vaccine protection declines over time,with almost all vaccines falling below 50%protection after 6 months[1].In the case of natural infections,protection lasts longer,but the incidence of reinfection is also quite high.

Rethinking sepsis after a two-year battle with COVID-19

Sepsis is an overwhelming host reaction to infection that results in high morbidity and mortality.The term sepsis or septicemia originated in 1914,and the definition of sepsis has evolved over time due to the complications of the disease.Systemic inflammatory response syndrome(SIRS)and infection are characteristics of sepsis;however,in the absence of infection,SIRS does not lead to sepsis,and not all cases of sepsis manifest symptoms of systemic inflammation,especially in elderly individuals.