The Janus-faced role of secreted spingomyelinase and its inhibition in host response

The increase in acid sphingomyelinase (aSMase) activity has been implicated in the severity of disease and its fatal outcome. In sepsis, aSMase activity has been shown to continuously increase throughout the continuum from SIRS (systemic inflammatory response syndrome) to severe sepsis. The inhibition of this enzyme with desipramine, a low molecular weight inhibitor, presents promising results in cystic fibrosis patients. We therefore addressed the question of whether secreted aSMase is involved in host response to infection, which is reflected in humoral and functional parameters of immune activation. We identified a dual function of this enzyme in host response where the activity of aSMase is essential during the early phase of host response with respect to bacterial elimination, yet the continuous increase in aSMase activity and ceramide generation presents with detrimental effects in the late phase of host response. We found a different cytokine profile between the genotypes (wt and ko) and yet more striking results following pharmacological inhibition with desipramine (i.e. Inhibition group). We observed a hyperresponsive state in the ko animals highlighted by an overwhelming bacterial burden and inflammatory response with poor outcome (20% survival), similar to wt. We observed a more favorable overall profile in the inhibition group highlighted by abrogated and alleviated cytokine levels and ROS release associated with a repressed gene expression profile. Additionally, desipramine pretreatment resulted in the downregulation in expression of surface markers with subsequent unchanged values in numbers of rolling and sticking leukocytes. We also measured stability in markers of liver dysfunction in desipramine pretreated animals compared to the other two groups. In summation, the altered parameters reflected on survival with a more favorable survival of 42% in the inhibition group. The use of the functional inhibitor desipramine reveals to be promising with respect to treatment of the host response. As it is already FDA approved for the treatment of several human conditions, the present study encourages further research into the use of desipramine for the treatment of host response. The presented data also encourage a clinical study with the use of desipramine in well defined sepsis patients

Immunogenicity and Effectiveness of Primary and Booster Vaccine Combination Strategies during Periods of SARS-CoV-2 Delta and Omicron Variants

In this study involving a cohort of employees of the National Airline company in Lebanon, we assessed humoral immunity levels and the effectiveness of two COVID-19 vaccines, Gam-COVID-Vac versus BNT162b2, after two doses and after a homologous and heterologous BNT162b2 booster, in addition to the impact of hybrid immunity. Vaccine effectiveness (VE) was retrospectively determined against laboratory-confirmed SARS-CoV-2 infection during the periods of Delta and Omicron variants’ predominance, separately, and was calculated based on a case–control study design. The humoral immune response, measured by a SARS-CoV-2 anti-spike receptor-binding domain (RBD) IgG titer, was prospectively assessed after the aforementioned vaccination schemes at different time points. This study showed higher effectiveness of BNT162b2 after two doses (81%) compared to two doses of Gam-COVID-Vac (41.8%) against the Delta variant of SARS-CoV-2, which correlated with anti-spike antibody levels. Regarding the Omicron variant, protection against infection and antibody levels were severely compromised and the correlation between an anti-spike IgG titer and effectiveness was lost, unlike the situation during the Delta wave. Considering the booster vaccination schemes, a homologous BNT162b2 booster after a BNT162b2 primary vaccination induced a higher humoral immune response when compared to that induced by a heterologous BNT162b2 booster after a Gam-COVID-Vac primary vaccination. However, the VE of both booster regimens against the Omicron variant was almost equal (64% in the homologous regimen and 57% in heterologous regimen). Hybrid immunity evidenced a better humoral response and a greater and longer protection against Delta and Omicron infections compared to vaccination-induced immunity in COVID-19-naïve individuals. Finally, the findings show that VE waned with time during the same wave, highlighting the importance of reinforcing primary and booster COVID-19 vaccination mainly at the beginning of each wave during the surge of a new variant of concern

Hyperresponsiveness of mice defi cient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response

Plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. Consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. Herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during sepsis. We found an exaggerated clinical course in mice genetically deficient in acid sphingomyelinase characterized by an increased bacterial burden, an increased phagocytotic activity, and a more pronounced cytokine storm. Moreover, on a functional level, leukocyte-endothelial interaction was found diminished in sphingomyelinase-deficient animals corresponding to a distinct leukocytes’ phenotype with respect to rolling and sticking as well as expression of cellular surface proteins. We conclude that hydrolysis of membrane-embedded sphingomyelin, triggered by circulating sphingomyelinase, plays a pivotal role in the first line of defense against invading microorganisms. This function might be essential during the early phase of infection leading to an adaptive response of remote cells and tissues