Screening Identifies Suboptimal Vaccination Protection in Illness-Susceptible Elite Athletes.

OBJECTIVE: Some groups of elite athletes have an apparent increased susceptibility to respiratory tract infection (RTI) with implications for their health and athletic performance. In this study, we aim to systemically evaluate vaccine response patterns as a potentially efficacious intervention strategy in elite athletes preparing for Olympic competition. DESIGN: Cross-sectional observational study. SETTING: A UK Sport-funded Olympic training program. PATIENTS: One hundred twenty elite athletes and 10 matched healthy controls were studied. A subset of athletes were classified as RTI highly susceptible (n = 22), RTI nonsusceptible (n = 23), and asthmatic (n = 33), with matched controls also recruited (n = 10, 27 ± 3 years). INTERVENTIONS/OUTCOME MEASURE: Serum samples were analysed from participants analysing enzyme-linked immunosorbent assay for Immunoglobulin G (IgG) responses against measles, mumps, rubella, and pneumococcus vaccines. RESULTS: Although a majority of athletes (>90%) had detectable IgG levels against measles and rubella, only 76% had detectable mumps responses, with similar findings apparent in controls. Of those RTI-susceptible and asthmatic athletes, 22% had suboptimal antipneumococcal responses below 30 mg/L. CONCLUSION: A significant proportion of elite athletes preparing for Olympic competition seem to be at risk of mumps infection. In addition, RTI-susceptible and asthmatic athletes exhibit suboptimal pneumococcal antibody responses, highlighting a need for prospective immune screening in athletes to ensure vaccination strategies are effectively delivered.

Impaired NK Cell Responses to Pertussis and H1N1 Influenza Vaccine Antigens in Human Cytomegalovirus-Infected Individuals.

NK cells contribute to postvaccination immune responses after activation by IL-2 from Ag-specific memory T cells or by cross-linking of the low-affinity IgG receptor, CD16, by Ag-Ab immune complexes. Sensitivity of NK cells to these signals from the adaptive immune system is heterogeneous and influenced by their stage of differentiation. CD56(dim)CD57(+) NK cells are less responsive to IL-2 and produce less IFN-γ in response to T cell-mediated activation than do CD56(bright) or CD56(dim)CD57(-) NK cells. Conversely, NK cell cytotoxicity, as measured by degranulation, is maintained across the CD56(dim) subsets. Human CMV (HCMV), a highly prevalent herpes virus causing lifelong, usually latent, infections, drives the expansion of the CD56(dim)CD57(+)NKG2C(+) NK cell population, skewing the NK cell repertoire in favor of cytotoxic responses at the expense of cytokine-driven responses. We hypothesized, therefore, that HCMV seropositivity would be associated with altered NK cell responses to vaccine Ags. In a cross-sectional study of 152 U.K. adults, with HCMV seroprevalence rate of 36%, we find that HCMV seropositivity is associated with lower NK cell IFN-γ production and degranulation after in vitro restimulation with pertussis or H1N1 influenza vaccine Ags. Higher expression of CD57/NKG2C and lower expression of IL-18Rα on NK cells from HCMV seropositive subjects do not fully explain these impaired responses, which are likely the result of multiple receptor-ligand interactions. This study demonstrates for the first time, to our knowledge, that HCMV serostatus influences NK cell contributions to adaptive immunity and raises important questions regarding the impact of HCMV infection on vaccine efficacy.

Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness.

BACKGROUND: Respiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility. METHODS: Peripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19). FINDINGS: Athletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005). INTERPRETATION: Athletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis. FUNDING: This study was funded by the English Institute of Sport (UK).

Salivary IgA as a Potential Biomarker in the Evaluation of Respiratory Tract Infection Risk in Athletes.

In recent years, there has been attention focused on the value of salivary IgA (sIgA) as a potential biomarker for the identification of athletes who may be at increased risk of developing respiratory tract infection (RTI). The utility of sIgA, in this context, is based on biological plausibility and several observational studies revealing an apparent association between sIgA and RTI susceptibility. The overall published evidence evaluating the value of sIgA in this context is however conflicting, and there is currently a lack of clear guidance as to whether this marker has a place in the health surveillance and care of athletes. In this review, we critically appraise the literature assessing the potential for sIgA to be used in this context, evaluating it against 4 key biomarker characteristics, including its (1) practicality, (2) reproducibility, (3) specificity/sensitivity, and (4) potential clinical impact and relevance. This process reveals that although there is an apparent association between respiratory illness and sIgA in many studies, with some promising results, overall there remains a paucity of evidence supporting its overall value in this context. Key deficiencies in the metrics employed to endorse a valid biomarker are apparent, including a lack of reproducibility and low specificity and sensitivity in the detection of RTI susceptibility. The review outlines these issues and makes future recommendations.

Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity.

Many chemotherapeutic drugs have a narrow therapeutic window due to inefficient tumour cell permeation. Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as next generation cancer drugs and/or therapeutic enhancement agents. Herein, we demonstrate the cytotoxicity of seven SSAs towards both ovarian and glioblastoma cancer cells. We also utilize the intrinsic fluorescent properties of one of these lead SSAs to provide evidence for this class of compound to both bind to the exterior cancer cell surface and permeate the cell membrane, to become internalized. Furthermore, we demonstrate synergistic effects of two lead SSAs on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone. This work provides the first evidence that SSAs interact with and permeate cancer cell membranes and enhance the cytotoxic activity of a chemotherapeutic drug in human cancer cells.