BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.

After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αß T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Dietary protein intake in older adults undergoing cardiac surgery.

BACKGROUND: Older adults undergoing major surgery have increased protein requirements in the postoperative period, but there are limited data describing actual protein intake following cardiac surgery. METHODS AND RESULTS: We performed a prospective sub-study within a registry of older adults ≥60 years of age undergoing cardiac surgery at a tertiary care centre. A dietician administered a food frequency questionnaire before surgery and 1-4 months after surgery. In-hospital food intake was recorded by direct observation for 3 days in the early postoperative period. Food intake was analyzed to calculate the protein intake per kilogram of body weight per day (g/kg/d) during the three phases of care, compared to the dietary reference intake. Frailty was measured by a questionnaire and physical performance tests before surgery. There were 22 patients (8 females, 14 males; 59% frail) enrolled in the study with a mean age of 72.0 ± 7.8 years. The mean protein intake was 1.3 ± 0.5 g/kg/d, 0.7 ± 0.3 g/kg/d, and 1.3 ± 0.6 g/kg/d in the preoperative, early postoperative, and postdischarge periods, respectively (P < 0.0001 for early postoperative compared to other periods). Compared to the targeted dietary reference intake of 1.5 g/kg/d, there was a mean protein deficit of 0.8 g/kg/d in the early postoperative period. Only one patient (5%) met the protein dietary reference intake in the early postoperative period. CONCLUSION: In older adults undergoing cardiac surgery, dietary protein intake was substantially lower than the recommended target in the early postoperative period. Strategies to improve protein intake, particularly in frail older patients, may be considered as a therapeutic target.

Transplacental and Breast Milk Transfer of IgG1 Are Both Required for Prolonged Protection of Offspring Against Influenza A Infection.

The immune system during pregnancy teeters between maintaining fetal tolerance and providing protection against pathogens. Due to this delicate balance, pregnant women and their offspring often have increased susceptibilities to infection. During the first year of life, infant immunity against infection is mainly mediated via passively transferred maternal antibodies. However, our understanding of the route of transfer of the maternal antibodies for conferring protection to influenza A virus (IAV) infection in offspring is incomplete. Here we have demonstrated that offspring from IAV-infected mice were significantly protected against IAV infection. This remarkable increase in survival is mediated via the elevated maternal serum IgG1. By cross-fostering, we further showed that this enhanced host resistance was only achieved in mice born to and nursed by IAV-infected mothers. Collectively, our data suggest that the prolonged protection of offspring against IAV infection requires maternal IgG1 from both the placenta and breast milk.

Nucleic Acid Sensing in Allergic Disorders.

Recent advances indicate that there is crosstalk between allergic disorders and nucleic acid sensing. Triggers that activate inflammatory mechanisms via nucleic acid sensors affect both allergic phenotypes and anti-viral responses, depending on the timing and the order of exposure. Viral respiratory infections, such as those caused by the rhinovirus, influenza, and respiratory syncytial virus, are the most frequent cause of significant asthma exacerbations through effects mediated predominantly by TLR3. However, agonists of other nucleic acid sensors, such as TLR7/8 and TLR9 agonists, may inhibit allergic inflammation and reduce clinical manifestations of disease. The allergic state can predispose the immune system to both exaggerated responses to viral infections or protection from anti-viral inflammatory responses. TH2 cytokines appear to alter the epithelium, leading to defective viral clearance or exaggerated responses to viral infections. However, a TH2 skewed allergic response may be protective against a TH1-dependent inflammatory anti-viral response. This review briefly introduces the receptors involved in nucleic acid sensing, addresses mechanisms by which nucleic acid sensing and allergic responses can counteract one another, and discusses the strategies in experimental settings, both in animal and human studies, to harness the nucleic acid sensing machinery for the intervention of allergic disorders.